Introduction - University of Pittsburgh



HEPATITIS C IN PREGNANCY: MAXIMIZING REPORTING ACCURACY IN EFFORT TO APPROPRIATELY TEST AND TREAT INFANTS EXPOSEDbyStephanie SnodgrassBS, Clinical Laboratory Science, University of Kansas, 2012Submitted to the Graduate Faculty ofDepartment of Infectious Diseases and MicrobiologyGraduate School of Public Health in partial fulfillmentOf the requirements for the degree ofMaster of Public HealthUniversity of Pittsburgh2018UNIVERSITY OF PITTSBURGHGRADUATE SCHOOL OF PUBLIC HEALTHThis essay is submittedbyStephanie SnodgrassonAugust 6th, 2018and approved byEssay Advisor:Jeremy J. Martinson, DPhil _________________________________Assistant Professor, Infectious Diseases and MicrobiologyAssistant Professor, Human GeneticsGraduate School of Public HealthUniversity of PittsburghEssay Reader:Kristen J. Mertz, MD, MPH_________________________________Medical EpidemiologistBureau of Assessment, Statistics, and EpidemiologyAllegheny County Health DepartmentPittsburgh, PennsylvaniaCopyright ? by Stephanie Snodgrass2018Jeremy J. Martinson, DPhilHEPATITIS C REPORTING IN PREGNANCY: MAXIMIZING REPORTING ACCURACY IN EFFORT TO APPROPRIATELY TEST AND TREAT INFANTS EXPOSEDStephanie Snodgrass, MPHUniversity of Pittsburgh, 2018ABSTRACTHepatitis C (HCV) is a chronic blood-borne pathogen which can remain asymptomatic in infected patients for decades, but which eventually leads to severe liver damage if left untreated. Due to the asymptomatic nature of this virus, many individuals are unaware of their infection leaving potential for additional viral transmission. While efforts have been put in place to close the gap between the actual number of infections and the number of reported infections, many studies suggest there is still much work to be done, including improving testing and reporting of infants exposed to HCV through vertical transmission. With HCV treatments for children three years of age and older on the horizon, improving testing and reporting of HCV infection in children is more important than ever if the damaging effects of this virus on these children are to be prevented. Treatment is imperative to the elimination of HCV, but without accurate disease identification and reporting through public health research and subsequent intervention, these treatments most likely will not be initiated, therefore leaving the population susceptible to this virus.TABLE OF CONTENTS TOC \o "2-4" \h \z \t "Heading 1,1,Appendix,1,Heading,1" preface PAGEREF _Toc522097795 \h viii1.0Introduction PAGEREF _Toc522097796 \h 12.0BACKGROUND PAGEREF _Toc522097797 \h 32.1HCV GENOTYPE EPIDEMIOLOGY PAGEREF _Toc522097798 \h 32.2OVERVIEW OF HCV LIFE CYCLE, THE HUMAN IMMUNE RESPONSE, AND DISEASE PROGRESSION PAGEREF _Toc522097799 \h 32.3HCV IN PREGNANCY AND VERTICAL TRANSMISSION PAGEREF _Toc522097800 \h 92.4HCV REPORTING THROUGHOUT THE UNITED STATES PAGEREF _Toc522097801 \h 142.5CURRENT GUIDELINES FOR INFANT SCREENING PAGEREF _Toc522097802 \h 162.6POTENTIAL FOR UNDERREPORTING OF HCV— ADULTS AND CHILDREN PAGEREF _Toc522097803 \h 162.7VALIDITY OF BIRTH CERTIFICATE REPORTING— OREGON, 2015 PAGEREF _Toc522097804 \h 193.0METHODS PAGEREF _Toc522097805 \h 214.0RESULTS PAGEREF _Toc522097806 \h 225.0DISCUSSION PAGEREF _Toc522097807 \h 256.0CONCLUSION PAGEREF _Toc522097808 \h 30bibliography PAGEREF _Toc522097809 \h 31List of tables TOC \h \z \c "Table" Table 1: Summary of evidence: effect of mode of delivery, labor management strategies, or breastfeeding practices on risk for mother-to-child transmission of HCV PAGEREF _Toc522092103 \h 14Table 2: Comparison of women identified with HCV infection on infant's birth certificates in 2015 with female HCV cases reported to the ACDP program- Oregon, 2001-2015 PAGEREF _Toc522092104 \h 23Table 3: Ongoing pediatric clinical trials with direct-acting antiviral agents PAGEREF _Toc522092105 \h 27List of figures TOC \h \z \c "Figure" Figure 1: HCV life cycle PAGEREF _Toc522092109 \h 5Figure 2: Natural history of HCV infection PAGEREF _Toc522092110 \h 8Figure 3: State requirements for reporting chronic cases of HCV infection. CDC, Centers for Disease Control and Prevention PAGEREF _Toc522092111 \h 15Figure 4: Live births from HCV infected mothers versus total live births according to Oregon birth certificate data by birth year PAGEREF _Toc522092112 \h 20Figure 5: Number of infants born to HCV infected women per 1,000 live births by County - 2015 PAGEREF _Toc522092113 \h 24Figure 6: Oregon Opioid Overdose Deaths by County - 2011-2015 PAGEREF _Toc522092114 \h 24prefaceI would like to thank my preceptor, Dr. Ann Thomas, for her continuous guidance during my internship at the Oregon Health Authority and throughout the remainder of my graduate school career. I would also like to thank my advisor, Dr. Jeremy Martinson, who has been an integral part of my success as a student through his unceasing advice and direction. Finally, I would like to thank Dr. Kristen Mertz for her aid throughout my essay and internship experiences. These individuals have shaped my graduate degree experience and encouraged me to pursue my specific interests within the public health field. IntroductionIn 2015, an estimated 71 million people worldwide were living with hepatitis C (HCV), including 1.75 million persons newly infected that year, with a global incidence rate of 23.7 per 100,000 people ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"ISBN 978-92-4-156545-5","ISBN":"9789241565455","abstract":"In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis 2016–2021. The GHSS calls for the elimination of viral hepatitis as a public health threat by 2030 (reducing new infections by 90% and mortality by 65%). This WHO Global hepatitis report describes, for the fi rst time, the global and regional estimates on viral hepatitis in 2015, setting the baseline for tracking progress in implementing the new global strategy. The report focuses on hepatitis B and C, which are responsible for 96% of all hepatitis mortality. It presents data along the fi ve strategic directions (strategic information, interventions, equity, fi nancing and innovation) – key pillars of the GHSS to facilitate monitoring of progress in countries, regions and globally, and to measure the impact of interventions on reducing new infections and saving lives between 2015 and 2030.","author":[{"dropping-particle":"","family":"World Health Organization","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Who","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"number-of-pages":"62","title":"Global hepatitis report, 2017","type":"book"},"uris":[""]}],"mendeley":{"formattedCitation":"(World Health Organization, 2017)","plainTextFormattedCitation":"(World Health Organization, 2017)","previouslyFormattedCitation":"(World Health Organization, 2017)"},"properties":{"noteIndex":0},"schema":""}(World Health Organization, 2017). In the United States, the reported incidence rate for HCV was 1.0 new infection per 100,000 persons per year equaling approximately 3,000 cases in 2016. HCV is considered the most common chronic blood-borne pathogen in the United States ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","7","16"]]},"author":[{"dropping-particle":"","family":"U.S. Preventive Services Task Force","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Final Recommendation Statement: Hepatitis C: Screening","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(U.S. Preventive Services Task Force, 2016)","plainTextFormattedCitation":"(U.S. Preventive Services Task Force, 2016)","previouslyFormattedCitation":"(U.S. Preventive Services Task Force, 2016)"},"properties":{"noteIndex":0},"schema":""}(U.S. Preventive Services Task Force, 2016). Because HCV is a chronic disease that potentially can remain asymptomatic for decades, most individuals are unaware of their infection. In light of this, many reports suggest that the previously listed statistics are significantly underestimated. Centers for Disease Control (CDC) estimates that the previously stated reported US statistic is 13.9 times less than the actual number of cases of acute HCV for 2016, resulting in an additional unreported 38,200 acute HCV cases ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"This FAQ list outlines thegeneral statistics and facts about HCV, and was created to inform health professionals about the function and effects of the disease. This list also outlines both the common and uncommon symptoms of the disease so infected individuals can be properly diagnosed. Treatment options are provided as well.","author":[{"dropping-particle":"","family":"Centers for Disease Control: Division of Viral Hepatitis","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Centres for Disease Control and Prevention","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"HCV FAQs for Health Professionals","type":"webpage"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1128/9781555816728","ISBN":"9781555816780","abstract":"The 10th edition of the Manual of Clinical Microbiology continues to set the standard for state-of-the-science laboratory practice as the most authoritative reference in the field. This 10th edition represents the collaborative efforts of 22 editors and more than 260 authors from around the world, all experienced researchers and practitioners in medical and diagnostic microbiology. Together, they have brought the manual fully up to date, producing a remarkable work of two volumes, nine sections, and 149 chapters that is filled with the latest research findings, infectious agents, methods, practices, and safety guidelines. Hardcover in two volumes, 2,630 pages, color illustrations, indexes. Are you interested in purchasing a site license to the Manual of Clinical","author":[{"dropping-particle":"","family":"James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry","given":"David W. Warnock","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Manual of Clinical Microbiology, 10th edition","id":"ITEM-2","issued":{"date-parts":[["2011"]]},"title":"Manual of Clinical Microbiology, 10th edition","type":"book"},"uris":[""]}],"mendeley":{"formattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011)","manualFormatting":"(Centers for Disease Control: Division of Viral Hepatitis, 2016; Versalovic et. al, 2011)","plainTextFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011)","previouslyFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011)"},"properties":{"noteIndex":0},"schema":""}(Centers for Disease Control: Division of Viral Hepatitis, 2016; Versalovic et. al, 2011). In 2013, the US Preventative Services Task Force (USPSTF) updated the screening recommendations for the US population to include a one-time screening of all individuals born between 1945 and 1965 due to the high prevalence rate (3-4%) in this birth cohort ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","7","16"]]},"author":[{"dropping-particle":"","family":"U.S. Preventive Services Task Force","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Final Recommendation Statement: Hepatitis C: Screening","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(U.S. Preventive Services Task Force, 2016)","plainTextFormattedCitation":"(U.S. Preventive Services Task Force, 2016)","previouslyFormattedCitation":"(U.S. Preventive Services Task Force, 2016)"},"properties":{"noteIndex":0},"schema":""}(U.S. Preventive Services Task Force, 2016). In 2016, 148,932 new reports of confirmed past or present HCV infection by states and jurisdictions were submitted to CDC, which may be a result of this recommendation therefore partially resolving this underestimation ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"This web page offers statistics and trends for HCV over the last 2 decades for hepatitis A, B, and C. While A and B have shown a dramatic decline, HCV has shown a re-emergence in the lst 10 years, with incidence and prevalence growing noticeably.","author":[{"dropping-particle":"","family":"Centers for Disease Control and Prevention (CDC)","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Division of Viral Hepatitis","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Statistics and Surveillance","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(Centers for Disease Control and Prevention (CDC), 2016)","plainTextFormattedCitation":"(Centers for Disease Control and Prevention (CDC), 2016)","previouslyFormattedCitation":"(Centers for Disease Control and Prevention (CDC), 2016)"},"properties":{"noteIndex":0},"schema":""}(Centers for Disease Control and Prevention (CDC), 2016). However, recent studies have indicated the need to screen additional underserved populations who do not have easy access to healthcare and are at high-risk for infection; these populations include but are not limited to first generation migrants, incarcerated persons, and the homeless population ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1186/1471-2458-14-66","ISBN":"0168-8278","ISSN":"14712458","PMID":"24450797","abstract":"BACKGROUND: Effective screening programs are urgently needed to provide undiagnosed hepatitis C virus (HCV)-infected individuals with therapy. This systematic review of characteristics and outcomes of screening programs for HCV focuses on strategies to identify HCV risk groups hidden in the general population.\\n\\nMETHODS: We conducted a comprehensive search of MEDLINE and EMBASE databases for articles published between 1991-2010, including studies that screened the general population using either a newly developed (nonintegrated) screening program or one integrated in existing health care facilities. Look-back studies, prevalence studies, and programs targeting high-risk groups in care (e.g., current drug users) were excluded.\\n\\nRESULTS: After reviewing 7052 studies, we identified 67 screening programs: 24 nonintegrated; 41 programs integrated in a variety of health care facilities (e.g., general practitioner); and 2 programs with both integrated and nonintegrated strategies. Together, these programs identified approximately 25,700 HCV-infected individuals. In general, higher HCV prevalence was found in programs in countries with intermediate to high HCV prevalence, in psychiatric clinics, and in programs that used a prescreening selection based on HCV risk factors. Only 6 programs used a comparison group for evaluation purposes, and 1 program used theory about effective promotion for screening. Comparison of the programs and their effectiveness was hampered by lack of reported data on program characteristics, clinical follow-up, and type of diagnostic test.\\n\\nCONCLUSIONS: A prescreening selection based on risk factors can increase the efficiency of screening in low-prevalence populations, and we need programs with comparison groups to evaluate effectiveness. Also, program characteristics such as type of diagnostic test, screening uptake, and clinical outcomes should be reported systematically.","author":[{"dropping-particle":"","family":"Zuure","given":"Freke R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Urbanus","given":"Anouk T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Langendam","given":"Miranda W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Helsper","given":"Charles W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berg","given":"Charlotte H.S.B.","non-dropping-particle":"Van Den","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Davidovich","given":"Udi","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prins","given":"Maria","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BMC Public Health","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014"]]},"page":"1-29","publisher":"BMC Public Health","title":"Outcomes of hepatitis C screening programs targeted at risk groups hidden in the general population: A systematic review","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"(Zuure et al., 2014)","plainTextFormattedCitation":"(Zuure et al., 2014)","previouslyFormattedCitation":"(Zuure et al., 2014)"},"properties":{"noteIndex":0},"schema":""}(Zuure et al., 2014).Other reports suggest significant underreporting of perinatal HCV infection, therefore imposing a deficiency in quality of care for infants exposed to this virus through the birthing process ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio, Newbern, Johnson, & Viner, 2016)","plainTextFormattedCitation":"(Kuncio, Newbern, Johnson, & Viner, 2016)","previouslyFormattedCitation":"(Kuncio, Newbern, Johnson, & Viner, 2016)"},"properties":{"noteIndex":0},"schema":""}(Kuncio, Newbern, Johnson, & Viner, 2016). With an estimated 6% vertical transmission rate, many children may acquire this virus without provider knowledge and eventually develop the symptoms of chronic HCV later in life potentially resulting in the need for a liver transplant due to liver cirrhosis, all of which could have been prevented with the current treatments available to children 12 and over in the United States ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/hep.29278","ISSN":"15273350","PMID":"28543053","abstract":"Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 ( NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balistreri","given":"William F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Chuan Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hardikar","given":"Winita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersey","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Massetto","given":"Benedetta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanwar","given":"Bittoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brainard","given":"Diana M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svarovskaia","given":"Evguenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirby","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnon","given":"Ronen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Karen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Kathleen B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"URL":"","accessed":{"date-parts":[["2018","6","24"]]},"author":[{"dropping-particle":"","family":"US Food & Drug Administration","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["0"]]},"title":"Highlights of prescribing information for SOVALDI? (sofosbuvir) tablets, for oral use.","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)","manualFormatting":"(US Food & Drug Administration, 2017; Wirth et al., 2017)","plainTextFormattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)","previouslyFormattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)"},"properties":{"noteIndex":0},"schema":""}(US Food & Drug Administration, 2017; Wirth et al., 2017). This paper will provide an overview of HCV in pregnancy, describe the current research involving efforts in reducing vertical transmission, assess current reporting methods for maternal HCV in the United States, and offer potential interventions for increased detection of vertical transmission of HCV in infants exposed.BACKGROUNDHCV GENOTYPE EPIDEMIOLOGYThe Hepatitis C virus is a single-stranded RNA virus classified within the Flaviviridae family and genus Hepacivirus. As of 2014, there are 7 known genotypes (GT) and more than 67 subtypes by genome sequence heterogeneity of HCV. The rapid mutation of the virus produces these genotypes while the high error prone rate of these mutations causes the multitude of variants within each genotype. GT1 accounts for 75% of infections in the United States followed by GT2 and GT3 with 13.5% and 5.5% of infections respectively. GT4 is present predominantly in the Middle East and North and Central Africa, while GT5 is found in South Africa. GT6 is most commonly present in areas throughout Asia, and GT7 originated in Central Africa ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/hep.26744","ISBN":"1527-3350 (Electronic)\\n0270-9139 (Linking)","ISSN":"15273350","PMID":"24115039","abstract":"UNLABELLED: The 2005 consensus proposal for the classification of hepatitis C virus (HCV) presented an agreed and uniform nomenclature for HCV variants and the criteria for their assignment into genotypes and subtypes. Since its publication, the available dataset of HCV sequences has vastly expanded through advancement in nucleotide sequencing technologies and an increasing focus on the role of HCV genetic variation in disease and treatment outcomes. The current study represents a major update to the previous consensus HCV classification, incorporating additional sequence information derived from over 1,300 (near-)complete genome sequences of HCV available on public databases in May 2013. Analysis resolved several nomenclature conflicts between genotype designations and using consensus criteria created a classification of HCV into seven confirmed genotypes and 67 subtypes. There are 21 additional complete coding region sequences of unassigned subtype. The study additionally describes the development of a Web resource hosted by the International Committee for Taxonomy of Viruses (ICTV) that maintains and regularly updates tables of reference isolates, accession numbers, and annotated alignments (). The Flaviviridae Study Group urges those who need to check or propose new genotypes or subtypes of HCV to contact the Study Group in advance of publication to avoid nomenclature conflicts appearing in the literature. While the criteria for assigning genotypes and subtypes remain unchanged from previous consensus proposals, changes are proposed in the assignment of provisional subtypes, subtype numbering beyond \"w,\" and the nomenclature of intergenotypic recombinant.\\n\\nCONCLUSION: This study represents an important reference point for the consensus classification of HCV variants that will be of value to researchers working in clinical and basic science fields.","author":[{"dropping-particle":"","family":"Smith","given":"Donald B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bukh","given":"Jens","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuiken","given":"Carla","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Muerhoff","given":"A. Scott","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rice","given":"Charles M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stapleton","given":"Jack T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simmonds","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-1","issued":{"date-parts":[["2014"]]},"title":"Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1128/9781555816728","ISBN":"9781555816780","abstract":"The 10th edition of the Manual of Clinical Microbiology continues to set the standard for state-of-the-science laboratory practice as the most authoritative reference in the field. This 10th edition represents the collaborative efforts of 22 editors and more than 260 authors from around the world, all experienced researchers and practitioners in medical and diagnostic microbiology. Together, they have brought the manual fully up to date, producing a remarkable work of two volumes, nine sections, and 149 chapters that is filled with the latest research findings, infectious agents, methods, practices, and safety guidelines. Hardcover in two volumes, 2,630 pages, color illustrations, indexes. Are you interested in purchasing a site license to the Manual of Clinical","author":[{"dropping-particle":"","family":"James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry","given":"David W. Warnock","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Manual of Clinical Microbiology, 10th edition","id":"ITEM-2","issued":{"date-parts":[["2011"]]},"title":"Manual of Clinical Microbiology, 10th edition","type":"book"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1128/JCM.02831-14","ISBN":"1098-660X (Electronic)\\r0095-1137 (Linking)","ISSN":"1098660X","PMID":"25520447","abstract":"We report a new hepatitis C virus (HCV) genotype identified in patients originating 24 riginating from the Democratic Republic of Congo.…","author":[{"dropping-particle":"","family":"Murphy","given":"Donald G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sablon","given":"Erwin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chamberland","given":"Jasmine","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fournier","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dandavino","given":"Raymond","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tremblay","given":"Cécile L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Microbiology","id":"ITEM-3","issued":{"date-parts":[["2015"]]},"title":"Hepatitis C virus genotype 7, a new genotype originating from Central Africa","type":"article-journal"},"uris":[""]},{"id":"ITEM-4","itemData":{"DOI":"10.5223/pghn.2016.19.2.83","ISSN":"2234-8646","PMID":"27437184","abstract":"Hepatitis C virus (HCV) infection is a major medical challenge affecting around 200 million people worldwide. The main site of HCV replication is the hepatocytes of the liver. HCV is a positive enveloped RNA virus from the flaviviridae family. Six major HCV genotypes are implicated in the human infection. In developed countries the children are infected mainly through vertical transmission during deliveries, while in developing countries it is still due to horizontal transmission from adults. Minimal nonspecific and brief symptoms are initially found in approximately 15% of children. Acute and chronic HCV infection is diagnosed through the recognition of HCV RNA. The main objective for treatment of chronic HCV is to convert detected HCV viremia to below the detection limit. Children with chronic HCV infection are usually asymptomatic and rarely develop severe liver damage. Therefore, the benefits from current therapies, pegylated-Interferon plus ribavirin, must be weighed against their adverse effects. This combined treatment offers a 50-90% chance of clearing HCV infection according to several studies and on different HCV genotype. Recent direct acting antiviral (DAA) drugs which are well established for adults have not yet been approved for children and young adults below 18 years. The most important field for the prevention of HCV infection in children would be the prevention of perinatal and parenteral transmission. There are areas of focus for new lines of research in pediatric HCV-related disease that can be addressed in the near future.","author":[{"dropping-particle":"","family":"El-Guindi","given":"Mohamed A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Pediatric gastroenterology, hepatology & nutrition","id":"ITEM-4","issued":{"date-parts":[["2016"]]},"title":"Hepatitis C Viral Infection in Children: Updated Review.","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(El-Guindi, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011; Murphy et al., 2015; Smith et al., 2014)","manualFormatting":"(El-Guindi, 2016; Versalovic et. al 2011; Murphy et al., 2015; Smith et al., 2014)","plainTextFormattedCitation":"(El-Guindi, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011; Murphy et al., 2015; Smith et al., 2014)","previouslyFormattedCitation":"(El-Guindi, 2016; James Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, 2011; Murphy et al., 2015; Smith et al., 2014)"},"properties":{"noteIndex":0},"schema":""}(El-Guindi, 2016; Versalovic et. al 2011; Murphy et al., 2015; Smith et al., 2014).OVERVIEW OF HCV LIFE CYCLE, THE HUMAN IMMUNE RESPONSE, AND DISEASE PROGRESSIONUpon infection of HCV into the host, the virions circulate throughout the bloodstream until they reach target hepatocytes, liver cells-- the most common cell type for HCV replication --where the virion attaches and gains entry into the cell through interactions with cell surface receptors including LDL-R, SRB1, and CD81. Once inside the target cell, following receptor-mediated endocytosis, the virus releases its RNA genome into the target cell cytoplasm by fusing its membrane with an acidic compartment within the cell. This RNA is then translated, yielding a single polyprotein precursor which is then further processed by cellular and viral proteases where it is cleaved into 10 viral proteins, including 3 structural proteins and 7 non-structural proteins. The non-structural proteins recruit the viral genome into an RNA replication complex where subsequent HCV RNA genome replication occurs producing many copies of HCV RNA. Following replication, the new viral genomes are packaged within the endoplasmic reticulum, where each copy acquires an envelope and envelope glycoproteins, E1 and E2. The envelopes then undergo maturation to form lipoviral particles. Finally, the new virions are released from the hepatocyte through exocytosis (Figure 1) where they will infect additional host cells and cause gradual damage to the liver ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.cmi.2016.08.025","ISSN":"1198-743X","abstract":"Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Since its discovery, which dates back to about 30 years ago, many details of the viral genome organization and the astonishing genetic diversity have been unveiled but, owing to the difficulty of culturing HCV in vitro and obtaining fully susceptible yet immunocompetent in vivo models, we are still a long way from the full comprehension of viral life cycle, host cell pathways facilitating or counteracting infection, pathogenetic mechanisms in vivo, and host defenses. Here, we illustrate the viral life cycle into cells, describe the interplay between immune and genetic host factors shaping the course of infection, and provide details of the molecular approaches currently used to genotype, monitor replication in vivo, and studying the emergence of drug-resistant viral variants. ","author":[{"dropping-particle":"","family":"Dustin","given":"Lynn B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bartolini","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Capobianchi","given":"Maria R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pistello","given":"Mauro","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases","id":"ITEM-1","issue":"10","issued":{"date-parts":[["2016","10","31"]]},"page":"826-832","title":"Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy","type":"article-journal","volume":"22"},"uris":[""]}],"mendeley":{"formattedCitation":"(Dustin, Bartolini, Capobianchi, & Pistello, 2016)","plainTextFormattedCitation":"(Dustin, Bartolini, Capobianchi, & Pistello, 2016)","previouslyFormattedCitation":"(Dustin, Bartolini, Capobianchi, & Pistello, 2016)"},"properties":{"noteIndex":0},"schema":""}(Dustin, Bartolini, Capobianchi, & Pistello, 2016).Figure SEQ Figure \* ARABIC 1: HCV life cycleIn the first few days after inoculation in the host, the viral load exponentially increases to between 105 and 107 IU/ml, where it plateaus for several weeks, likely due to the innate immune response. In response to a viral infection, the innate immune response reacts to the pathogen with type I and type III interferons produced by the virus-infected cells, dendritic cells, and macrophages, and type II interferons which are produced by natural killer (NK) cells and antigen-specific T cells (CD4+ and CD8+). These interferons stimulate genes, which are called interferon stimulated genes (ISGs) and are specifically responsible for controlling a viral infection. For an infection with HCV specifically, ISGs are strongly induced during the first several weeks of infection; however, it remains unclear as to which specific cells and types of interferon are the sources of production and responsible for ISG production respectively. Nonetheless, the interferon system is ineffective at clearing an HCV infection alone ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jhep.2014.06.035","ISSN":"0168-8278","author":[{"dropping-particle":"","family":"Heim","given":"Markus H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thimme","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","11","1"]]},"note":"doi: 10.1016/j.jhep.2014.06.035","page":"S14-S25","publisher":"Elsevier","title":"Innate and adaptive immune responses in HCV infections","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"(Heim & Thimme, 2014)","plainTextFormattedCitation":"(Heim & Thimme, 2014)","previouslyFormattedCitation":"(Heim & Thimme, 2014)"},"properties":{"noteIndex":0},"schema":""}(Heim & Thimme, 2014).While the exact mechanisms for ISG production in HCV infection are unclear, there is strong evidence for the role of NK cells in the control of HCV infection. In response to viral infection, NK cells not only produce interferon as previously mentioned, but also contain cytolytic effector functions to induce apoptosis in virus-infected cells. Several studies have shown the direct influence of NK cells in their role in controlling HCV infection, including a study of healthcare workers who were exposed to HCV, which reported that an early NK response to the infection resulted in the prevention of an infection in those healthcare workers ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jhep.2014.06.035","ISSN":"0168-8278","author":[{"dropping-particle":"","family":"Heim","given":"Markus H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thimme","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","11","1"]]},"note":"doi: 10.1016/j.jhep.2014.06.035","page":"S14-S25","publisher":"Elsevier","title":"Innate and adaptive immune responses in HCV infections","type":"article-journal","volume":"61"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jhep.2011.01.005","ISSN":"01688278","PMID":"21236311","author":[{"dropping-particle":"","family":"Nattermann","given":"Jacob","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-2","issued":{"date-parts":[["2011"]]},"title":"NK cells in acute hepatitis C","type":"article-magazine"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/hep.26353","ISBN":"1527-3350 (Electronic)\\r0270-9139 (Linking)","ISSN":"02709139","PMID":"23463364","abstract":"UNLABELLED: Hepatitis C virus (HCV) infection typically results in chronic disease with HCV outpacing antiviral immune responses. Here we asked whether innate immune responses are induced in healthcare workers who are exposed to small amounts of HCV, but do not develop systemic infection and acute liver disease. Twelve healthcare workers with accidental percutaneous exposure to HCV-infected blood were prospectively studied for up to 6 months for phenotype and function of natural killer T (NKT) and NK cells, kinetics of serum chemokines, and vigor and specificity of HCV-specific T-cell responses. Eleven healthcare workers tested negative for HCV RNA and HCV antibodies. All but one of these aviremic cases displayed NKT cell activation, increased serum chemokines levels, and NK cell responses with increased CD122, NKp44, NKp46, and NKG2A expression, cytotoxicity (as determined by TRAIL and CD107a expression), and interferon-gamma (IFN-γ) production. This multifunctional NK cell response appeared a month earlier than in the one healthcare worker who developed high-level viremia, and it differed from the impaired IFN-γ production, which is typical for NK cells in chronic HCV infection. The magnitude of NKT cell activation and NK cell cytotoxicity correlated with the magnitude of the subsequent HCV-specific T-cell response. T-cell responses targeted nonstructural HCV sequences that require translation of viral RNA, which suggests that transient or locally contained HCV replication occurred without detectable systemic viremia.\\n\\nCONCLUSION: Exposure to small amounts of HCV induces innate immune responses, which correlate with the subsequent HCV-specific T-cell response and may contribute to antiviral immunity.","author":[{"dropping-particle":"","family":"Werner","given":"Jens Martin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heller","given":"Theo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gordon","given":"Ann Marie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sheets","given":"Arlene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sherker","given":"Averell H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kessler","given":"Ellen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bean","given":"Kathleen S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stevens","given":"M'Lou","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schmitt","given":"James","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rehermann","given":"Barbara","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-3","issued":{"date-parts":[["2013"]]},"title":"Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Heim & Thimme, 2014; Nattermann, 2011; Werner et al., 2013)","plainTextFormattedCitation":"(Heim & Thimme, 2014; Nattermann, 2011; Werner et al., 2013)","previouslyFormattedCitation":"(Heim & Thimme, 2014; Nattermann, 2011; Werner et al., 2013)"},"properties":{"noteIndex":0},"schema":""}(Heim & Thimme, 2014; Nattermann, 2011; Werner et al., 2013). 6-8 weeks after exposure, the gene expression switches from IFN I/III to IFN- and the adaptive immune response begins with the recruitment of HCV specific T-cells that target viral epitopes to assist in elimination of the virus. In addition to T-cell responses, anti-viral neutralizing antibodies are also produced in an attempt to inhibit viral entry into host cells and subsequent replication of the virus. Also during this time, Alanine aminotransferase (ALT) levels begin to spike, due to the damage of the liver caused by the indirect immune response effects of the virus ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ajog.2017.07.039","ISSN":"10976868","PMID":"28782502","abstract":"In the United States, 1-2.5% of pregnant women are infected with hepatitis C virus, which carries an approximately 5% risk of transmission from mother to infant. Hepatitis C virus can be transmitted to the infant in utero or during the peripartum period, and infection during pregnancy is associated with increased risk of adverse fetal outcomes, including fetal growth restriction and low birthweight. The purpose of this document is to discuss the current evidence regarding hepatitis C virus in pregnancy and to provide recommendations on screening, treatment, and management of this disease during pregnancy. The following are Society for Maternal-Fetal Medicine recommendations: (1) We recommend that obstetric care providers screen women who are at increased risk for hepatitis C infection by testing for anti-hepatitis C virus antibodies at their first prenatal visit. If initial results are negative, hepatitis C screening should be repeated later in pregnancy in women with persistent or new risk factors for hepatitis C infection (eg, new or ongoing use of injected or intranasal illicit drugs) (GRADE 1B). (2) We recommend that obstetric care providers screen hepatitis C virus–positive pregnant women for other sexually transmitted diseases, including HIV, syphilis, gonorrhea, chlamydia, and hepatitis B virus (GRADE 1B). (3) We suggest that patients with hepatitis C virus, including pregnant women, be counseled to abstain from alcohol (Best Practice). (4) We recommend that direct-acting antiviral regimens only be used in the setting of a clinical trial or that antiviral treatment be deferred to the postpartum period as direct-acting antiviral regimens are not currently approved for use in pregnancy (GRADE 1C). (5) We suggest that if invasive prenatal diagnostic testing is requested, women be counseled that data on the risk of vertical transmission are reassuring but limited; amniocentesis is recommended over chorionic villus sampling given the lack of data on the latter (GRADE 2C). (6) We recommend against cesarean delivery solely for the indication of hepatitis C virus (GRADE 1B). (7) We recommend that obstetric care providers avoid internal fetal monitoring, prolonged rupture of membranes, and episiotomy in managing labor in hepatitis C virus–positive women (GRADE 1B). (8) We recommend that providers not discourage breast-feeding based on a positive hepatitis C virus infection status (GRADE 1A).","author":[{"dropping-particle":"","family":"Hughes","given":"Brenna L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Page","given":"Charlotte M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuller","given":"Jeffrey A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Obstetrics and Gynecology","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2017"]]},"page":"B2-B12","publisher":"Elsevier Inc.","title":"Hepatitis C in pregnancy: screening, treatment, and management","type":"article-journal","volume":"217"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jhep.2014.06.035","ISSN":"0168-8278","author":[{"dropping-particle":"","family":"Heim","given":"Markus H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thimme","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2014","11","1"]]},"note":"doi: 10.1016/j.jhep.2014.06.035","page":"S14-S25","publisher":"Elsevier","title":"Innate and adaptive immune responses in HCV infections","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"(Heim & Thimme, 2014; Hughes, Page, & Kuller, 2017)","plainTextFormattedCitation":"(Heim & Thimme, 2014; Hughes, Page, & Kuller, 2017)","previouslyFormattedCitation":"(Heim & Thimme, 2014; Hughes, Page, & Kuller, 2017)"},"properties":{"noteIndex":0},"schema":""}(Heim & Thimme, 2014; Hughes, Page, & Kuller, 2017).Approximately 30% of patients will be able to clear the infection with these immune responses in the acute phase of HCV therefore allowing ALT levels to return to normal. If the virus is able to escape all of these immune defenses, the patient will develop chronic hepatitis C. The virus is capable of remaining in the patient’s liver for decades gradually causing increased damage to the liver and putting the patient at increased risk for liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma as time progresses. Between 10-20% of people with chronic HCV will develop cirrhosis over 20-30 years of infection, with a 1-5% increased risk for hepatocellular carcinoma for every year of infection and a 3-6% annual risk of hepatic decompensation putting the patient at significant risk of death without a liver transplant ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"This FAQ list outlines thegeneral statistics and facts about HCV, and was created to inform health professionals about the function and effects of the disease. This list also outlines both the common and uncommon symptoms of the disease so infected individuals can be properly diagnosed. Treatment options are provided as well.","author":[{"dropping-particle":"","family":"Centers for Disease Control: Division of Viral Hepatitis","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Centres for Disease Control and Prevention","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"HCV FAQs for Health Professionals","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)","plainTextFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)","previouslyFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)"},"properties":{"noteIndex":0},"schema":""}(Centers for Disease Control: Division of Viral Hepatitis, 2016). Patients who develop a chronic infection continue to demonstrate evidence of an activated immune response. While the innate response of high levels of ISG expression are only seen in some patients, the adaptive immunity -- HCV specific neutralizing antibodies and T-cell responses -- are present in most. Figure 2 illustrates the natural history of HCV disease progression explained above: Figure SEQ Figure \* ARABIC 2: Natural history of HCV infection ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jhep.2014.06.035","ISSN":"0168-8278","author":[{"dropping-particle":"","family":"Heim","given":"Markus H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thimme","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","11","1"]]},"note":"doi: 10.1016/j.jhep.2014.06.035","page":"S14-S25","publisher":"Elsevier","title":"Innate and adaptive immune responses in HCV infections","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"(Heim & Thimme, 2014)","plainTextFormattedCitation":"(Heim & Thimme, 2014)","previouslyFormattedCitation":"(Heim & Thimme, 2014)"},"properties":{"noteIndex":0},"schema":""}(Heim & Thimme, 2014)Many study results with suggestions as to why the virus is able to persist even in the presence of these continuous heightened responses. One example is that those who are chronically infected with HCV have NK cells with impaired antiviral effector functions due to the chronic exposure to the virus, affecting the efficiency in viral clearance. With regard to the adaptive immunity responses, different studies suggest a variety of possibly explanations including the rapid and frequent mutation of the virus, which allows the virus to escape the neutralizing antibodies and T-cells. It has also been suggested that there is direct cell to cell transfer of the virus to avoid neutralization ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1128/JVI.01592-10","ISBN":"1098-5514 (Electronic)\\n0022-538X (Linking)","ISSN":"0022-538X","PMID":"20962076","abstract":"Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal antibodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins representing the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell transmission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver.","author":[{"dropping-particle":"","family":"Brimacombe","given":"C. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grove","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Meredith","given":"L. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Syder","given":"A. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Flores","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Timpe","given":"J. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krieger","given":"S. E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baumert","given":"T. F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tellinghuisen","given":"T. L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wong-Staal","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balfe","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McKeating","given":"J. A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Virology","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1002/hep.21959","ISBN":"0896-8608 (Print)\\r0896-8608 (Linking)","ISSN":"02709139","PMID":"17941058","abstract":"Hepatitis C virus (HCV) infection of Huh-7.5 hepatoma cells results in focal areas of infection where transmission is potentiated by cell-cell contact. To define route(s) of transmission, HCV was allowed to infect hepatoma cells in the presence or absence of antibodies that neutralize cell-free virus infectivity. Neutralizing antibodies (nAbs) reduced cell-free virus infectivity by >95% and had minimal effect(s) on the frequency of infected cells in the culture. To assess whether cell-cell transfer of viral infectivity occurs, HCV-infected cells were cocultured with fluorescently labeled naive cells in the presence or absence of nAbs. Enumeration by flow cytometry demonstrated cell-cell transfer of infectivity in the presence or absence of nAbs and immunoglobulins from HCV(+) patients. The host cell molecule CD81 and the tight junction protein Claudin 1 (CLDN1) are critical factors defining HCV entry. Soluble CD81 and anti-CD81 abrogated cell-free infection of Huh-7.5 and partially inhibited cell-cell transfer of infection. CD81-negative HepG2 hepatoma cells were resistant to cell-free virus infection but became infected after coculturing with JFH-infected cells in the presence of nAb, confirming that CD81-independent routes of cell-cell transmission exist. Further experiments with 293T and 293T-CLDN1 targets suggested that cell-cell transmission is dependent on CLDN1 expression. CONCLUSION: These data suggest that HCV can transmit in vitro by at least two routes, cell-free virus infection and direct transfer between cells, with the latter offering a novel route for evading nAbs.","author":[{"dropping-particle":"","family":"Timpe","given":"Jennifer M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Stamataki","given":"Zania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jennings","given":"Adam","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Ke","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Farquhar","given":"Michelle J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Harris","given":"Helen J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Anne","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Desombere","given":"Isabelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roels","given":"Geert Leroux","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balfe","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McKeating","given":"Jane A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-2","issued":{"date-parts":[["2008"]]},"title":"Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Brimacombe et al., 2011; Timpe et al., 2008)","plainTextFormattedCitation":"(Brimacombe et al., 2011; Timpe et al., 2008)","previouslyFormattedCitation":"(Brimacombe et al., 2011; Timpe et al., 2008)"},"properties":{"noteIndex":0},"schema":""}(Brimacombe et al., 2011; Timpe et al., 2008). In addition, several groups have specific mechanisms outlined for how the ongoing replication of HCV may result in CD8+ T cell failure. While much about the persistence of HCV still requires confirmation in additional studies, there is growing evidence for the mechanisms which result in chronic HCV ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jhep.2014.06.035","ISSN":"0168-8278","author":[{"dropping-particle":"","family":"Heim","given":"Markus H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thimme","given":"Robert","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2014","11","1"]]},"note":"doi: 10.1016/j.jhep.2014.06.035","page":"S14-S25","publisher":"Elsevier","title":"Innate and adaptive immune responses in HCV infections","type":"article-journal","volume":"61"},"uris":[""]}],"mendeley":{"formattedCitation":"(Heim & Thimme, 2014)","plainTextFormattedCitation":"(Heim & Thimme, 2014)","previouslyFormattedCitation":"(Heim & Thimme, 2014)"},"properties":{"noteIndex":0},"schema":""}(Heim & Thimme, 2014).HCV is most commonly transmitted through contaminated blood or body fluids so high-risk factors include sharing needles for IV drug use, receiving a blood transfusion before 1992, receiving hemodialysis, receiving unregulated tattoos, occupational exposure, and vertical transmission from HCV infected mothers to infants during birth. Less commonly, HCV can also be transmitted during sexual intercourse with increased risk in men who have sex with men (MSM). In addition, a new report suggests HCV transmission occurs through sharing straws for nasal drug use ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/AOG.0000000000001507","ISSN":"1873233X","abstract":"OBJECTIVE: To evaluate possible modes of hepatitis C virus (HCV)\\nacquisition in pregnant women found to be HCV-infected in the prenatal\\nperiod and to assess transmission risk factors.\\nMETHODS: This was a prospective cohort study conducted from March 2014\\nthrough June 2015 involving the distribution of an anonymous survey to\\nHCV-infected pregnant women that assessed for numerous modes of\\npotential HCV transmission involving, intravenous drug use, blood\\ntransfusion, organ transplant, sexual contact, tattoos, and snorting\\ndrugs with a straw. Participants were drawn from our institutional\\nobstetric high-risk clinic. Statistical analysis involved simple\\npercentages and chi(2) comparisons where appropriate; P <.05 was\\nconsidered significant. To test biologic plausibility, snorting utensils\\nconfiscated by law enforcement authorities from patients not in this\\nstudy were tested for the presence of human blood.\\nRESULTS: A total of 189 HCV-infected pregnant patients completed the\\nsurvey, and no approached patients declined. Of these, 136 (72%, 95%\\nconfidence interval {[}CI] 65-78%) admitted to intravenous drug use, of\\nwhom 89 (65%, 95% CI 57-73%) reported sharing needles. Of the 178\\n(94%, 95% CI 90-97%) who admitted snorting drugs, 164 (92%, 95% CI\\n87-96%) reported sharing straws. The difference between the proportion\\nreporting sharing of snorting utensils compared with the proportion\\nsharing intravenous drug use utensils was significant (P <.001).\\nTwenty-nine patients (15%, 95% CI 11-21%) reported snorting drugs and\\nsharing straws but denied any other risk factor except sexual contact.\\nOf the 54 straws confiscated by law enforcement authorities, 13 (24%,\\n95% CI 13-38%) tested positive for the presence of human blood.\\nCONCLUSION: Sharing snorting utensils (straws) in noninjection drug use\\nmay be an additional risk factor for HCV and other virus transmission.","author":[{"dropping-particle":"","family":"Fernandez","given":"Noelle","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V.","family":"Towers","given":"Craig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wolfe","given":"Lynlee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hennessy","given":"Mark D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Weitz","given":"Beth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Porter","given":"Stephanie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Obstetrics and Gynecology","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"Sharing of Snorting Straws and Hepatitis C Virus Infection in Pregnant Women","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Fernandez et al., 2016)","plainTextFormattedCitation":"(Fernandez et al., 2016)","previouslyFormattedCitation":"(Fernandez et al., 2016)"},"properties":{"noteIndex":0},"schema":""}(Fernandez et al., 2016), but this has yet to be confirmed by the CDC. Upon transmission, 15-30% of those infected will spontaneously clear the virus within the first six months after exposure while 70-85% will develop a chronic infection ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"This FAQ list outlines thegeneral statistics and facts about HCV, and was created to inform health professionals about the function and effects of the disease. This list also outlines both the common and uncommon symptoms of the disease so infected individuals can be properly diagnosed. Treatment options are provided as well.","author":[{"dropping-particle":"","family":"Centers for Disease Control: Division of Viral Hepatitis","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Centres for Disease Control and Prevention","id":"ITEM-1","issued":{"date-parts":[["2016"]]},"title":"HCV FAQs for Health Professionals","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)","plainTextFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)","previouslyFormattedCitation":"(Centers for Disease Control: Division of Viral Hepatitis, 2016)"},"properties":{"noteIndex":0},"schema":""}(Centers for Disease Control: Division of Viral Hepatitis, 2016). Those who do not clear the virus may be asymptomatic for years due to the chronic nature of the virus, remaining unaware of their infection and allowing the potential for further spread.HCV IN PREGNANCY AND VERTICAL TRANSMISSION Because there is approximately a 6% vertical transmission rate of HCV from mother to infant during childbirth, a variety of studies have been performed not only to elucidate potential biological mechanisms responsible for this transmission rate, but also to assess the current methods of perinatal monitoring in women with HCV in order to make recommendations in efforts to reduce fetal/infant exposure. To understand biological mechanisms potentially responsible for this transmission rate, we must first discuss how pregnancy affects an HCV infection. When a woman infected with HCV becomes pregnant, her once elevated ALT levels begin to decline along with an increase in viral load. Because ALT levels rise from injury to the liver due to the human immune response rather than the virus itself, scientists postulate the reason for this decline is because pregnancy causes maternal immunosuppression in order to prevent the rejection of the fetus whose human leukocyte antigen (HLA) genotype differs from the mother ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"0036-5548 (Print)","PMID":"9730293","abstract":"Alanine aminotransferase (ALT) levels decline during pregnancy in women chronically infected with hepatitis C virus (HCV). In order to understand further the underlying mechanisms, we prospectively followed 10 chronically infected women before, during and after pregnancy. ALT levels were analysed together with quantification of serum HCV-RNA using the branched DNA technology. As anticipated, the ALT levels significantly declined late in pregnancy and increased again after delivery. HCV-RNA levels, conversely, significantly increased late in pregnancy and returned to baseline levels 1 y after delivery. These findings suggest the importance of immune mediated mechanisms in controlling the viral replication and contributing to the liver injury in chronic hepatitis C","author":[{"dropping-particle":"","family":"Wejstal","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Widell","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Norkrans","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scandinavian Journal of Infectious Diseases","id":"ITEM-1","issued":{"date-parts":[["1998"]]},"title":"HCV-RNA levels increase during pregnancy in women with chronic hepatitis C","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISBN":"0168-8278 (Print)\\r0168-8278 (Linking)","ISSN":"0168-8278","PMID":"10707870","abstract":"BACKGROUND/AIMS: The natural history of chronic hepatitis C infection during pregnancy has not been clearly established, and thus our aim was to assess serum alanine aminotransferase levels and serum HCV RNA levels during pregnancy. METHODS: Twenty-six pregnant women with chronic hepatitis C were studied. Serum alanine aminotransferase was assessed within the 3 months before, monthly during and within the 3 months after pregnancy. In 12 women, serum HCV RNA levels were quantified by the branched DNA assay. Twenty-six age-matched non-pregnant women with chronic hepatitis C were followed up for 1 year, and used as a comparison group. RESULTS: During pregnancy, serum alanine aminotransferase levels decreased in the second and third trimesters. The third trimester levels were significantly lower than serum alanine aminotransferase levels before pregnancy (p=0.0001). Seventy-seven percent of the pregnant women with increased pre-pregnancy levels had normalization of serum alanine aminotransferase levels. In the second or third trimesters, serum HCV RNA levels increased. The third trimester serum HCV RNA levels were significantly higher than levels before pregnancy (p=0.01). No significant change in serum alanine aminotransferase or HCV RNA levels was observed in the control group. CONCLUSION: In pregnant women with chronic hepatitis C, serum alanine aminotransferase levels decrease, and serum HCV RNA levels increase during the second and third trimesters.","author":[{"dropping-particle":"","family":"Gervais","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bacq","given":"Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bernuau","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martinot","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Auperin","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boyer","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kilani","given":"a","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Erlinger","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Valla","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Marcellin","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of hepatology","id":"ITEM-2","issued":{"date-parts":[["2000"]]},"title":"Decrease in serum ALT and increase in serum HCV RNA during pregnancy in women with chronic hepatitis C.","type":"article-journal"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1016/S0002-9270(01)02697-1","ISBN":"0002-9270 (Print)\\r0002-9270 (Linking)","ISSN":"00029270","PMID":"11569706","abstract":"OBJECTIVES: The risk of hepatitis C virus (HCV) infection in the newborn is estimated to be around 5%, but becomes very high in the case of coinfection with HIV. One of the main factors associated with the vertical transmission of HCV is the viral load. Our objective was to investigate the behavior of HCV viral load during pregnancy in relation to HIV coinfection, liver enzymes, and vertical transmission. METHODS: Three thousand seven hundred forty-eight women seen consecutively in their first trimester of pregnancy were screened for HCV infection. Sixty-five were found to be anti-HCV+/HCV RNA + and were followed up with clinical and serological assessment (i.e., transaminases and quantitative polymerase chain reaction [PCR] for viral load) in their second and third trimesters and 6 months after delivery. All were anti-HIV and hepatitis B surface antigen negative. HCV RNA was 12.0 ± 19.9 × 106copies/ml in the first trimester and 10.9 ± 13.3 × 106in the second, but increased to 19.5 ± 25.1 × 106in the third trimester. Six months after delivery the viral load returned to the baseline levels; the changes in viral load did not reach any statistical significance, however. Transaminases tended toward a reduction from the baseline during the second and third trimesters, and then an increase in both AST and ALT was recorded 6 months after delivery. However, when the group whose AST/ALT were found abnormal at the first test was considered, no significant changes were recorded during the follow-up. The overall rate of vertical transmission was 4.6%. CONCLUSIONS: With HCV+ mothers monitoring transaminases during pregnancy is unnecessary, and testing liver enzymes at the beginning of pregnancy is sufficient. Qualitative PCR should be done once during the pregnancy, but any staging of the liver disease should be taken after delivery. Quantitative PCR testing is expensive and pointless. Any decision for elective cesarean section in HCV RNA+ mothers should be confirmed by other studies. ? 2001 Am. Coll. of Gastroenterology.","author":[{"dropping-particle":"","family":"Paternoster","given":"D. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Santarossa","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grella","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Pal?","given":"G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Baldo","given":"V.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Boccagni","given":"P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Floreani","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Gastroenterology","id":"ITEM-3","issued":{"date-parts":[["2001"]]},"title":"Viral load in HCV RNA-positive pregnant women","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Gervais et al., 2000; Paternoster et al., 2001; Wejstal, Widell, & Norkrans, 1998)","plainTextFormattedCitation":"(Gervais et al., 2000; Paternoster et al., 2001; Wejstal, Widell, & Norkrans, 1998)","previouslyFormattedCitation":"(Gervais et al., 2000; Paternoster et al., 2001; Wejstal, Widell, & Norkrans, 1998)"},"properties":{"noteIndex":0},"schema":""}(Gervais et al., 2000; Paternoster et al., 2001; Wejstal, Widell, & Norkrans, 1998). In terms of potential routes of exposure in utero, there are many possible scenarios including but not limited to HCV transmission across the placenta or injury to the placenta ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0033-1334459","ISBN":"0735-1631","PMID":"23389935","abstract":"Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.","author":[{"dropping-particle":"","family":"Prasad","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honegger","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Perinatol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"149-159","title":"Hepatitis C virus in pregnancy","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(Prasad & Honegger, 2013)","plainTextFormattedCitation":"(Prasad & Honegger, 2013)","previouslyFormattedCitation":"(Prasad & Honegger, 2013)"},"properties":{"noteIndex":0},"schema":""}(Prasad & Honegger, 2013), transportation of HCV through maternal mononuclear cells ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmv.21023","ISBN":"0146-6615 (Print)\\r0146-6615 (Linking)","ISSN":"02507005","PMID":"18041020","abstract":"Maternal injection drug use and peripheral blood mononuclear cell infection by hepatitis C virus are important risk factors for perinatal transmission of the virus. The aim of present study was to evaluate the independent association of these two factors on perinatal transmission. Forty-eight consecutive mothers who transmitted infection to their offspring and 122 consecutive mothers who did not, together with their children, were examined. Both maternal injection drug use and peripheral blood mononuclear cell infection were significantly more frequent in infected than in uninfected children (respectively P = 0.04; odds ratio 2.33, 95% confidence intervals 1.02-5.42 and P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values). Multivariate analysis confirmed the link between maternal peripheral blood mononuclear cell infection and perinatal transmission (P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values) but no association was found with maternal injection drug use. The high risk of perinatal transmission found in injection drug use mothers is dependent on maternal peripheral blood mononuclear cell infection by hepatitis C virus. Peripheral blood mononuclear cell infection represents one of the most important risk factors for hepatitis C virus perinatal transmission.","author":[{"dropping-particle":"","family":"Azzari","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moriondo","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Indolfi","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Betti","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gambineri","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martino","given":"M","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resti","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Med Virol","id":"ITEM-1","issued":{"date-parts":[["2008"]]},"title":"Higher risk of hepatitis C virus perinatal transmission from drug user mothers is mediated by peripheral blood mononuclear cell infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISBN":"0006-4971 (Print)\\r0006-4971 (Linking)","ISSN":"0006-4971","PMID":"10979945","abstract":"Infection of peripheral blood mononuclear cells (PBMNCs) has been demonstrated to be a crucial event in the vertical transmission of viruses, and it is known that hepatitis C virus (HCV) can infect PBMNCs. The relationship between vertical transmission of HCV and the presence of positive and negative strands of HCV-RNA in the PBMNCs of HCV-carrier mothers was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). During the study, 13 consecutive mothers who transmitted infection to their offspring and 53 consecutive mothers who did not were examined. The positive strand of HCV-RNA was identified in the PBMNCs of all mothers who transmitted the infection and in 13 of 53 mothers who did not (P < 10(-6)). The HCV-RNA(-) strand was found in 5 of 13 mothers who transmitted the infection, and the strand was not found in the mothers who did not transmit the infection (P =.0001). Neither maternal PBMNC infection nor HCV transmission to the offspring was significantly related to the viral genotype or to the maternal viral load. These data show that maternal PBMNC infection by HCV and viral replicative activity in PBMNCs are important factors in the transmission of HCV from mother to child. The mechanism through which HCV infection of PBMNC favors vertical transmission of the virus is still incompletely understood.","author":[{"dropping-particle":"","family":"Azzari","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resti","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moriondo","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ferrari","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lionetti","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vierucci","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-2","issued":{"date-parts":[["2000"]]},"title":"Vertical transmission of HCV is related to maternal peripheral blood mononuclear cell infection","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Azzari et al., 2000, 2008)","plainTextFormattedCitation":"(Azzari et al., 2000, 2008)","previouslyFormattedCitation":"(Azzari et al., 2000, 2008)"},"properties":{"noteIndex":0},"schema":""}(Azzari et al., 2000, 2008), or HCV infection of trophoblasts ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmv.23380","ISBN":"1096-9071 (Electronic)\\r0146-6615 (Linking)","PMID":"22930506","abstract":"Hepatitis C virus (HCV) infection in the uterus is a significant path of vertical HCV transmission. Some studies consider vertical HCV transmission in the uterus as the result of maternal blood leakage into infant blood, whereas others theorize that HCV is transmitted by the mother to the infant through cells constituting the placenta barrier. Although trophoblasts play an important role in the placenta barrier, no definitive evidence has been presented to prove that cytotrophoblasts can be infected with HCV. The current study investigated whether or not these can be infected with HCV by conducting an experiment, in which cultured human cytotrophoblasts were infected with HCV in vitro. The results were analyzed using reverse transcription polymerase chain reaction (RT-PCR), ultrastructural characteristic changes under an electron microscope, and immunoelectron microscopy. HCV RNA in the supernatant of the cultured medium of the infected group was intermittently detected during the 16-day incubation period using RT-PCR. Under an electron microscope, the ultrastructures of infected human cytotrophoblasts were markedly different from normal cells, demonstrating lysosomal hyperplasia, rough endoplasmic reticulum, decreased lipid droplets, presence of vacuoles, and the appearance of HCV-like particles. Using immunoelectron microscopy, HCV-like particles conjoined with golden granules were also observed. Based on the data, the current study concludes that HCV infects a human cytotrophoblast cultured in vitro; moreover, its ultrastructure changes dramatically upon infection.","author":[{"dropping-particle":"","family":"Nie","given":"Q H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gao","given":"L H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cheng","given":"Y Q","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"X F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhang","given":"Y F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Luo","given":"X D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"J Q","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wang","given":"Y Y","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Med Virol","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"title":"Hepatitis C virus infection of human cytotrophoblasts cultured in vitro","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"abstract":"1338","author":[{"dropping-particle":"","family":"Mostafavi","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arshad","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Qiang","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bradrick","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jhaveri","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["2012"]]},"title":"Examining cells of trophoblastic origin for permissiveness for hepatitis C virus replication.","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Mostafavi, Arshad, Qiang, Bradrick, & Jhaveri, 2012; Nie et al., 2012)","plainTextFormattedCitation":"(Mostafavi, Arshad, Qiang, Bradrick, & Jhaveri, 2012; Nie et al., 2012)","previouslyFormattedCitation":"(Mostafavi, Arshad, Qiang, Bradrick, & Jhaveri, 2012; Nie et al., 2012)"},"properties":{"noteIndex":0},"schema":""}(Mostafavi, Arshad, Qiang, Bradrick, & Jhaveri, 2012; Nie et al., 2012). Also, virions may have the potential to enter the fetal bloodstream without any of these methods as an estimated 1013 to 1014 virions circulate through the placental bed daily ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/infdis/jiq044","ISSN":"1537-6613","PMID":"21288819","abstract":"BACKGROUND: Although the rate of mother-to-child transmission of hepatitis C virus (HCV) is low, the effect of HCV exposure in utero on the fetal immune system is unknown.\\n\\nMETHODS: Umbilical cord blood was obtained from 7 neonates born to HCV-seropositive, HCV RNA-positive women and 8 neonates born to HCV-seronegative women. Cord blood mononuclear cells were analyzed by immunophenotyping and by intracellular cytokine staining after HCV-specific and polyclonal stimulation. Plasma was analyzed for anti-HCV immunoglobulin M (IgM), cytokine/granzyme concentrations, and indoleamine 2,3-dioxygenase (IDO) activity.\\n\\nRESULTS: HCV-exposed neonates had significantly lower levels of regulatory T cells expressing HLA-DR, lower CD4(+) and CD8(+) T cell activation, and lower plasma levels of pro-inflammatory markers than did controls. However, CD4(+) and CD8(+) T cells from HCV-exposed neonates had higher IFN-γ production in response to polyclonal stimulation than did T cells from controls. IDO activity was similar between groups. No HCV-specific T cell responses or anti-HCV IgM were detected in any neonates.\\n\\nCONCLUSIONS: HCV-exposed neonates showed a relative suppression of immune activation and pro-inflammatory markers, which was counterbalanced by an increased production capacity for IFN-γ. These results suggest that HCV encounters the fetal immune system in utero, and alters the balance between suppressive and pro-inflammatory responses.","author":[{"dropping-particle":"","family":"Babik","given":"Jennifer M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cohan","given":"Deborah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Monto","given":"Alexander","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hartigan-O'Connor","given":"Dennis J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCune","given":"Joseph M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of infectious diseases","id":"ITEM-1","issued":{"date-parts":[["2011"]]},"title":"The human fetal immune response to hepatitis C virus exposure in utero.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Babik, Cohan, Monto, Hartigan-O’Connor, & McCune, 2011)","plainTextFormattedCitation":"(Babik, Cohan, Monto, Hartigan-O’Connor, & McCune, 2011)","previouslyFormattedCitation":"(Babik, Cohan, Monto, Hartigan-O’Connor, & McCune, 2011)"},"properties":{"noteIndex":0},"schema":""}(Babik, Cohan, Monto, Hartigan-O’Connor, & McCune, 2011). With the previous statements in consideration, fetuses may have a higher risk of HCV transmission the more similar their HLA type is to their mother. Fetal alloimmune responses target maternal mononuclear cells, but if the HLA types are similar enough then these maternal HCV-infected cells will remain undetected and enter the fetal bloodstream ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmv.21023","ISBN":"0146-6615 (Print)\\r0146-6615 (Linking)","ISSN":"02507005","PMID":"18041020","abstract":"Maternal injection drug use and peripheral blood mononuclear cell infection by hepatitis C virus are important risk factors for perinatal transmission of the virus. The aim of present study was to evaluate the independent association of these two factors on perinatal transmission. Forty-eight consecutive mothers who transmitted infection to their offspring and 122 consecutive mothers who did not, together with their children, were examined. Both maternal injection drug use and peripheral blood mononuclear cell infection were significantly more frequent in infected than in uninfected children (respectively P = 0.04; odds ratio 2.33, 95% confidence intervals 1.02-5.42 and P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values). Multivariate analysis confirmed the link between maternal peripheral blood mononuclear cell infection and perinatal transmission (P < 10(-6); odds ratio and 95% confidence intervals not calculable due to zero values) but no association was found with maternal injection drug use. The high risk of perinatal transmission found in injection drug use mothers is dependent on maternal peripheral blood mononuclear cell infection by hepatitis C virus. Peripheral blood mononuclear cell infection represents one of the most important risk factors for hepatitis C virus perinatal transmission.","author":[{"dropping-particle":"","family":"Azzari","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moriondo","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Indolfi","given":"G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Betti","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gambineri","given":"E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Martino","given":"M","non-dropping-particle":"de","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resti","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Med Virol","id":"ITEM-1","issued":{"date-parts":[["2008"]]},"title":"Higher risk of hepatitis C virus perinatal transmission from drug user mothers is mediated by peripheral blood mononuclear cell infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"ISBN":"0006-4971 (Print)\\r0006-4971 (Linking)","ISSN":"0006-4971","PMID":"10979945","abstract":"Infection of peripheral blood mononuclear cells (PBMNCs) has been demonstrated to be a crucial event in the vertical transmission of viruses, and it is known that hepatitis C virus (HCV) can infect PBMNCs. The relationship between vertical transmission of HCV and the presence of positive and negative strands of HCV-RNA in the PBMNCs of HCV-carrier mothers was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). During the study, 13 consecutive mothers who transmitted infection to their offspring and 53 consecutive mothers who did not were examined. The positive strand of HCV-RNA was identified in the PBMNCs of all mothers who transmitted the infection and in 13 of 53 mothers who did not (P < 10(-6)). The HCV-RNA(-) strand was found in 5 of 13 mothers who transmitted the infection, and the strand was not found in the mothers who did not transmit the infection (P =.0001). Neither maternal PBMNC infection nor HCV transmission to the offspring was significantly related to the viral genotype or to the maternal viral load. These data show that maternal PBMNC infection by HCV and viral replicative activity in PBMNCs are important factors in the transmission of HCV from mother to child. The mechanism through which HCV infection of PBMNC favors vertical transmission of the virus is still incompletely understood.","author":[{"dropping-particle":"","family":"Azzari","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resti","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moriondo","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ferrari","given":"R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lionetti","given":"P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vierucci","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Blood","id":"ITEM-2","issued":{"date-parts":[["2000"]]},"title":"Vertical transmission of HCV is related to maternal peripheral blood mononuclear cell infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/jmv.21437","ISBN":"0146-6615 1096-9071","ISSN":"01466615","PMID":"19319981","abstract":"In industrialized countries, hepatitis C virus (HCV) is the most common cause of chronic liver disease in children. Perinatal transmission is the leading cause of infection. Perinatal transmission is confined almost always to women with detectable HCV ribonucleic acid (RNA) in the peripheral blood by the polymerase chain reaction but all children born to women with anti-HCV antibodies should be tested for HCV. Some but not all studies found that a high concentration of serum HCV RNA is associated with a higher risk of transmission. Maternal peripheral blood mononuclear cell infection by HCV, membrane rupture of longer than 6 hr before delivery, and procedures exposing the infant to maternal blood infected with HCV during vaginal delivery are associated with an increased risk of transmission. Maternal coinfection with HCV and human immunodeficiency virus, maternal history of intravenous drug use and of HCV infection of the sexual partner of the mother predict the risk of perinatal transmission and are dependent on the peripheral blood mononuclear cell infection by HCV. Delivery by Cesarean section is not recommended in pregnant women infected with HCV. Infected mothers can breast feed safely their infants if the nipples are not damaged. A previous delivery of a child infected perinatally with HCV does not increase the risk of transmission in subsequent pregnancies. Immunogenetic factors and HCV genotypes are not related to HCV perinatal transmission. Despite an increased understanding of the risk factors involved in perinatal transmission of HCV, to date little is known about the transmission mechanisms and timing.","author":[{"dropping-particle":"","family":"Indolfi","given":"Giuseppe","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Resti","given":"Massimo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Medical Virology","id":"ITEM-3","issued":{"date-parts":[["2009"]]},"title":"Perinatal transmission of hepatitis C virus infection","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Azzari et al., 2000, 2008; Indolfi & Resti, 2009)","plainTextFormattedCitation":"(Azzari et al., 2000, 2008; Indolfi & Resti, 2009)","previouslyFormattedCitation":"(Azzari et al., 2000, 2008; Indolfi & Resti, 2009)"},"properties":{"noteIndex":0},"schema":""}(Azzari et al., 2000, 2008; Indolfi & Resti, 2009). Another point Prasad mentions is that considering some viral particles enter the fetal bloodstream during pregnancy, it is uncertain which immune mechanisms are responsible for an HCV transmission rate of 2-8% when human immunodeficiency virus (HIV) has a mother-to-child transmission rate of 25% ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0033-1334459","ISBN":"0735-1631","PMID":"23389935","abstract":"Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.","author":[{"dropping-particle":"","family":"Prasad","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honegger","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Perinatol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"149-159","title":"Hepatitis C virus in pregnancy","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(Prasad & Honegger, 2013)","plainTextFormattedCitation":"(Prasad & Honegger, 2013)","previouslyFormattedCitation":"(Prasad & Honegger, 2013)"},"properties":{"noteIndex":0},"schema":""}(Prasad & Honegger, 2013). This issue has prompted researchers to delve into research regarding the immune response between mother and child that reduces HCV transmission. Hurtado and colleagues conducted a study to determine and quantify the presence of innate immune cells in the placenta, cord blood, and decidua of women who were HCV positive compared to pregnant women who were negative for the virus. They found higher concentrations of NK T and γδ T cells and greater cytotoxicities of NK T and NK cells when comparing placental tissue to cord blood in HCV-negative women. HCV infection further enhanced all of the previously listed results, except NK cell activation marker expression was decreased. As HCV infection has been shown to alter NK cells resulting in chronic infection, these phenotypic changes are anticipated. However, the NK cells still exhibited strong interferon production. These study results suggest that placental immune cells play an active role in the antiviral response to HCV in efforts to prevent transmission to the fetus ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1371/journal.pone.0012232","ISBN":"1932-6203 (Electronic)\\r1932-6203 (Linking)","ISSN":"1932-6203","PMID":"20814429","abstract":"Vertical transmission accounts for the majority of pediatric cases of hepatitis C viral (HCV) infection. In contrast to the adult population who develop persistent viremia in approximately 80% of cases following exposure, the rate of mother-to-child transmission (2-6%) is strikingly low. Protection from vertical transmission likely requires the coordination of multiple components of the immune system. Placenta and decidua provide a direct connection between mother and infant. We hypothesized that innate immune responses would differ across the three compartments (decidua, placenta and cord blood) and that hepatitis C exposure would modify innate immunity in these tissues. The study was comprised of HCV-infected and healthy control mother and infant pairs from whom cord blood, placenta and decidua were collected with isolation of mononuclear cells. Multiparameter flow cytometry was performed to assess the phenotype, intracellular cytokine production and cytotoxicity of the cells. In keeping with a model where the maternal-fetal interface provides antiviral protection, we found a gradient in proportional frequencies of NKT and gammadelta-T cells being higher in placenta than cord blood. Cytotoxicity of NK and NKT cells was enhanced in placenta and placental NKT cytotoxicity was further increased by HCV infection. HCV exposure had multiple effects on innate cells including a decrease in activation markers (CD69, TRAIL and NKp44) on NK cells and a decrease in plasmacytoid dendritic cells in both placenta and cord blood of exposed infants. In summary, the placenta represents an active innate immunological organ that provides antiviral protection against HCV transmission in the majority of cases; the increased incidence in preterm labor previously described in HCV-seropositive mothers may be related to enhanced cytotoxicity of NKT cells.","author":[{"dropping-particle":"","family":"Hurtado","given":"C W","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Golden-Mason","given":"L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brocato","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Krull","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Narkewicz","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosen","given":"H R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"PLoS One","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"Innate immune function in placenta and cord blood of hepatitis C--seropositive mother-infant dyads","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Hurtado et al., 2010)","plainTextFormattedCitation":"(Hurtado et al., 2010)","previouslyFormattedCitation":"(Hurtado et al., 2010)"},"properties":{"noteIndex":0},"schema":""}(Hurtado et al., 2010).Following delivery, some HCV-positive mothers have been reported to experience a decline in viral load 1 to 3 months postpartum ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"ISSN":"1470-0328","PMID":"11192107","abstract":"OBJECTIVE: To assess whether pregnancy and delivery influence serum levels of hepatitis C virus (HCV) in carrier mothers.\\n\\nDESIGN: A prospective study.\\n\\nSETTING: University department of obstetrics and gynaecology.\\n\\nPARTICIPANTS: Ten pregnant HCV carriers (group A) and 8 nonpregnant HCV carriers (group B).\\n\\nMETHODS: Serum samples were collected for group A at first and third trimesters, delivery, postpartum 1, 3, 6, 9 and 12 months, and at every three months for 1 year for group B.\\n\\nMAIN OUTCOME MEASURES: Each serum sample was tested for serum alanine aminotransferase (ALT), anti-HCV titre and HCV-cDNA concentration by a competitive polymerase chain reaction (PCR) with a sensitivity of 250 copies/mL serum.\\n\\nRESULTS: In group A, the HCV levels remained unremarkably changed during pregnancy and delivery. However, all women had decreased HCV levels 1 and 3 months after delivery. Two women had undetectable serum HCV level postpartum and thereafter. Serum ALT values in 3 women were sporadically elevated, but did not correlate with decreased serum HCV levels. Anti-HCV titres remained unchanged during the study period. In two women from group B, the serum HCV levels were undetectable during follow up. Other 6 women showed fluctuations in the serum HCV levels but all were above 250 copies/mL. Serum ALT values were normal and anti-HCV titres remained stationary in all 8 nonpregnant carriers.\\n\\nCONCLUSION: Serum HCV levels are decreased 1 and 3 months after delivery. This fact might suggest that puerperium is an optimal time for antiviral therapy in HCV carrier mothers.","author":[{"dropping-particle":"","family":"Lin","given":"H H","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kao","given":"J H","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"BJOG : an international journal of obstetrics and gynaecology","id":"ITEM-1","issued":{"date-parts":[["2000"]]},"title":"Hepatitis C virus load during pregnancy and puerperium.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(H H Lin & Kao, 2000)","plainTextFormattedCitation":"(H H Lin & Kao, 2000)","previouslyFormattedCitation":"(H H Lin & Kao, 2000)"},"properties":{"noteIndex":0},"schema":""}(H H Lin & Kao, 2000). In some cases the woman is even able to clear her chronic infection within this time period ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/jmv.10471","ISBN":"0146-6615 (Print)\\r0146-6615 (Linking)","PMID":"12938194","abstract":"It is unclear whether pregnancy has any influence on chronic hepatitis C virus (HCV) infection. The aim of this study was to investigate the relationship between pregnancy and parturition with HCV viremia levels and the natural resolution of HCV RNA. Twenty-two pregnant patients and 120 nonpregnant control female patients, both positive for anti-HCV and HCV RNA, were studied. The HCV core protein levels were quantified by enzyme immunoassay, and HCV RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR). Of the pregnant group, two females whose HCV RNA was negative continuously for more than 6 months lost HCV RNA permanently after parturition, and one female whose level of HCV core protein was intermittently under the limit of detection level lost HCV RNA intermittently. In the control group, only one female lost HCV RNA persistently, and one lost HCV RNA intermittently after she developed liver cirrhosis. At 3 months after parturition, the HCV core protein level was <15 fmol/L in all patients who lost HCV RNA, while the HCV core protein level was >/=15 fmol/L in 81.3% of the patients who persistently had HCV RNA (P = 0.03). Significantly more pregnant patients lost HCV RNA than did nonpregnant controls. These findings suggest that pregnancy and parturition appear to influence the clinical course of HCV infection","author":[{"dropping-particle":"","family":"Hattori","given":"Y.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Orito","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ohno","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sugauchi","given":"F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suzuki","given":"S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sugiura","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Suzumori","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hattori","given":"K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ueda","given":"R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mizokami","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Med Virol","id":"ITEM-1","issued":{"date-parts":[["2003"]]},"title":"Loss of hepatitis C virus RNA after parturition in female patients with chronic HCV infection","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Hattori et al., 2003)","plainTextFormattedCitation":"(Hattori et al., 2003)","previouslyFormattedCitation":"(Hattori et al., 2003)"},"properties":{"noteIndex":0},"schema":""}(Hattori et al., 2003). Researchers have discovered these women have enhanced HCV specific T-cell IFN-γ-producing responses ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"abstract":"1225","author":[{"dropping-particle":"","family":"Honegger","given":"J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Prasad","given":"M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Walker","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["2012"]]},"publisher-place":"In: Infectious Diseases Society of America Annual Meeting. San Diego, CA","title":"Broadened virus-specific T-cell responses are associated with postpartum declines in hepatitis C viremia","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Honegger, Prasad, & Walker, 2012)","plainTextFormattedCitation":"(Honegger, Prasad, & Walker, 2012)","previouslyFormattedCitation":"(Honegger, Prasad, & Walker, 2012)"},"properties":{"noteIndex":0},"schema":""}(Honegger, Prasad, & Walker, 2012) which would suggest that these cells are being restored allowing an immune boost and subsequent viral decline. Not only is research into mother and child immune responses in HCV infection important, but it is also important to evaluate current fetal/pregnancy monitoring methods for HCV-infected women to decrease infant HCV exposure. A systematic review was conducted by Cottrell and colleagues to advise the USPSTF on making current national recommendations for reducing the risk for mother-to-infant transmission of HCV where the mode of delivery, methods for labor management, and breastfeeding were evaluated. Researchers selected 444 articles for full-text review, and 18 of those articles met the inclusion criteria. With regard to the mode of delivery, cesarean versus vaginal delivery, results conflicted on whether elective cesarean would be beneficial or not for HCV-positive women ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-158-2-201301150-00575","ISSN":"15393704","PMID":"23437438","abstract":"BACKGROUND: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION: Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS: Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.","author":[{"dropping-particle":"","family":"Cottrell","given":"Erika Barth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chou","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasson","given":"Ngoc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahman","given":"Basmah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guise","given":"Jeanne Marie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Internal Medicine","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Reducing risk for mother-to-infant transmission of hepatitis C virus: A systematic review for the U.S. preventive services task force","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Cottrell, Chou, Wasson, Rahman, & Guise, 2013)","plainTextFormattedCitation":"(Cottrell, Chou, Wasson, Rahman, & Guise, 2013)","previouslyFormattedCitation":"(Cottrell, Chou, Wasson, Rahman, & Guise, 2013)"},"properties":{"noteIndex":0},"schema":""}(Cottrell, Chou, Wasson, Rahman, & Guise, 2013). The Cochrane database agrees there is no good evidence to support using elective cesarean section as a standardized delivery method for these women to reduce HCV transmission ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/14651858.CD005546.pub2","ISSN":"14651858","PMID":"17054264","abstract":"BACKGROUND Observational studies have generally not provided evidence that delivery by caesarean section reduces perinatal hepatitis C virus (HCV) transmission. However, these studies have methodological weaknesses with potential for bias and their findings should be interpreted with caution. OBJECTIVES To assess the evidence from randomised controlled trials that a policy of delivery by planned caesarean section versus vaginal delivery reduces mother to infant HCV transmission. SEARCH STRATEGY We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (April 2006) and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA Controlled trials using random or quasi-random participant allocation that compared a policy of planned elective caesarean section versus vaginal birth for mothers with HCV infection. DATA COLLECTION AND ANALYSIS We did not identify any randomised controlled trials. MAIN RESULTS We did not identify any randomised controlled trials. AUTHORS' CONCLUSIONS Currently, there is no evidence from randomised controlled trials upon which to base any practice recommendations regarding planned caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. In the absence of trial data, evidence to inform women and carers is only available from observational studies that are subject to biases. Systematic review of these studies is needed. There is a need to determine whether women and healthcare providers would support a large pragmatic randomised controlled trial to provide evidence regarding the benefits and harms of planned elective caesarean section versus planned vaginal birth for women with HCV infection.","author":[{"dropping-particle":"","family":"McIntyre","given":"Paul G","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tosh","given":"Karen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McGuire","given":"William","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cochrane Database of Systematic Reviews","id":"ITEM-1","issued":{"date-parts":[["2006"]]},"title":"Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(McIntyre, Tosh, & McGuire, 2006)","plainTextFormattedCitation":"(McIntyre, Tosh, & McGuire, 2006)","previouslyFormattedCitation":"(McIntyre, Tosh, & McGuire, 2006)"},"properties":{"noteIndex":0},"schema":""}(McIntyre, Tosh, & McGuire, 2006). Labor management methods, such as internal fetal monitoring and prolonged duration of ruptured membranes, have been shown to increase mother to child transmission (MTCT) in individual studies, though the metanalysis concluded there was insufficient evidence for an association between internal fetal monitoring and the increased risk of HCV transmission. However, there was high consistency between the articles reviewed for the duration of ruptured membranes. Studies show a statistically significant association between greater than six hours between membrane rupture and delivery and MTCT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1046/j.1365-2893.1997.00073.x","ISBN":"1352-0504; 1352-0504","ISSN":"13520504","PMID":"9430360","abstract":"The risk of perinatal transmission of hepatitis C virus (HCV) from a cohort of 95 human immunodeficiency virus (HIV)-negative intravenous drug users (IVDU) is described, 89 of whom were positive for antibodies to HCV (anti-HCV). Infection, defined as the presence of HCV RNA in a serum sample collected from an infant at any time during follow-up, was detected in six of 63 (9.5%) infants born to HCV antibody-positive viraemic mothers. No mother who was HCV RNA negative at delivery transmitted HCV to her infant. Hepatitis C virus antibodies became undetectable in uninfected infants by 15 months, but persisted in all HCV-infected infants throughout follow-up. An abnormal alanine aminotransferase (ALT) level was observed on at least one occasion in all HCV-infected infants and in six occasions in uninfected infants. Two of the six HCV-infected infants became HCV RNA negative during follow-up by 27 and 29 months. Both of these infants had a large ALT elevation (mean peak ALT 398U l-1) at around 12 months of age. Analysis of a range of potential risk factors revealed that maternal HCV RNA load was important in predicting transmission, but suggested that other factors play a role in perinatal transmission from mother to child. No difference was found between mothers who transmitted HCV to their infants and those who did not for HCV genotype, duration of drug use, duration of methadone use, methadone dose, history of alcohol abuse, past hepatitis B virus (HBV) infection, mode of delivery, maternal and gestational age, birth weight and incidence of breast-feeding. Mothers who transmitted HCV to their infants had a longer duration between membrane rupture and delivery than the mothers who did not transmit (P = 0.03). HCV RNA was not detected in breast milk and colostrum samples from 38 viraemic mothers, including two who transmitted HCV to their infant.","author":[{"dropping-particle":"","family":"Spencer","given":"J. D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Latt","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Beeby","given":"P. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Collins","given":"E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saunders","given":"J. B.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McCaughan","given":"G. W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cossart","given":"Y. E.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Viral Hepatitis","id":"ITEM-1","issued":{"date-parts":[["1997"]]},"title":"Transmission of hepatitis C virus to infants of human immunodeficiency virus-negative intravenous drug-using mothers: Rate of infection and assessment of risk factors for transmission","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1086/497701","ISBN":"0022-1899 (Print)\\r0022-1899 (Linking)","ISSN":"0022-1899","PMID":"16267758","abstract":"BACKGROUND: The goal of the present study was to assess risk factors for perinatal hepatitis C virus (HCV) transmission and the natural history of infection among HCV-infected infants. METHODS: In a cohort study, 244 infants born to HCV-positive mothers were followed from birth until age > or =12 months. Maternal serum was collected at enrollment and delivery; infant serum was collected at birth and at 8 well-child visits. Testing included detection of antibody to HCV, detection of HCV RNA (qualitative and quantitative), and genotyping. HCV-infected infants were followed annually until age 5 years. RESULTS: Overall, 9 of 190 (4.7% [95% confidence interval (CI), 2.3%-9.1%]) infants born to mothers who were HCV RNA positive at delivery became infected, compared with 0 of 54 infants born to HCV RNA-negative mothers (P=.10). Among HCV RNA-positive mothers, the rate of transmission was 3.8% (95% CI, 1.7%-8.1%) from the 182 who were human immunodeficiency virus (HIV) negative, compared with 25.0% (95% CI, 4.5%-64.4%) from the 8 who were HIV positive (P<.05). Three infected infants resolved their infection (i.e., became HCV RNA negative). In multivariate analysis restricted to HCV RNA-positive mothers, membrane rupture > or =6 h (odds ratio [OR], 9.3 [95% CI, 1.5-179.7]) and internal fetal monitoring (OR, 6.7 [95% CI, 1.1-35.9]) were associated with transmission of HCV to infants. CONCLUSION: If duration of membrane rupture and internal fetal monitoring are confirmed to be associated with transmission, interventions may be possible to decrease the risk of transmission.","author":[{"dropping-particle":"","family":"Mast","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hwang","given":"Lu-Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seto","given":"Dexter S Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nolte","given":"Frederick S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Nainan","given":"Omana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wurtzel","given":"Heather","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alter","given":"Miriam J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of infectious diseases","id":"ITEM-2","issue":"February","issued":{"date-parts":[["2005"]]},"page":"1880-1889","title":"Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy.","type":"article-journal","volume":"192"},"uris":[""]}],"mendeley":{"formattedCitation":"(Mast et al., 2005; Spencer et al., 1997)","plainTextFormattedCitation":"(Mast et al., 2005; Spencer et al., 1997)","previouslyFormattedCitation":"(Mast et al., 2005; Spencer et al., 1997)"},"properties":{"noteIndex":0},"schema":""}(Mast et al., 2005; Spencer et al., 1997). Mast’s study, in particular, concluded women who had more than 6 hours between membrane rupture and delivery were at 9.3 times increased odds (95% CI 1.5-179.7) of transmitting the virus to their infants when compared to those who had less than 6 hours between rupture and delivery ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1086/497701","ISBN":"0022-1899 (Print)\\r0022-1899 (Linking)","ISSN":"0022-1899","PMID":"16267758","abstract":"BACKGROUND: The goal of the present study was to assess risk factors for perinatal hepatitis C virus (HCV) transmission and the natural history of infection among HCV-infected infants. METHODS: In a cohort study, 244 infants born to HCV-positive mothers were followed from birth until age > or =12 months. Maternal serum was collected at enrollment and delivery; infant serum was collected at birth and at 8 well-child visits. Testing included detection of antibody to HCV, detection of HCV RNA (qualitative and quantitative), and genotyping. HCV-infected infants were followed annually until age 5 years. RESULTS: Overall, 9 of 190 (4.7% [95% confidence interval (CI), 2.3%-9.1%]) infants born to mothers who were HCV RNA positive at delivery became infected, compared with 0 of 54 infants born to HCV RNA-negative mothers (P=.10). Among HCV RNA-positive mothers, the rate of transmission was 3.8% (95% CI, 1.7%-8.1%) from the 182 who were human immunodeficiency virus (HIV) negative, compared with 25.0% (95% CI, 4.5%-64.4%) from the 8 who were HIV positive (P<.05). Three infected infants resolved their infection (i.e., became HCV RNA negative). In multivariate analysis restricted to HCV RNA-positive mothers, membrane rupture > or =6 h (odds ratio [OR], 9.3 [95% CI, 1.5-179.7]) and internal fetal monitoring (OR, 6.7 [95% CI, 1.1-35.9]) were associated with transmission of HCV to infants. CONCLUSION: If duration of membrane rupture and internal fetal monitoring are confirmed to be associated with transmission, interventions may be possible to decrease the risk of transmission.","author":[{"dropping-particle":"","family":"Mast","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hwang","given":"Lu-Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seto","given":"Dexter S Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nolte","given":"Frederick S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Nainan","given":"Omana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wurtzel","given":"Heather","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alter","given":"Miriam J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of infectious diseases","id":"ITEM-1","issue":"February","issued":{"date-parts":[["2005"]]},"page":"1880-1889","title":"Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy.","type":"article-journal","volume":"192"},"uris":[""]}],"mendeley":{"formattedCitation":"(Mast et al., 2005)","plainTextFormattedCitation":"(Mast et al., 2005)","previouslyFormattedCitation":"(Mast et al., 2005)"},"properties":{"noteIndex":0},"schema":""}(Mast et al., 2005). The broad 95% confidence interval is most likely due to the small sample size of HCV infected infants in this study (9). Because HCV has a 6% transmission rate, studies assessing risk factors require large sample sizes. The study would have required over 1,000 HCV-positive mothers under observation to have a sample size large enough to result in a narrower 95% confidence interval. The 14 journal articles reviewed by Cottrell and colleagues regarding breastfeeding in this metanalysis concluded there is no association between breastfeeding and an increased risk for MTCT ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-158-2-201301150-00575","ISSN":"15393704","PMID":"23437438","abstract":"BACKGROUND: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION: Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS: Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.","author":[{"dropping-particle":"","family":"Cottrell","given":"Erika Barth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chou","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasson","given":"Ngoc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahman","given":"Basmah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guise","given":"Jeanne Marie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Internal Medicine","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Reducing risk for mother-to-infant transmission of hepatitis C virus: A systematic review for the U.S. preventive services task force","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Cottrell et al., 2013)","plainTextFormattedCitation":"(Cottrell et al., 2013)","previouslyFormattedCitation":"(Cottrell et al., 2013)"},"properties":{"noteIndex":0},"schema":""}(Cottrell et al., 2013). There are virions present in breastmilk and colostrum, ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/S0022-3476(95)70356-X","ISBN":"0022-3476 (Print)\\r0022-3476 (Linking)","ISSN":"00223476","PMID":"7535353","abstract":"The role of breast-feeding in perinatal transmission of hepatitis C virus (HCV) was explored in 15 HCV-infected mothers and their infants. The 15 carrier mothers had anti-HCV titers ranging from 1:80 to 1:40,000 and also had HCV-ribonucleic acid with concentrations ranging from 104to 2.5 × 108copies/ml. Both anti-HCV antibody and HCV-ribonucleic acid were present in colostral samples in much lower levels, but none of the 11 breast-fed infants had evidence of HCV infection for up to 1 year of age. Thus breast-feeding seems safe for these infants. (J PEDIATR 1995;126:589-91). ? 1995 Mosby, Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Lin","given":"Ho Hsiung","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kao","given":"Jia Horng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hsu","given":"Hong Yuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ni","given":"Yen Hsuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Mei Hwei","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Huang","given":"Su Cheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hwang","given":"Lih Hwa","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Pei Jer","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Ding Shinn","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Pediatrics","id":"ITEM-1","issued":{"date-parts":[["1995"]]},"title":"Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/S0168-8278(98)80003-2","ISBN":"0168-8278 (Print)\\r0168-8278 (Linking)","ISSN":"01688278","PMID":"9722199","abstract":"Background/Aims: The aim of this study was to explore the role of breast-feeding in transmission of hepatitis C virus (HCV) to infants of HCV- infected mothers. Methods: Sixty-five parturient asymptomatic carrier mothers with anti-HCV antibody (index patients) and 42 healthy parturient anti-HCV negative mothers (control subjects) were studied from September 1994 to June 1996. Maternal blood and colostrum were taken from each subject within 5 days post-partum and tested for anti-HCV and HCV RNA. Blood samples were collected from all infants at birth (cord blood) and at 1, 3, 6, 9 and 12 months of age. All infants were breast-fed. By 3 months post-partum, five of 65 index patients developed symptomatic liver disease and three of their infants developed acute viral hepatitis. Genotyping and subsequent nucleotide sequencing of the hepatitis C genome was done on these three symptomatic mother-baby pairs. Results: Within 5 days post-partum, the 65 carrier mothers had anti-HCV ranging from 1:40 to 1:30 000 and HCV-RNA ranging from 102to 2.5x106copies/ml. Both anti-HCV antibody and HCV-RNA were present in colostral samples but in significantly lower levels (p<0.0001). The five symptomatic mothers had anti-HCV titers ranging from 1:45 000 to 1:90 000 and HCV-RNA ranging from 2.5x108to 4.5x109copies/ml; three of their infants were symptomatic by 3 months of age. Hepatitis C virus genotype (3a) was concordant within each of the three mother-baby pairs, and all three pairs demonstrated greater than 97% homologies between pairs. These three infants were delivered by elective cesarean section at term, breast-fed regularly and there was no apparent maternal breast nipple trauma. None of the remaining infants had evidence of HCV infection up to 1 year of age. All 42 mother- infant pairs from the control group remained anti-HCV negative throughout this study. Conclusion: Among asymptomatic mothers breast-feeding seems safe. Symptomatic women, especially with high viral loads, should not breast-feed to avoid the risk of viral transmission through breast-feeding.","author":[{"dropping-particle":"","family":"Kumar","given":"Rachana M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shahul","given":"Sajid","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-2","issued":{"date-parts":[["1998"]]},"title":"Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kumar & Shahul, 1998; Ho Hsiung Lin et al., 1995)","plainTextFormattedCitation":"(Kumar & Shahul, 1998; Ho Hsiung Lin et al., 1995)","previouslyFormattedCitation":"(Kumar & Shahul, 1998; Ho Hsiung Lin et al., 1995)"},"properties":{"noteIndex":0},"schema":""}(Kumar & Shahul, 1998; Ho Hsiung Lin et al., 1995) but the quantity is too low to infect the child ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0033-1334459","ISBN":"0735-1631","PMID":"23389935","abstract":"Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.","author":[{"dropping-particle":"","family":"Prasad","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honegger","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Perinatol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"149-159","title":"Hepatitis C virus in pregnancy","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(Prasad & Honegger, 2013)","plainTextFormattedCitation":"(Prasad & Honegger, 2013)","previouslyFormattedCitation":"(Prasad & Honegger, 2013)"},"properties":{"noteIndex":0},"schema":""}(Prasad & Honegger, 2013). The only instances in which breastfeeding should be avoided is when the mother’s nipples are cracked or bleeding or the mother has an HIV coinfection ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0033-1334459","ISBN":"0735-1631","PMID":"23389935","abstract":"Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.","author":[{"dropping-particle":"","family":"Prasad","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honegger","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Perinatol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"149-159","title":"Hepatitis C virus in pregnancy","type":"article-journal","volume":"30"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.7326/0003-4819-158-2-201301150-00575","ISSN":"15393704","PMID":"23437438","abstract":"BACKGROUND: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION: Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS: Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.","author":[{"dropping-particle":"","family":"Cottrell","given":"Erika Barth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chou","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasson","given":"Ngoc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahman","given":"Basmah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guise","given":"Jeanne Marie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Internal Medicine","id":"ITEM-2","issued":{"date-parts":[["2013"]]},"title":"Reducing risk for mother-to-infant transmission of hepatitis C virus: A systematic review for the U.S. preventive services task force","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Cottrell et al., 2013; Prasad & Honegger, 2013)","plainTextFormattedCitation":"(Cottrell et al., 2013; Prasad & Honegger, 2013)","previouslyFormattedCitation":"(Cottrell et al., 2013; Prasad & Honegger, 2013)"},"properties":{"noteIndex":0},"schema":""}(Cottrell et al., 2013; Prasad & Honegger, 2013). Table 1 summarizes the evidence for the current USPSTF recommendations. Additional factors considered by individual studies include viral load, HIV coinfection, and amniocentesis. With respect to viral load, studies have shown that there is an increased risk for transmission as the maternal viral load increases ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1086/367704","ISBN":"0022-1899","ISSN":"0022-1899","PMID":"12552417","abstract":"Virological and clinical data from 73 hepatitis C virus (HCV)-infected pregnant women who gave birth to 75 children were merged retrospectively, by logistic regression analysis, to investigate risk factors for vertical transmission of HCV. Eighty-two percent of the HCV-infected mothers were HCV-RNA-positive during pregnancy, and 10% were coinfected with human immunodeficiency virus (HIV). Nine children were HCV infected, 1 was HIV infected, but none was HIV-HCV coinfected. Among vaginal deliveries, the mean HCV load of mothers who transmitted HCV to their infants was higher than that of those who did not (8.1 x 10(5) vs. 1.4 x 10(4) copies/mL; P=.056). A reduction in umbilical cord-blood pH (relative risk, 3.9; P=.04) or the occurrence of perineal or vaginal laceration (relative risk, 6.4; P=.028) during vaginal delivery significantly increased the risk of vertical HCV transmission. In conclusion, high maternal viremia, infantile hypoxia, and intrapartum exposure to virus-contaminated maternal blood increased the risk of HCV transmission during vaginal deliveries. Consequently, cesarean section may reduce the risk of vertical HCV transmission in selected cases.","author":[{"dropping-particle":"","family":"Steininger","given":"Christoph","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kundi","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jatzko","given":"Gerlinde","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kiss","given":"Herbert","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lischka","given":"Andreas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Holzmann","given":"Heidemarie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of Infectious Diseases","id":"ITEM-1","issued":{"date-parts":[["2003"]]},"title":"Increased Risk of Mother‐to‐Infant Transmission of Hepatitis C Virus by Intrapartum Infantile Exposure to Maternal Blood","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1086/497701","ISBN":"0022-1899 (Print)\\r0022-1899 (Linking)","ISSN":"0022-1899","PMID":"16267758","abstract":"BACKGROUND: The goal of the present study was to assess risk factors for perinatal hepatitis C virus (HCV) transmission and the natural history of infection among HCV-infected infants. METHODS: In a cohort study, 244 infants born to HCV-positive mothers were followed from birth until age > or =12 months. Maternal serum was collected at enrollment and delivery; infant serum was collected at birth and at 8 well-child visits. Testing included detection of antibody to HCV, detection of HCV RNA (qualitative and quantitative), and genotyping. HCV-infected infants were followed annually until age 5 years. RESULTS: Overall, 9 of 190 (4.7% [95% confidence interval (CI), 2.3%-9.1%]) infants born to mothers who were HCV RNA positive at delivery became infected, compared with 0 of 54 infants born to HCV RNA-negative mothers (P=.10). Among HCV RNA-positive mothers, the rate of transmission was 3.8% (95% CI, 1.7%-8.1%) from the 182 who were human immunodeficiency virus (HIV) negative, compared with 25.0% (95% CI, 4.5%-64.4%) from the 8 who were HIV positive (P<.05). Three infected infants resolved their infection (i.e., became HCV RNA negative). In multivariate analysis restricted to HCV RNA-positive mothers, membrane rupture > or =6 h (odds ratio [OR], 9.3 [95% CI, 1.5-179.7]) and internal fetal monitoring (OR, 6.7 [95% CI, 1.1-35.9]) were associated with transmission of HCV to infants. CONCLUSION: If duration of membrane rupture and internal fetal monitoring are confirmed to be associated with transmission, interventions may be possible to decrease the risk of transmission.","author":[{"dropping-particle":"","family":"Mast","given":"Eric E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hwang","given":"Lu-Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Seto","given":"Dexter S Y","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Nolte","given":"Frederick S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Nainan","given":"Omana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wurtzel","given":"Heather","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alter","given":"Miriam J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of infectious diseases","id":"ITEM-2","issue":"February","issued":{"date-parts":[["2005"]]},"page":"1880-1889","title":"Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy.","type":"article-journal","volume":"192"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1002/jmv.2202","ISBN":"0146-6615 (Print)","ISSN":"01466615","PMID":"11992574","abstract":"One hundred twenty-six mother-infant couples were studied and 105 exposed babies were monitored for at least 12 months to define the risk of mother-to-infant HCV transmission. Infection occurred in 5 out of 76 infants (6.6%) born to 69 viraemic mothers and in none of 29 born to 26 non-viraemic mothers. Only one child was HCV RNA positive one month after birth, while the remaining children became positive at the 3rd to 4th month. HCV genotypes of the babies matched those of their mothers. No difference was found between women who transmitted the virus and those who did not with regard to age, history of drug abuse, HIV infection, ALT abnormal values, HCV genotype, type of delivery, and breast-feeding. Four out of 5 infected infants were born to mothers with IgM anti-HCV (P = 0.04). The mean viral titre in transmitting women (10(7.2)) was higher than in non-transmitting (10(6.5)), and the proportion of mothers with viral load > or = 10(7) was statistically higher in transmitting than non-transmitting women (P = 0.03). These data show that HCV perinatal infection is a rare event and suggest that IgM positivity and high viral load (> or = 10(7)) in the mother are independent variables correlated with HCV transmission (O.R. = 14.5; 95% CI: 1.3-160.7 and O.R. = 16.3; 95% CI: 1.5-179.9, respectively).","author":[{"dropping-particle":"","family":"Molin","given":"Gianna Dal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"D'Agaro","given":"Pierlanfranco","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ansaldi","given":"Filippo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ciana","given":"Giovanni","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fertz","given":"Cristina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alberico","given":"Salvatore","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Campello","given":"Cesare","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Medical Virology","id":"ITEM-3","issued":{"date-parts":[["2002"]]},"title":"Mother-to-infant transmission of hepatitis C virus: Rate of infection and assessment of viral load and IgM anti-HCV as risk factors","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Mast et al., 2005; Molin et al., 2002; Steininger et al., 2003)","plainTextFormattedCitation":"(Mast et al., 2005; Molin et al., 2002; Steininger et al., 2003)","previouslyFormattedCitation":"(Mast et al., 2005; Molin et al., 2002; Steininger et al., 2003)"},"properties":{"noteIndex":0},"schema":""}(Mast et al., 2005; Molin et al., 2002; Steininger et al., 2003) and no lower limit for which viral load will not result in transmission to the infant has been determined ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1055/s-0033-1334459","ISBN":"0735-1631","PMID":"23389935","abstract":"Despite recent advances in the pathogenesis, treatment, and public health response to hepatitis C virus (HCV), HCV as it specifically relates to pregnancy has been a neglected condition. HCV-monoinfected pregnant women have a 2-8% risk of viral transmission to their infant, but the mechanism and timing of mother to child transmission (MTCT) are not fully understood, nor is the natural history of the illness in pregnant women and their offspring. Recognition of HCV-infected pregnant women is relevant because of the long-term health implications for the mother, potential adverse effects of infection on pregnancy outcomes, and the possibility of transmission to their infants. Certain risk factors for MTCT of HCV appear similar to those for human immunodeficiency virus (HIV); however, unlike HIV, effective methods for prevention of HCV vertical transmission have not been developed. It is possible that a better understanding of HCV MTCT and pathogenesis in pregnancy will guide development of useful prevention strategies, particularly as we enter an era where interferon-free drug cocktails may emerge as viable treatment options for HCV.","author":[{"dropping-particle":"","family":"Prasad","given":"M R","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Honegger","given":"J R","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Am J Perinatol","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2013"]]},"page":"149-159","title":"Hepatitis C virus in pregnancy","type":"article-journal","volume":"30"},"uris":[""]}],"mendeley":{"formattedCitation":"(Prasad & Honegger, 2013)","plainTextFormattedCitation":"(Prasad & Honegger, 2013)","previouslyFormattedCitation":"(Prasad & Honegger, 2013)"},"properties":{"noteIndex":0},"schema":""}(Prasad & Honegger, 2013). A meta-analysis reviewing results of the impact of HIV coinfection on HCV vertical transmission concluded mothers with an HIV coinfection were at 90% increased odds (OR 1.9, 95% CI 1.36-2.67) of HCV transmission to their infants when compared to mothers who had an HCV infection alone ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1086/512815","ISBN":"1537-6591 (Electronic)\\r1058-4838 (Linking)","ISSN":"1058-4838","PMID":"17366462","abstract":"BACKGROUND: Observational studies suggest that maternal human immunodeficiency virus (HIV)-hepatitis C virus (HCV) coinfection is associated with increased odds of vertical HCV transmission. We performed a meta-analysis to summarize current evidence. METHODS: We systematically searched for relevant articles published during the period from January 1992 through July 2006 and independently abstracted articles that met our inclusion criteria. Under a random effects model, we calculated the pooled odds ratio for vertical HCV transmission according to maternal HIV-HCV coinfection status and performed sensitivity analyses. RESULTS: Ten articles met our inclusion criteria. Study quality varied widely, and study estimates displayed high statistical heterogeneity. Restriction of the analysis to studies that included >50 HIV-HCV-coinfected women provided our most reliable estimate: maternal HIV-HCV coinfection increases the odds of vertical HCV transmission by approximately 90% (odds ratio, 1.9; 95% confidence interval, 1.36-2.67), compared with maternal HCV infection alone. When we restricted analyses to HIV-infected mothers with HCV viremia, the odds of vertical HCV transmission were 2.82-fold (95% confidence interval, 1.17-fold to 6.81-fold) greater than the odds for HIV-infected mothers without HCV viremia. CONCLUSIONS: HIV-HCV-coinfected women have significantly higher odds of transmitting HCV to their infants than do women who are infected with HCV alone.","author":[{"dropping-particle":"","family":"Polis","given":"C B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shah","given":"S N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"K E","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clin Infect Dis","id":"ITEM-1","issued":{"date-parts":[["2007"]]},"title":"Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Polis, Shah, Johnson, & Gupta, 2007)","plainTextFormattedCitation":"(Polis, Shah, Johnson, & Gupta, 2007)","previouslyFormattedCitation":"(Polis, Shah, Johnson, & Gupta, 2007)"},"properties":{"noteIndex":0},"schema":""}(Polis, Shah, Johnson, & Gupta, 2007). This increased transmission rate could be due to altered immunity of the placenta barrier or the HIV-infected trophoblasts in the placenta, which disturb the normal functions the placenta provides ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.3390/v4123531","ISBN":"1999-4915 (Electronic)\\r1999-4915 (Linking)","ISSN":"19994915","PMID":"23223189","abstract":"The worldwide prevalence of HCV infection is between 1% and 8% in pregnant women and between 0.05% and 5% in children. Yet the pathogenesis of hepatitis C during pregnancy and in the neonatal period remains poorly understood. Mother-to-child transmission (MTCT), a leading cause of pediatric HCV infection, takes place at a rate of <10%. Factors that increase the risk of MTCT include high maternal HCV viral load and coinfection with HIV-1 but, intriguingly, not breastfeeding and mode of delivery. Pharmacological prevention of MTCT is not possible at the present time because both pegylated interferon alfa and ribavirin are contraindicated for use in pregnancy and during the neonatal period. However, this may change with the recent introduction of direct acting antiviral agents. This review summarizes what is currently known about HCV infection during pregnancy and childhood. Particular emphasis is placed on how pregnancy-associated immune modulation may influence the progression of HCV disease and impact MTCT, and on the differential evolution of perinatally acquired HCV infection in children. Taken together, these developments provide insights into the pathogenesis of hepatitis C and may inform strategies to prevent the transmission of HCV from mother to child.","author":[{"dropping-particle":"","family":"Campion","given":"Armelle","non-dropping-particle":"Le","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Larouche","given":"Ariane","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fauteux-Daniel","given":"Sébastien","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Soudeyns","given":"Hugo","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Viruses","id":"ITEM-1","issued":{"date-parts":[["2012"]]},"title":"Pathogenesis of hepatitis C during pregnancy and childhood","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Le Campion, Larouche, Fauteux-Daniel, & Soudeyns, 2012)","plainTextFormattedCitation":"(Le Campion, Larouche, Fauteux-Daniel, & Soudeyns, 2012)","previouslyFormattedCitation":"(Le Campion, Larouche, Fauteux-Daniel, & Soudeyns, 2012)"},"properties":{"noteIndex":0},"schema":""}(Le Campion, Larouche, Fauteux-Daniel, & Soudeyns, 2012). Finally, limited data is available on the risk of MTCT through amniocentesis, but current results conclude there is no significant increase in vertical transmission ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"S0168-8278(99)80031-2 [pii]","ISBN":"0168-8278 (Print)\\r0168-8278 (Linking)","PMID":"10488698","abstract":"BACKGROUND/AIMS: Mother-to-infant transmission of hepatitis C virus (HCV) has been reported, but the transmission route is unknown. The aim of our study was to detect HCV RNA in amniotic fluid of pregnant women seropositive for HCV. METHODS: Twenty-two HCV seropositive women were included in the study (median age: 39 years). An amniocentesis was performed in all patients during the 4th month of pregnancy. Sixteen women also tested positive for HCV RNA in serum. The range of HCV RNA titers was 0.3 to 15.1x10(6) Eq/ml (Quantiplex HCV RNA 2.0 Assay, Chiron Diagnostics). Of these 16 viremic patients, four had an anterior placenta, ten had a posterior placenta and the position of the placenta was not determined in two cases. PCR (Amplicor HCV, Roche Diagnostics) was used to detect HCV RNA in the amniotic fluid. We also studied 11 HCV seronegative women as a control group. RESULTS: In the viremic group (n = 16), HCV RNA was detected once in amniotic fluid. The positive specimen was collected from a patient with an HCV RNA serum value equal to 1.1x10(6) Eq/ml. The placenta was in an anterior position. A PCR inhibitor was detected in one case. No HCV RNA was detected in the amniotic fluid of six seropositive non-viremic patients, nor in the control group. Serum HCV RNA was negative in the ten children tested. The woman whose amniotic fluid contained HCV RNA was the mother of one of them. CONCLUSIONS: HCV RNA detection in amniotic fluid is rarely positive. The anterior position of the placenta in the only positive detection cannot rule out contamination of the amniotic fluid during the transplacental amniocentesis.","author":[{"dropping-particle":"","family":"Delamare","given":"C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Carbonne","given":"B","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heim","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Berkane","given":"N","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Petit","given":"J C","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Uzan","given":"S","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grange","given":"J D","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"J Hepatol","id":"ITEM-1","issued":{"date-parts":[["1999"]]},"title":"Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Delamare et al., 1999)","plainTextFormattedCitation":"(Delamare et al., 1999)","previouslyFormattedCitation":"(Delamare et al., 1999)"},"properties":{"noteIndex":0},"schema":""}(Delamare et al., 1999). Table SEQ Table \* ARABIC 1: Summary of evidence: effect of mode of delivery, labor management strategies, or breastfeeding practices on risk for mother-to-child transmission of HCVADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.7326/0003-4819-158-2-201301150-00575","ISSN":"15393704","PMID":"23437438","abstract":"BACKGROUND: Mother-to-infant transmission is the leading cause of childhood hepatitis C virus (HCV) infection, with up to 4000 new cases each year in the United States. PURPOSE: To evaluate effects of mode of delivery, labor management strategies, and breastfeeding practices on risk for mother-to-infant transmission of HCV. DATA SOURCES: MEDLINE (1947 to May 2012), the Cochrane Library Database, clinical trial registries, and reference lists. STUDY SELECTION: Randomized trials and observational studies on mode of delivery, labor management strategies, and breastfeeding practices and risk for mother-to-infant transmission of HCV. DATA EXTRACTION: Investigators abstracted and reviewed study details and quality using predefined criteria. DATA SYNTHESIS: Eighteen observational studies evaluated the association between mode of delivery, labor management strategies, or breastfeeding practices and risk for mother-to-infant HCV transmission. Fourteen studies (2 good-quality, 4 fair-quality, and 8 poor-quality studies) found no clear association between mode of delivery (vaginal versus cesarean delivery) and risk for transmission. Two studies (1 good-quality and 1 poor-quality study) reported an association between prolonged duration of ruptured membranes and increased risk for transmission. Fourteen studies (2 good-quality, 2 fair-quality, and 10 poor-quality studies) found no association between breastfeeding and risk for transmission. LIMITATIONS: Only English-language articles were included. Studies were observational, and most had important methodological shortcomings, including failure to adjust for potential confounders and small sample sizes. CONCLUSION: No intervention has been clearly demonstrated to reduce the risk for mother-to-infant HCV transmission. Avoidance of breastfeeding does not seem to be indicated for reducing transmission risk. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.","author":[{"dropping-particle":"","family":"Cottrell","given":"Erika Barth","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chou","given":"Roger","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasson","given":"Ngoc","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rahman","given":"Basmah","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Guise","given":"Jeanne Marie","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Internal Medicine","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Reducing risk for mother-to-infant transmission of hepatitis C virus: A systematic review for the U.S. preventive services task force","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(Cottrell et al., 2013)","plainTextFormattedCitation":"(Cottrell et al., 2013)","previouslyFormattedCitation":"(Cottrell et al., 2013)"},"properties":{"noteIndex":0},"schema":""}(Cottrell et al., 2013)HCV REPORTING THROUGHOUT THE UNITED STATESReportable conditions vary by state throughout the United States. For HCV, only 5 states receive funding from the CDC for enhanced HCV surveillance (Colorado, Oregon, Minnesota, New York, and Connecticut), 29 states have some method of chronic HCV mandatory reporting, 8 states consider chronic HCV a reportable condition but have no method to manage this data, and 7 states do not consider HCV a reportable condition (Figure 3) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2012.05.002","ISBN":"1097-6833 (Electronic)\r0022-3476 (Linking)","ISSN":"00223476","PMID":"22765955","abstract":"Objective: To evaluate the rate of pediatric hepatitis C virus (HCV) case ascertainment relative to the estimated number of actual cases. Study design: Data from Florida and United States health departments were used to assess pediatric HCV case ascertainment rates in Florida and nationwide. The percentage of children infected with HCV from Miami-Dade County receiving medical care by a pediatric gastroenterologist was estimated based on data obtained from physician questionnaires. Results: From 2000 through 2009, 2007 children were identified as having positive HCV antibody tests in Florida, only 12% of the expected number (n = 12 155). An estimated 1.6% of the expected children with HCV who tested Ab-positive (37 of 1935) were actively followed by a pediatric gastroenterologist in Miami-Dade County, Florida. Across the United States, only 4.9% of the expected cases have been identified. Conclusions: The identification of children infected with HCV in the nation as a whole is grossly inadequate. Only a small fraction of cases are identified. In Florida, less than 2% of children identified receive treatment. Lack of identification and lack of treatment of children infected with HCV constitute critical public health problems. Strategies to increase awareness of HCV infection and to screen at-risk individuals could substantially improve morbidity and mortality while reducing health care costs. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Delgado-Borrego","given":"Aymin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Lesley","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hall","given":"Cyndena A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Negre","given":"Betania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jordan","given":"Sergio H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogrodowicz","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raza","given":"Roshan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ludwig","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Tracie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lipshultz","given":"Steven E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Raymond T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"915-921","publisher":"Mosby, Inc.","title":"Expected and actual case ascertainment and treatment rates for children infected with hepatitis c in florida and the united states: Epidemiologic evidence from statewide and nationwide surveys","type":"article-journal","volume":"161"},"uris":[""]}],"mendeley":{"formattedCitation":"(Delgado-Borrego et al., 2012)","plainTextFormattedCitation":"(Delgado-Borrego et al., 2012)","previouslyFormattedCitation":"(Delgado-Borrego et al., 2012)"},"properties":{"noteIndex":0},"schema":""}(Delgado-Borrego et al., 2012). In Pennsylvania, positive HCV test results are reportable conditions through the Pennsylvania Electronic Disease Reporting System, or PA-NEDSS. In Allegheny County specifically, heath department staff investigated cases in 2015 and 2016 to determine specific risk factors and provide educational materials to prevent further spread of the virus; therefore, Pennsylvania would be included within the group of 29 states with some method of chronic HCV mandatory reporting method. Figure SEQ Figure \* ARABIC 3: State requirements for reporting chronic cases of HCV infection. CDC, Centers for Disease Control and PreventionADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2012.05.002","ISBN":"1097-6833 (Electronic)\r0022-3476 (Linking)","ISSN":"00223476","PMID":"22765955","abstract":"Objective: To evaluate the rate of pediatric hepatitis C virus (HCV) case ascertainment relative to the estimated number of actual cases. Study design: Data from Florida and United States health departments were used to assess pediatric HCV case ascertainment rates in Florida and nationwide. The percentage of children infected with HCV from Miami-Dade County receiving medical care by a pediatric gastroenterologist was estimated based on data obtained from physician questionnaires. Results: From 2000 through 2009, 2007 children were identified as having positive HCV antibody tests in Florida, only 12% of the expected number (n = 12 155). An estimated 1.6% of the expected children with HCV who tested Ab-positive (37 of 1935) were actively followed by a pediatric gastroenterologist in Miami-Dade County, Florida. Across the United States, only 4.9% of the expected cases have been identified. Conclusions: The identification of children infected with HCV in the nation as a whole is grossly inadequate. Only a small fraction of cases are identified. In Florida, less than 2% of children identified receive treatment. Lack of identification and lack of treatment of children infected with HCV constitute critical public health problems. Strategies to increase awareness of HCV infection and to screen at-risk individuals could substantially improve morbidity and mortality while reducing health care costs. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Delgado-Borrego","given":"Aymin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Lesley","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hall","given":"Cyndena A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Negre","given":"Betania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jordan","given":"Sergio H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogrodowicz","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raza","given":"Roshan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ludwig","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Tracie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lipshultz","given":"Steven E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Raymond T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"915-921","publisher":"Mosby, Inc.","title":"Expected and actual case ascertainment and treatment rates for children infected with hepatitis c in florida and the united states: Epidemiologic evidence from statewide and nationwide surveys","type":"article-journal","volume":"161"},"uris":[""]}],"mendeley":{"formattedCitation":"(Delgado-Borrego et al., 2012)","plainTextFormattedCitation":"(Delgado-Borrego et al., 2012)","previouslyFormattedCitation":"(Delgado-Borrego et al., 2012)"},"properties":{"noteIndex":0},"schema":""}(Delgado-Borrego et al., 2012)CURRENT GUIDELINES FOR INFANT SCREENING “Current guidelines from the American Association for the Study of Liver Diseases (AASLD) and the North America Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASHGHAN) recommend that children born to HCV-positive women be tested for anti-HCV antibody after 18 months of age; screening before this age is unreliable due to the likely presence of maternal antibodies. Any positive antibody test should be followed by an HCV RNA test to con?rm that the child is infected. HCV RNA tests may also be performed after 2 months of age, with retesting after an additional 2 months, or performed once after 12 months of age” ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio et al., 2016)","plainTextFormattedCitation":"(Kuncio et al., 2016)","previouslyFormattedCitation":"(Kuncio et al., 2016)"},"properties":{"noteIndex":0},"schema":""}(Kuncio et al., 2016).POTENTIAL FOR UNDERREPORTING OF HCV— ADULTS AND CHILDRENMany recent studies have reported the likelihood of underreporting of HCV in many states, which results in subsequent lack of necessary follow-up treatment for these individuals who are infected with HCV. Delgado-Borrego and colleagues conducted a study to evaluate the accuracy of HCV reporting and subsequent treatment by analyzing expected vs. actual reported HCV cases in Florida and the United States as a whole. Florida was chosen for this study because the state requires reporting of all acute and chronic HCV cases to the Medical Emergency Relief International (MERLIN) database. Children ages 0-18 years and adults 19 years who tested positive for HCV antibodies (HCV-Ab) between January 1, 2000, and December 31, 2009, were selected for analysis. The authors assumed that the expected number of children younger than 19 years old who were positive for HCV-Ab in 2009 was 12,311 people, using the average NHANES III prevalence rate (0.3%) of HCV for children 6-12 years old (0.2%) and children 13-18 years old (0.4%) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"MJBA-410802 [pii]\\n10.1056/NEJM199908193410802","ISBN":"0028-4793 (Print)","ISSN":"0028-4793","PMID":"10451460","abstract":"BACKGROUND: Because many persons with chronic hepatitis C virus (HCV) infection are asymptomatic, population-based serologic studies are needed to estimate the prevalence of the infection and to develop and evaluate prevention efforts. METHODS: We performed tests for antibody to HCV (anti-HCV) on serum samples from 21,241 persons six years old or older who participated in the third National Health and Nutrition Examination Survey, conducted during 1988 through 1994. We determined the prevalence of HCV RNA by means of nucleic acid amplification and the genotype by means of sequencing. RESULTS: The overall prevalence of anti-HCV was 1.8 percent, corresponding to an estimated 3.9 million persons nationwide (95 percent confidence interval, 3.1 million to 4.8 million) with HCV infection. Sixty-five percent of the persons with HCV infection were 30 to 49 years old. Seventy-four percent were positive for HCV RNA, indicating that an estimated 2.7 million persons in the United States (95 percent confidence interval, 2.4 million to 3.0 million) were chronically infected, of whom 73.7 percent were infected with genotype 1 (56.7 percent with genotype 1a, and 17.0 percent with genotype 1b). Among subjects 17 to 59 years of age, the strongest factors independently associated with HCV infection were illegal drug use and high-risk sexual behavior. Other factors independently associated with infection included poverty, having had 12 or fewer years of education, and having been divorced or separated. Neither sex nor racial-ethnic group was independently associated with HCV infection. CONCLUSIONS: In the United States, about 2.7 million persons are chronically infected with HCV. People who use illegal drugs or engage in high-risk sexual behavior account for most persons with HCV infection.","author":[{"dropping-particle":"","family":"Alter","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kruszon-Moran","given":"D","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"V","family":"Nainan","given":"O","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McQuillan","given":"G M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gao","given":"F","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Moyer","given":"L A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaslow","given":"R A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Margolis","given":"H S","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"N Engl J Med","id":"ITEM-1","issued":{"date-parts":[["1999"]]},"title":"The prevalence of hepatitis C virus infection in the United States, 1988 through 1994","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Alter et al., 1999)","plainTextFormattedCitation":"(Alter et al., 1999)","previouslyFormattedCitation":"(Alter et al., 1999)"},"properties":{"noteIndex":0},"schema":""}(Alter et al., 1999). After adjusting for the children who had aged into adulthood by 2009, 1444 children had been reported between 2000 and 2009, resulting in an 11.7% ascertainment rate for child HCV-Ab cases in Florida in 2009. Using a 2.0% seroprevalence rate for adults, calculated from age-group specific NHANES data from 1999-2002 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"144/10/705 [pii]","ISBN":"1539-3704 (Electronic)\r0003-4819 (Linking)","ISSN":"1539-3704","PMID":"16702586","abstract":"BACKGROUND: Defining the primary characteristics of persons infected with hepatitis C virus (HCV) enables physicians to more easily identify persons who are most likely to benefit from testing for the disease. OBJECTIVE: To describe the HCV-infected population in the United States. DESIGN: Nationally representative household survey. SETTING: U.S. civilian, noninstitutionalized population. PARTICIPANTS: 15,079 participants in the National Health and Nutrition Examination Survey between 1999 and 2002. MEASUREMENTS: All participants provided medical histories, and those who were 20 to 59 years of age provided histories of drug use and sexual practices. Participants were tested for antibodies to HCV (anti-HCV) and HCV RNA, and their serum alanine aminotransferase (ALT) levels were measured. RESULTS: The prevalence of anti-HCV in the United States was 1.6% (95% CI, 1.3% to 1.9%), equating to an estimated 4.1 million (CI, 3.4 million to 4.9 million) anti-HCV-positive persons nationwide; 1.3% or 3.2 million (CI, 2.7 million to 3.9 million) persons had chronic HCV infection. Peak prevalence of anti-HCV (4.3%) was observed among persons 40 to 49 years of age. A total of 48.4% of anti-HCV-positive persons between 20 and 59 years of age reported a history of injection drug use, the strongest risk factor for HCV infection. Of all persons reporting such a history, 83.3% had not used injection drugs for at least 1 year before the survey. Other significant risk factors included 20 or more lifetime sex partners and blood transfusion before 1992. Abnormal serum ALT levels were found in 58.7% of HCV RNA-positive persons. Three characteristics (abnormal serum ALT level, any history of injection drug use, and history of blood transfusion before 1992) identified 85.1% of HCV RNA-positive participants between 20 and 59 years of age. LIMITATIONS: Incarcerated and homeless persons were not included in the survey. CONCLUSIONS: Many Americans are infected with HCV. Most were born between 1945 and 1964 and can be identified with current screening criteria. History of injection drug use is the strongest risk factor for infection.","author":[{"dropping-particle":"","family":"Armstrong","given":"G L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wasley","given":"A","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Simard","given":"E P","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"McQuillan","given":"G M","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuhnert","given":"W L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Alter","given":"M J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Ann Intern Med","id":"ITEM-1","issued":{"date-parts":[["2006"]]},"title":"The prevalence of hepatitis C virus infection in the United States, 1999 through 2002","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Armstrong et al., 2006)","plainTextFormattedCitation":"(Armstrong et al., 2006)"},"properties":{"noteIndex":0},"schema":""}(Armstrong et al., 2006), 166,857 of 288,685 expected HCV-Ab adults had been identified resulting in a 58% ascertainment rate of adult cases in 2009. To evaluate active treatment for infection in children, the researchers narrowed the pediatric population to Miami-Dade County, where the expected number of HCV-Ab children in 2009 was 1,935 children, and 440 cases were reported to MERLIN between 2000 and 2009. The researchers sent questionnaires to every pediatric gastroenterologist in that county requesting information regarding the number of children being treated for HCV infection in 2009 and the previous five years leading up to 2009. They received a 100% response rate where 31 children were reported for receiving treatment for HCV in 2009 and an additional 55 had been treated in the previous five years. Therefore, only 1.6% of the expected number of HCV-Ab children were being treated in 2009 (31/1935) and 2.8% (55/1935) between 2004-2009. For the nationwide study, the authors contacted each of the 50 state health department HCV coordinators to request the pediatric HCV-Ab case data between 2000 and 2009. Using the NHANES-based 0.3% prevalence rate of HCV in children 0-18 and unadjusted for children aging into adulthood during this time period, 19 states identified 0-20% of expected cases, one state identified 20-40%, one state identified 40-60%, and the remaining did not have sufficient data or did not respond to the survey. Overall, only 4.9% of expected cases had been identified nationwide. Kuncio and colleagues conducted a study to assess follow-up testing on children born to HCV-infected mothers in Philadelphia. The researchers matched the city’s electronic hepatitis registry to birth records from 2011-2013 to determine the number of children born to HCV-infected mothers during this time period. Following this initial match, the infants born to HCV-infected mothers were then matched to the same hepatitis registry to determine if these infants had received any HCV testing after 20 months of age, in accordance with current North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines that children born to HCV-infected mothers be tested for HCV-Ab after 18 months to allow for the clearance of maternal HCV antibodies. Following the first match, 568 infants were identified as being born to HCV-positive mothers between 2011 and 2013. Those infants who were adopted, died, or moved were excluded from the study because there would be no reliable record of their follow-up testing in the registry used in this study (31 infants). The remaining 537 infants were then matched to the Hepatitis registry to evaluate follow-up testing. Of the 537 HCV-exposed infants, only 84 children (16%) had been tested, four of which were considered to have confirmed perinatal HCV infection according to the case definition outlined in the study. The study concluded that 453 of the exposed infants had not been tested, resulting in the potential for 23 expected infants to have become chronically infected with HCV through perinatal transmission but not identified ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio et al., 2016)","plainTextFormattedCitation":"(Kuncio et al., 2016)","previouslyFormattedCitation":"(Kuncio et al., 2016)"},"properties":{"noteIndex":0},"schema":""}(Kuncio et al., 2016). This study uses a 5% HCV MTCT rate, but if the most common estimate of 6% perinatal HCV transmission rate were used in this analysis, this would result in an additional 6 expected infants to have acquired the virus for a total of 29 infants. VALIDITY OF BIRTH CERTIFICATE REPORTING— OREGON, 2015Between 2008 and 2016, total live births in Oregon declined while the number of infants born to HCV-positive mothers increased over time, from 2.9 per 1,000 live births in 2009 to 3.9 per 1,000 live births in 2014, a 33% increase (Figure 5). This trend was also observed nationally with rates of live births from HCV-infected mothers increasing 89% from 1.8 to 3.4 per 1,000 live births among reporting states between 2009-2014 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.15585/mmwr.mm6618a3","ISSN":"0149-2195","author":[{"dropping-particle":"","family":"Patrick","given":"Stephen W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bauer","given":"Audrey M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Timothy F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wester","given":"Carolyn","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"MMWR. Morbidity and Mortality Weekly Report","id":"ITEM-1","issue":"18","issued":{"date-parts":[["2017"]]},"page":"470-473","title":"Hepatitis C Virus Infection Among Women Giving Birth — Tennessee and United States, 2009–2014","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(Patrick, Bauer, Warren, Jones, & Wester, 2017)","plainTextFormattedCitation":"(Patrick, Bauer, Warren, Jones, & Wester, 2017)","previouslyFormattedCitation":"(Patrick, Bauer, Warren, Jones, & Wester, 2017)"},"properties":{"noteIndex":0},"schema":""}(Patrick, Bauer, Warren, Jones, & Wester, 2017). As previously described, studies suggest that exposed infants are not receiving adequate follow-up testing and treatment. During my internship at the Oregon Health Authority in the summer of 2017, I conducted a study to determine the accuracy of maternal HCV status on infants’ birth certificates in Oregon for 2015. The purpose of this study was to evaluate how accurate this reporting method is when compared to the state reportable conditions database, Oregon Public Health Epidemiology User System (ORHPEUS), in order to explain lack of follow-up care in exposed infants.Figure SEQ Figure \* ARABIC 4: Live births from HCV infected mothers versus total live births according to Oregon birth certificate data by birth yearMETHODSBirth certificate data contains a plethora of information, including parental information such as mother and father name, age, race, contact information, level of education, and insurance type, and information regarding the pregnancy process such as method of delivery, maternal morbidities, or birth risk factors. Maternal infectious diseases are also included, with HCV being one of the seven infectious diseases monitored through this reporting method. Utilizing Linkplus 2.0, a probabilistic record linkage program for registry database linkage and deduplication, all Oregon live birth records from 2015 were matched with the ORPHEUS database of HCV-positive women of childbearing age from 2001-2015 using the mother’s first and last name and date of birth for matching variables between the two datasets. The program-generated matches were manually reviewed by me and my preceptor to confirm their accuracy. These matches were then compared to the original 2015 birth certificate data to determine the number of HCV-positive women delivering infants according to the state reporting system but not reported on the infant’s birth certificate as HCV positive. RESULTSOf the 44,712 women who gave birth in 2015, maternal HCV infection was recorded on the birth certificates of 181 (0.4%) infants. Of these, 150 (82.9%) certificates were matched to women with a positive HCV laboratory result reported to the state (Acute and Communicable Disease Prevention, ACDP) and 31 (17.1%) of the 181 women identified as HCV-positive on birth certificates had not been reported to ACDP between 2001–2015 (Table 2). An additional 113 women with a positive HCV laboratory result reported to ACDP gave birth in 2015, but maternal HCV infection was not reported on their infant’s birth certificate. The linkage resulted in the identification of 263 women with HCV infection who gave birth in 2015, a 62% increase over the estimate of 181 women using birth certificates reporting method alone. Using an estimated 6% rate of perinatal HCV transmission, 18 of the 294 exposed infants would be expected to have acquired an HCV chronic infection. As of July 31, 2017 (at which time all children born in 2015 would have reached age 18 months, the recommended age for testing children born to HCV-infected mothers), ORPHEUS had recorded five positive HCV reports from infants born in 2015. Negative HCV tests are not reportable in Oregon, so it is unknown how many of the exposed infants were appropriately tested. However, the discrepancy between the number of reported positive results and the expected number based on estimates of perinatal transmission suggests that as many as 13 infants with HCV might not have been tested by age 18 months.Table SEQ Table \* ARABIC 2: Comparison of women identified with HCV infection on infant's birth certificates in 2015 with female HCV cases reported to the ACDP program- Oregon, 2001-2015Using Epi Info 7, a geospatial map showing the number of infants born to HCV-positive women per 1,000 live births (Figure 6) was constructed using the current address listed on the infant’s birth certificate from all live births in 2015, now including the additional 113 HCV-positive women identified by ACDP, to identify the counties with the highest rates of maternal HCV infection. When compared to an Oregon opioid overdose map during the same time period (Figure 7), many similarities appear between the two maps suggesting the current opioid epidemic is not only affecting those who are addicted to opioids, but also likely harming future generations as well. The large discrepancy between these two maps in Malheur County may be due to the small population of this county. Figure SEQ Figure \* ARABIC 5: Number of infants born to HCV infected women per 1,000 live births by County – 2015Figure SEQ Figure \* ARABIC 6: Oregon Opioid Overdose Deaths by County - 2011-2015ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2017","8","16"]]},"author":[{"dropping-particle":"","family":"Oregon Health Authority Opioid Overdose and Misuse: Public Health Division","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Prescribing and Overdose Data for Oregon","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(Oregon Health Authority Opioid Overdose and Misuse: Public Health Division, n.d.)","plainTextFormattedCitation":"(Oregon Health Authority Opioid Overdose and Misuse: Public Health Division, n.d.)","previouslyFormattedCitation":"(Oregon Health Authority Opioid Overdose and Misuse: Public Health Division, n.d.)"},"properties":{"noteIndex":0},"schema":""}(Oregon Health Authority Opioid Overdose and Misuse: Public Health Division, n.d.)DISCUSSIONCurrently there is no treatment recommended for HCV-positive pregnant women due to lack of clinical trials in pregnancy for fear of teratogenic effects of the medication used to treat non-pregnant HCV-positive adults. Ribavirin, specifically, has been shown to cause embryocidal and teratogenic effects in many animal studies. Furthermore, drug companies strongly advise against conception before 6 months post-treatment with Ribavirin in both the female or male partner due to the risk of drug exposure to the fetus ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"URL":"","accessed":{"date-parts":[["2018","6","23"]]},"author":[{"dropping-particle":"","family":"US National Library of Medicine","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-1","issued":{"date-parts":[["0"]]},"title":"Drug label information: Ribasphere-ribavirin tablet.","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(US National Library of Medicine, n.d.)","manualFormatting":"(US National Library of Medicine, 2015)","plainTextFormattedCitation":"(US National Library of Medicine, n.d.)","previouslyFormattedCitation":"(US National Library of Medicine, n.d.)"},"properties":{"noteIndex":0},"schema":""}(US National Library of Medicine, 2015). Since pregnant women cannot be treated for HCV infection, accurate reporting and follow-up for perinatal HCV are imperative for infants exposed to the virus to receive the medical care they require. As observed in the Florida, Philadelphia, and Oregon studies, there appears to be a significant deficiency in pediatric HCV exposure follow-up testing and reporting. Delgado and colleagues concluded only 11.7% of expected pediatric HCV-Ab cases were reported in Florida in 2009, a state that requires the reporting of both acute and chronic HCV infections, and only 1.6% of the expected children who developed chronic HCV in Miami-Dade County were actually being treated for HCV infection in 2009. In contrast, 58% of expected HCV-Ab-positive adults were reported in Florida during this time, illustrating a significant gap between case ascertainment of children and adults. In the United States as a whole, the study determined only 4.9% of expected pediatric cases were identified ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.jpeds.2012.05.002","ISBN":"1097-6833 (Electronic)\r0022-3476 (Linking)","ISSN":"00223476","PMID":"22765955","abstract":"Objective: To evaluate the rate of pediatric hepatitis C virus (HCV) case ascertainment relative to the estimated number of actual cases. Study design: Data from Florida and United States health departments were used to assess pediatric HCV case ascertainment rates in Florida and nationwide. The percentage of children infected with HCV from Miami-Dade County receiving medical care by a pediatric gastroenterologist was estimated based on data obtained from physician questionnaires. Results: From 2000 through 2009, 2007 children were identified as having positive HCV antibody tests in Florida, only 12% of the expected number (n = 12 155). An estimated 1.6% of the expected children with HCV who tested Ab-positive (37 of 1935) were actively followed by a pediatric gastroenterologist in Miami-Dade County, Florida. Across the United States, only 4.9% of the expected cases have been identified. Conclusions: The identification of children infected with HCV in the nation as a whole is grossly inadequate. Only a small fraction of cases are identified. In Florida, less than 2% of children identified receive treatment. Lack of identification and lack of treatment of children infected with HCV constitute critical public health problems. Strategies to increase awareness of HCV infection and to screen at-risk individuals could substantially improve morbidity and mortality while reducing health care costs. Copyright ? 2012 Mosby Inc.","author":[{"dropping-particle":"","family":"Delgado-Borrego","given":"Aymin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Smith","given":"Lesley","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hall","given":"Cyndena A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Negre","given":"Betania","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jordan","given":"Sergio H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ogrodowicz","given":"Matthew","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Raza","given":"Roshan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Ludwig","given":"David A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miller","given":"Tracie","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lipshultz","given":"Steven E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Raymond T.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatrics","id":"ITEM-1","issue":"5","issued":{"date-parts":[["2012"]]},"page":"915-921","publisher":"Mosby, Inc.","title":"Expected and actual case ascertainment and treatment rates for children infected with hepatitis c in florida and the united states: Epidemiologic evidence from statewide and nationwide surveys","type":"article-journal","volume":"161"},"uris":[""]}],"mendeley":{"formattedCitation":"(Delgado-Borrego et al., 2012)","plainTextFormattedCitation":"(Delgado-Borrego et al., 2012)","previouslyFormattedCitation":"(Delgado-Borrego et al., 2012)"},"properties":{"noteIndex":0},"schema":""}(Delgado-Borrego et al., 2012). Kuncio and colleagues demonstrated how maternal HCV is very prevalent (1% between 2011-2013) in Philadelphia and how 84% of these children exposed to HCV are not being adequately tested at 18 months of age ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio et al., 2016)","plainTextFormattedCitation":"(Kuncio et al., 2016)","previouslyFormattedCitation":"(Kuncio et al., 2016)"},"properties":{"noteIndex":0},"schema":""}(Kuncio et al., 2016). Finally, in Oregon, the birth certificate reporting method proved to be inaccurate as there were 62% more HCV-exposed infants identified after matching the birth certificate data for 2015 with the state reportable conditions database. However, the Oregon study did rely explicitly on reporting so there may also be some missing data that was not reported by either method. The current recommended treatments available for HCV in children are direct acting antivirals (DAA), which have been approved for children 12 and older with genotypes 2 or 3 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/hep.29278","ISSN":"15273350","PMID":"28543053","abstract":"Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 ( NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balistreri","given":"William F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Chuan Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hardikar","given":"Winita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersey","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Massetto","given":"Benedetta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanwar","given":"Bittoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brainard","given":"Diana M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svarovskaia","given":"Evguenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirby","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnon","given":"Ronen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Karen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Kathleen B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"URL":"","accessed":{"date-parts":[["2018","6","24"]]},"author":[{"dropping-particle":"","family":"US Food & Drug Administration","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"id":"ITEM-2","issued":{"date-parts":[["0"]]},"title":"Highlights of prescribing information for SOVALDI? (sofosbuvir) tablets, for oral use.","type":"webpage"},"uris":[""]}],"mendeley":{"formattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)","manualFormatting":"(US Food & Drug Administration, 2017; Wirth et al., 2017)","plainTextFormattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)","previouslyFormattedCitation":"(US Food & Drug Administration, n.d.; Wirth et al., 2017)"},"properties":{"noteIndex":0},"schema":""}(US Food & Drug Administration, 2017; Wirth et al., 2017). Interferon treatments can cause adverse systemic complications in children such as flu-like illnesses and growth interruption ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sokal","given":"Etienne M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Gastroenterology &Amp; Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017","7","26"]]},"page":"452","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Direct-acting antivirals for paediatric HCV: we got there","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"(Sokal, 2017)","plainTextFormattedCitation":"(Sokal, 2017)","previouslyFormattedCitation":"(Sokal, 2017)"},"properties":{"noteIndex":0},"schema":""}(Sokal, 2017). Clinical trials are currently in process to develop FDA-approved treatments for HCV-infected children ages 3-11 with genotypes 1-6, some with anticipated study completion dates in 2018 (Table 3) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sokal","given":"Etienne M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Gastroenterology &Amp; Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017","7","26"]]},"page":"452","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Direct-acting antivirals for paediatric HCV: we got there","type":"article-journal","volume":"14"},"uris":[""]},{"id":"ITEM-2","itemData":{"abstract":" is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. Learn more about clinical studies and about this site, including relevant history, policies, and laws.","author":[{"dropping-particle":"","family":"National Institute of Health","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"U.S. National Library of Medicine","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"title":"Home - ","type":"article"},"uris":[""]}],"mendeley":{"formattedCitation":"(National Institute of Health, 2017; Sokal, 2017)","plainTextFormattedCitation":"(National Institute of Health, 2017; Sokal, 2017)","previouslyFormattedCitation":"(National Institute of Health, 2017; Sokal, 2017)"},"properties":{"noteIndex":0},"schema":""}(National Institute of Health, 2017; Sokal, 2017). With these new treatments on the horizon, accuracy of reporting of HCV-exposed children is of utmost importance in order to link them to specialty care for testing and treatment to prevent the chronic devastating effects of HCV, which include fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Sokal also emphasizes the importance of treatment and cure before these children are of childbearing age in the on-going effort to eradicate viral hepatitis ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sokal","given":"Etienne M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Gastroenterology &Amp; Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017","7","26"]]},"page":"452","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Direct-acting antivirals for paediatric HCV: we got there","type":"article-journal","volume":"14"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"ISBN 978-92-4-156545-5","ISBN":"9789241565455","abstract":"In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis 2016–2021. The GHSS calls for the elimination of viral hepatitis as a public health threat by 2030 (reducing new infections by 90% and mortality by 65%). This WHO Global hepatitis report describes, for the fi rst time, the global and regional estimates on viral hepatitis in 2015, setting the baseline for tracking progress in implementing the new global strategy. The report focuses on hepatitis B and C, which are responsible for 96% of all hepatitis mortality. It presents data along the fi ve strategic directions (strategic information, interventions, equity, fi nancing and innovation) – key pillars of the GHSS to facilitate monitoring of progress in countries, regions and globally, and to measure the impact of interventions on reducing new infections and saving lives between 2015 and 2030.","author":[{"dropping-particle":"","family":"World Health Organization","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Who","id":"ITEM-2","issued":{"date-parts":[["2017"]]},"number-of-pages":"62","title":"Global hepatitis report, 2017","type":"book"},"uris":[""]}],"mendeley":{"formattedCitation":"(Sokal, 2017; World Health Organization, 2017)","plainTextFormattedCitation":"(Sokal, 2017; World Health Organization, 2017)","previouslyFormattedCitation":"(Sokal, 2017; World Health Organization, 2017)"},"properties":{"noteIndex":0},"schema":""}(Sokal, 2017; World Health Organization, 2017).Table SEQ Table \* ARABIC 3: Ongoing pediatric clinical trials with direct-acting antiviral agentsADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"","family":"Sokal","given":"Etienne M","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Reviews Gastroenterology &Amp; Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017","7","26"]]},"page":"452","publisher":"Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.","title":"Direct-acting antivirals for paediatric HCV: we got there","type":"article-journal","volume":"14"},"uris":[""]}],"mendeley":{"formattedCitation":"(Sokal, 2017)","plainTextFormattedCitation":"(Sokal, 2017)","previouslyFormattedCitation":"(Sokal, 2017)"},"properties":{"noteIndex":0},"schema":""}(Sokal, 2017) The most recent treatments for children 12 years old have a 12-week sustained virologic response (SVR) rates of 44-59% for genotype 1 (pegylated interferon α-2a or α-2b plus ribavirin treatment) and 93-100% (DAA treatment) for genotypes 2 and 3 ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/hep.29278","ISSN":"15273350","PMID":"28543053","abstract":"Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 ( NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balistreri","given":"William F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Chuan Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hardikar","given":"Winita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersey","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Massetto","given":"Benedetta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanwar","given":"Bittoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brainard","given":"Diana M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svarovskaia","given":"Evguenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirby","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnon","given":"Ronen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Karen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Kathleen B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.3748/wjg.v18.i2.99","ISSN":"10079327","PMID":"22253515","abstract":"Vertical transmission has become the most common mode of transmission of hepatitis C virus (HCV) in children. The rate of perinatal transmission from an HCV-infected mother to her child ranges from 2% to 5% and the prevalence of HCV in children in developed countries ranges between 0.1% and 0.4%. Spontaneous viral clearance seems to be dependent on the genotype and has been reported between 2.4%-25%. For chronically infected patients, treatment with recombinant polyethylene glycol (PEG)-interferon α-2b and daily ribavirin has now been approved as standard treatment for children 2-17 years of age. In five large prospective studies, a total of 318 children and adolescents aged 3-17 years were treated either with subcutaneous PEG-interferon α-2b at a dose of 1-1.5 μg/kg or 60 μg/m? once a week in combination with oral ribavirin (15 mg/kg per day) or PEG-interferon α-2a with ribavirin. Subjects with genotype 1 and 4 received the medication for 48 wk and individuals with genotype 2 and 3 mainly for 24 wk. Overall sustained viral response (SVR) was achieved in 193/318 (60.7%) of treated patients. Stratified for genotype; 120/234 (51%) with genotype 1, 68/73 (93%) with genotype 2/3, and 6/11 (55%) with genotype 4 showed SVR. Relapse rate was between 7.7% and 17%. Overall, treatment was well tolerated; however, notable side effects were present in approximately 20%. According to recent experiences in the treatment of chronic hepatitis C in children and adolescents, a combination of PEG-interferon α with ribavirin has been found to be well tolerated and highly efficacious, particularly in individuals with genotype 2/3. Thus, this treatment can be recommended as standard of care until more effective treatment options will become available for genotype 1 patients.","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Journal of Gastroenterology","id":"ITEM-2","issued":{"date-parts":[["2012"]]},"title":"Current treatment options and response rates in children with chronic hepatitis C","type":"article-magazine"},"uris":[""]},{"id":"ITEM-3","itemData":{"DOI":"10.1093/cid/cis1031","ISBN":"1537-6591 (Electronic)\\r1058-4838 (Linking)","ISSN":"1537-6591","PMID":"23243171","abstract":"BACKGROUND: A systematic review and meta-analysis were conducted to examine the efficacy and safety of pegylated interferon (peg-IFN) alfa-2a and peg-IFN alfa-2b plus ribavirin (RBV) in children and adolescents with chronic hepatitis C virus (HCV). METHODS: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched. Clinical trials examining peg-IFN alfa-2a or peg-IFN alfa-2b plus RBV among persons ages 3-18 years with HCV were included. Data were abstracted for complete early virologic response (EVR), sustained virologic response (SVR), relapse, treatment discontinuations, hematologic and dermatologic adverse events, and growth inhibition. RESULTS: Eight trials met the inclusion criteria. Results indicate that 70% of subjects (95% confidence interval [CI], 58%-81%) achieved EVR, and 58% (95% CI, 53%-64%) achieved SVR. EVR and SVR were higher for those with HCV genotypes 2/3 than 1/4. Discontinuation due to adverse events and discontinuation due to viral breakthrough were each 4%, discontinuation due to a lack of response was 15%, and relapse was 7%. Anemia, neutropenia, leukopenia, and thrombcytopenia were 11%, 32%, 52%, and 5%, respectively. Alopecia, injection site erythema, and pruritus were 13%, 27%, and 10%, respectively. Small growth inhibitions were observed during treatment. CONCLUSION: The results of this meta-analysis indicate that peg-IFN/RBV combination treatment is effective and safe in treating children and adolescents with HCV.","author":[{"dropping-particle":"","family":"Druyts","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thorlund","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Ping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanters","given":"Steve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yaya","given":"Sanni","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Curtis L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mills","given":"Edward J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","id":"ITEM-3","issued":{"date-parts":[["2013"]]},"title":"Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis.","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Druyts et al., 2013; Wirth, 2012; Wirth et al., 2017)","plainTextFormattedCitation":"(Druyts et al., 2013; Wirth, 2012; Wirth et al., 2017)","previouslyFormattedCitation":"(Druyts et al., 2013; Wirth, 2012; Wirth et al., 2017)"},"properties":{"noteIndex":0},"schema":""}(Druyts et al., 2013; Wirth, 2012; Wirth et al., 2017). With respect to the Florida study, 10,867 expected HCV-Ab positive children less than 19 years old were not identified in 2009. Using the previously listed prevalence rates of genotypes 1 through 3 in the United States, 75%, 13.5%, and 5.5% respectively, if 80% of positive HCV-Ab tests resulted in chronic infection an estimated 6,521 children would have acquired genotype 1 and 1,652 children would possess genotypes 2 or 3. With the current SVR rates, 5,500 children would be cured of their infection if the estimated appropriate treatment were in effect in Florida alone. Early detection of HCV infection in children is important because treatments are generally more successful in children than adults ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/cis1031","ISBN":"1537-6591 (Electronic)\\r1058-4838 (Linking)","ISSN":"1537-6591","PMID":"23243171","abstract":"BACKGROUND: A systematic review and meta-analysis were conducted to examine the efficacy and safety of pegylated interferon (peg-IFN) alfa-2a and peg-IFN alfa-2b plus ribavirin (RBV) in children and adolescents with chronic hepatitis C virus (HCV). METHODS: Medline, Embase, and Cochrane Central Register of Controlled Trials were searched. Clinical trials examining peg-IFN alfa-2a or peg-IFN alfa-2b plus RBV among persons ages 3-18 years with HCV were included. Data were abstracted for complete early virologic response (EVR), sustained virologic response (SVR), relapse, treatment discontinuations, hematologic and dermatologic adverse events, and growth inhibition. RESULTS: Eight trials met the inclusion criteria. Results indicate that 70% of subjects (95% confidence interval [CI], 58%-81%) achieved EVR, and 58% (95% CI, 53%-64%) achieved SVR. EVR and SVR were higher for those with HCV genotypes 2/3 than 1/4. Discontinuation due to adverse events and discontinuation due to viral breakthrough were each 4%, discontinuation due to a lack of response was 15%, and relapse was 7%. Anemia, neutropenia, leukopenia, and thrombcytopenia were 11%, 32%, 52%, and 5%, respectively. Alopecia, injection site erythema, and pruritus were 13%, 27%, and 10%, respectively. Small growth inhibitions were observed during treatment. CONCLUSION: The results of this meta-analysis indicate that peg-IFN/RBV combination treatment is effective and safe in treating children and adolescents with HCV.","author":[{"dropping-particle":"","family":"Druyts","given":"Eric","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thorlund","given":"Kristian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wu","given":"Ping","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanters","given":"Steve","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Yaya","given":"Sanni","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cooper","given":"Curtis L","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mills","given":"Edward J","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","id":"ITEM-1","issued":{"date-parts":[["2013"]]},"title":"Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis.","type":"article-journal"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.3748/wjg.v18.i2.99","ISSN":"10079327","PMID":"22253515","abstract":"Vertical transmission has become the most common mode of transmission of hepatitis C virus (HCV) in children. The rate of perinatal transmission from an HCV-infected mother to her child ranges from 2% to 5% and the prevalence of HCV in children in developed countries ranges between 0.1% and 0.4%. Spontaneous viral clearance seems to be dependent on the genotype and has been reported between 2.4%-25%. For chronically infected patients, treatment with recombinant polyethylene glycol (PEG)-interferon α-2b and daily ribavirin has now been approved as standard treatment for children 2-17 years of age. In five large prospective studies, a total of 318 children and adolescents aged 3-17 years were treated either with subcutaneous PEG-interferon α-2b at a dose of 1-1.5 μg/kg or 60 μg/m? once a week in combination with oral ribavirin (15 mg/kg per day) or PEG-interferon α-2a with ribavirin. Subjects with genotype 1 and 4 received the medication for 48 wk and individuals with genotype 2 and 3 mainly for 24 wk. Overall sustained viral response (SVR) was achieved in 193/318 (60.7%) of treated patients. Stratified for genotype; 120/234 (51%) with genotype 1, 68/73 (93%) with genotype 2/3, and 6/11 (55%) with genotype 4 showed SVR. Relapse rate was between 7.7% and 17%. Overall, treatment was well tolerated; however, notable side effects were present in approximately 20%. According to recent experiences in the treatment of chronic hepatitis C in children and adolescents, a combination of PEG-interferon α with ribavirin has been found to be well tolerated and highly efficacious, particularly in individuals with genotype 2/3. Thus, this treatment can be recommended as standard of care until more effective treatment options will become available for genotype 1 patients.","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"World Journal of Gastroenterology","id":"ITEM-2","issued":{"date-parts":[["2012"]]},"title":"Current treatment options and response rates in children with chronic hepatitis C","type":"article-magazine"},"uris":[""]}],"mendeley":{"formattedCitation":"(Druyts et al., 2013; Wirth, 2012)","plainTextFormattedCitation":"(Druyts et al., 2013; Wirth, 2012)","previouslyFormattedCitation":"(Druyts et al., 2013; Wirth, 2012)"},"properties":{"noteIndex":0},"schema":""}(Druyts et al., 2013; Wirth, 2012). In addition, because HCV is a chronic disease, infections in children allow the virus more time to cause detrimental damage to the liver. While there are other barriers to successful treatment of patients with HCV, the most important barriers are lack of testing and referral ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/jac/dkq157","ISBN":"1734936894","ISSN":"1460-2091","PMID":"20460398","abstract":"Despite the long-term morbidity associated with hepatitis C and the availability of effective treatment, fewer than a quarter of infected individuals are treated with antiviral therapy. While this is partly related to inherent limitations of currently available medications and the underlying patient population, numerous health system barriers also exist. Fewer than half of chronic hepatitis C infections are diagnosed, relatively few are referred for treatment, and misperceptions about the disease and its treatment abound amongst patients and physicians alike. This article will discuss patient and physician factors that contribute to the undertreatment of chronic hepatitis C.","author":[{"dropping-particle":"","family":"Volk","given":"Michael L","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"The Journal of antimicrobial chemotherapy","id":"ITEM-1","issued":{"date-parts":[["2010"]]},"title":"Antiviral therapy for hepatitis C: why are so few patients being treated?","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Volk, 2010)","plainTextFormattedCitation":"(Volk, 2010)","previouslyFormattedCitation":"(Volk, 2010)"},"properties":{"noteIndex":0},"schema":""}(Volk, 2010), particularly in pediatrics, as was demonstrated in the Delgado-Borrego study. A potential reason for this deficiency in reporting, testing, and subsequent treatment is the lack of universal screening for HCV in pregnant women; risk factor-based screening leaves room for potentially significant error if women do not communicate their risk factors to their doctors because, for example, they are embarrassed to disclose IV drug usage or do not understand the severity of the disease. Since HCV has been routinely screened for in blood products since 1992, the most common route of transmission for HCV-infected children is vertical transmission. In Wirth’s recent study of DAA treatment for younger children chronically infected with HCV, 73% of the study population had been infected by vertical transmission ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1002/hep.29278","ISSN":"15273350","PMID":"28543053","abstract":"Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 ( NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).","author":[{"dropping-particle":"","family":"Wirth","given":"Stefan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jonas","given":"Maureen M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Balistreri","given":"William F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Chuan Hao","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hardikar","given":"Winita","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kersey","given":"Kathryn","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Massetto","given":"Benedetta","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kanwar","given":"Bittoo","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Brainard","given":"Diana M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shao","given":"Jiang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Svarovskaia","given":"Evguenia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kirby","given":"Brian","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Arnon","given":"Ronen","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Murray","given":"Karen F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Kathleen B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Hepatology","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"title":"Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"(Wirth et al., 2017)","plainTextFormattedCitation":"(Wirth et al., 2017)","previouslyFormattedCitation":"(Wirth et al., 2017)"},"properties":{"noteIndex":0},"schema":""}(Wirth et al., 2017). Therefore, screening women of childbearing age is being recommended by international organizations including the WHO and the European Association for the Study of the Liver (EASL) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"ISBN 978-92-4-156545-5","ISBN":"9789241565455","abstract":"In May 2016, the World Health Assembly endorsed the Global Health Sector Strategy (GHSS) on viral hepatitis 2016–2021. The GHSS calls for the elimination of viral hepatitis as a public health threat by 2030 (reducing new infections by 90% and mortality by 65%). This WHO Global hepatitis report describes, for the fi rst time, the global and regional estimates on viral hepatitis in 2015, setting the baseline for tracking progress in implementing the new global strategy. The report focuses on hepatitis B and C, which are responsible for 96% of all hepatitis mortality. It presents data along the fi ve strategic directions (strategic information, interventions, equity, fi nancing and innovation) – key pillars of the GHSS to facilitate monitoring of progress in countries, regions and globally, and to measure the impact of interventions on reducing new infections and saving lives between 2015 and 2030.","author":[{"dropping-particle":"","family":"World Health Organization","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Who","id":"ITEM-1","issued":{"date-parts":[["2017"]]},"number-of-pages":"62","title":"Global hepatitis report, 2017","type":"book"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1016/j.jhep.2016.09.001","ISBN":"0168-8278","ISSN":"16000641","PMID":"27667367","author":[{"dropping-particle":"","family":"European Association for the Study of the Liver","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Hepatology","id":"ITEM-2","issue":"1","issued":{"date-parts":[["2017"]]},"page":"153-194","publisher":"European Association for the Study of the Liver","title":"EASL Recommendations on Treatment of Hepatitis C 2016","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(European Association for the Study of the Liver, 2017; World Health Organization, 2017)","plainTextFormattedCitation":"(European Association for the Study of the Liver, 2017; World Health Organization, 2017)","previouslyFormattedCitation":"(European Association for the Study of the Liver, 2017; World Health Organization, 2017)"},"properties":{"noteIndex":0},"schema":""}(European Association for the Study of the Liver, 2017; World Health Organization, 2017). However, current cost-effectiveness studies in the United States still recommend against universal screening over risk-factor based screening ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ajog.2004.10.600","ISBN":"0002-9378 (Print)\\r0002-9378 (Linking)","ISSN":"00029378","PMID":"15846195","abstract":"Objective: The purpose of this study was to determine whether routine hepatitis C virus screening in pregnancy is cost-effective. Study design: A decision tree with Markov analysis was developed to compare 3 approaches to asymptomatic hepatitis C virus infection in low-risk pregnant women: (1) no hepatitis C virus screening, (2) hepatitis C virus screening and subsequent treatment for progressive disease, and (3) hepatitis C virus screening, subsequent treatment for progressive disease, and elective cesarean delivery to avert perinatal transmission. Lifetime costs and quality-adjusted life years were evaluated for mother and child. Results: In our base case, hepatitis C virus screening and subsequent treatment of progressive disease was dominated (more costly and less effective) by no screening, with an incremental cost of $108 and a decreased incremental effectiveness of 0.00011 quality-adjusted life years. When compared with no screening, the marginal cost and effectiveness of screening, treatment, and cesarean delivery was $117 and 0.00010 quality-adjusted life years, respectively, which yields a cost-effectiveness ratio of $1,170,000 per quality-adjusted life year. Conclusion: The screening of asymptomatic pregnant women for hepatitis C virus infection is not cost-effective. ? 2005 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Plunkett","given":"Beth A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grobman","given":"William A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Obstetrics and Gynecology","id":"ITEM-1","issued":{"date-parts":[["2005"]]},"title":"Routine hepatitis C virus screening in pregnancy: A cost-effectiveness analysis","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(Plunkett & Grobman, 2005)","plainTextFormattedCitation":"(Plunkett & Grobman, 2005)","previouslyFormattedCitation":"(Plunkett & Grobman, 2005)"},"properties":{"noteIndex":0},"schema":""}(Plunkett & Grobman, 2005). Additional reasons for this testing and reporting deficiency include poor communication between the patient’s obstetrician and pediatrician and inaccurate electronic reporting methods. Communication between doctors is imperative to ensure children are appropriately tested. The pediatrician may be unaware of the mother’s status and the child may never be tested for infection ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1097/MPG.0b013e318258328d","ISSN":"02772116","PMID":"22487950","abstract":"Hepatitis C virus (HCV) is an RNA virus that affects >180 million individuals worldwide with a high propensity for chronic infection. Children with HCV infection differ from adults in several ways including some modes of transmission, rates of clearance, progression of fibrosis, and the duration of potential chronic infection when acquired at birth. Since the discovery of HCV in 1989, there have been significant advances in the understanding of the virology and natural history of chronic HCV infection in children. In addition, there are now several treatment options for children with chronic hepatitis C infection and many new therapies on the horizon. As a consequence, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition brought together experts in pediatric hepatology to review the available data in children and provide clinicians with approaches to the diagnosis, management, and prevention of HCV infection in children and adolescents. The guideline details the epidemiology and natural history of HCV infection in children, the diagnostic workup, monitoring and treatment of disease, and provides an update on future treatment options and areas of research.","author":[{"dropping-particle":"","family":"Mack","given":"Cara L.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gonzalez-Peralta","given":"Regino P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gupta","given":"Nitika","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Leung","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Narkewicz","given":"Michael R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Roberts","given":"Eve A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Rosenthal","given":"Philip","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Schwarz","given":"Kathleen B.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Pediatric Gastroenterology and Nutrition","id":"ITEM-1","issue":"6","issued":{"date-parts":[["2012"]]},"page":"838-855","title":"NASPGHAN Practice guidelines: Diagnosis and management of hepatitis c infection in infants, children, and adolescents","type":"article-journal","volume":"54"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-2","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio et al., 2016; Mack et al., 2012)","plainTextFormattedCitation":"(Kuncio et al., 2016; Mack et al., 2012)","previouslyFormattedCitation":"(Kuncio et al., 2016; Mack et al., 2012)"},"properties":{"noteIndex":0},"schema":""}(Kuncio et al., 2016; Mack et al., 2012). In addition, as was observed in the Oregon study, current electronic reporting methods are inaccurate therefore increasing the potential for gaps in follow-up medical care. The birth certificate reporting method in Oregon did not identify 113 HCV-positive women who gave birth in 2015; these maternal HCV infections were identified after matching the birth certificate data for 2015 with the state reportable conditions database prior to 2015. Interventions targeting these barriers would be beneficial to improving reporting rates of maternal HCV infection and infant exposure. Improved communication between doctors and patients on the severity of HCV, the virus-specific risk factors, and its risk for vertical transmission is essential to educate women who are at risk for HCV to encourage mother/infant testing and open communication with their doctor. While screening for infection before pregnancy is ideal, universal screening during pregnancy allows for identification of patients who may not usually seek medical care otherwise ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/cid/ciw026","ISSN":"15376591","PMID":"26797211","abstract":"BACKGROUND Vertical transmission of hepatitis C virus (HCV) is the most common route of pediatric HCV infection. Approximately 5% of children born to HCV-infected mothers develop chronic infection. Recommendations employ risk-based HCV testing of pregnant women, and screening children at a young age. This study assesses testing rates of children born to mothers tested HCV-positive in a major US city with a high burden of HCV infection. METHODS HCV surveillance data reported to the Philadelphia Department of Public Health are housed in the Hepatitis Registry. Additional tests, including negative results, were retrospectively collected. HCV data were matched with 2011-2013 birth certificates of children aged ≥20 months to identify mothers tested HCV-positive and screened children. The observed perinatal HCV seropositivity rate was compared to the expected rate (5%). RESULTS A total of 8119 females aged 12-54 years tested HCV-positive and in the Hepatitis Registry. Of these, 500 (5%) had delivered ≥1 child, accounting for 537 (1%) of the 55 623 children born in Philadelphia during the study period. Eighty-four (16%) of these children had HCV testing; 4 (1% of the total) were confirmed cases. Twenty-three additional children are expected to have chronic HCV infection, but were not identified by 20 months of age. CONCLUSIONS These findings illustrate that a significant number of women giving birth in Philadelphia test positive for HCV and that most of their at-risk children remain untested. To successfully identify all HCV-infected children and integrate them into HCV-specific care, practices for HCV screening of pregnant women and their children should be improved.","author":[{"dropping-particle":"","family":"Kuncio","given":"Danica E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Newbern","given":"E. Claire","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Johnson","given":"Caroline C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Viner","given":"Kendra M.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Clinical Infectious Diseases","id":"ITEM-1","issue":"8","issued":{"date-parts":[["2016"]]},"page":"980-985","title":"Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women","type":"article-journal","volume":"62"},"uris":[""]}],"mendeley":{"formattedCitation":"(Kuncio et al., 2016)","plainTextFormattedCitation":"(Kuncio et al., 2016)","previouslyFormattedCitation":"(Kuncio et al., 2016)"},"properties":{"noteIndex":0},"schema":""}(Kuncio et al., 2016). Even though current analysis concludes universal screening is not cost-effective ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ajog.2004.10.600","ISBN":"0002-9378 (Print)\\r0002-9378 (Linking)","ISSN":"00029378","PMID":"15846195","abstract":"Objective: The purpose of this study was to determine whether routine hepatitis C virus screening in pregnancy is cost-effective. Study design: A decision tree with Markov analysis was developed to compare 3 approaches to asymptomatic hepatitis C virus infection in low-risk pregnant women: (1) no hepatitis C virus screening, (2) hepatitis C virus screening and subsequent treatment for progressive disease, and (3) hepatitis C virus screening, subsequent treatment for progressive disease, and elective cesarean delivery to avert perinatal transmission. Lifetime costs and quality-adjusted life years were evaluated for mother and child. Results: In our base case, hepatitis C virus screening and subsequent treatment of progressive disease was dominated (more costly and less effective) by no screening, with an incremental cost of $108 and a decreased incremental effectiveness of 0.00011 quality-adjusted life years. When compared with no screening, the marginal cost and effectiveness of screening, treatment, and cesarean delivery was $117 and 0.00010 quality-adjusted life years, respectively, which yields a cost-effectiveness ratio of $1,170,000 per quality-adjusted life year. Conclusion: The screening of asymptomatic pregnant women for hepatitis C virus infection is not cost-effective. ? 2005 Elsevier Inc. All rights reserved.","author":[{"dropping-particle":"","family":"Plunkett","given":"Beth A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Grobman","given":"William A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"American Journal of Obstetrics and Gynecology","id":"ITEM-1","issued":{"date-parts":[["2005"]]},"title":"Routine hepatitis C virus screening in pregnancy: A cost-effectiveness analysis","type":"paper-conference"},"uris":[""]}],"mendeley":{"formattedCitation":"(Plunkett & Grobman, 2005)","plainTextFormattedCitation":"(Plunkett & Grobman, 2005)","previouslyFormattedCitation":"(Plunkett & Grobman, 2005)"},"properties":{"noteIndex":0},"schema":""}(Plunkett & Grobman, 2005), new treatments are being developed for HCV infection which may motivate reevaluation of cost-effectiveness of universal HCV screening versus risk factor-based screening in pregnancy. There must also be improved communication between obstetricians and pediatricians regarding children who are exposed to HCV which could be emphasized through policy changes in hospitals or corresponding doctors’ offices. Hospital medical staff should relay these results to the infant’s pediatrician before or following delivery. Finally, interventions to improve data collection on birth certificates or other electronic reporting methods to ensure accurate results can be easily transferrable to pediatricians’ offices. In Oregon specifically, there are plans to create linked accounts between the mother and child in the state disease reporting system to better track exposed infants. CONCLUSIONThe opioid epidemic continues to affect the nation, and it may be responsible for the significant increase in percentage of children being born to HCV-positive mothers— an 89% increase between 2009 and 2014 in reporting states ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.15585/mmwr.mm6618a3","ISSN":"0149-2195","author":[{"dropping-particle":"","family":"Patrick","given":"Stephen W.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bauer","given":"Audrey M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warren","given":"Michael D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jones","given":"Timothy F.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wester","given":"Carolyn","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"MMWR. Morbidity and Mortality Weekly Report","id":"ITEM-1","issue":"18","issued":{"date-parts":[["2017"]]},"page":"470-473","title":"Hepatitis C Virus Infection Among Women Giving Birth — Tennessee and United States, 2009–2014","type":"article-journal","volume":"66"},"uris":[""]}],"mendeley":{"formattedCitation":"(Patrick et al., 2017)","plainTextFormattedCitation":"(Patrick et al., 2017)","previouslyFormattedCitation":"(Patrick et al., 2017)"},"properties":{"noteIndex":0},"schema":""}(Patrick et al., 2017). Studies suggest that HCV is not only being underreported in individuals nationwide due to the chronicity of the virus but also is being underreported in infants exposed to the virus through vertical transmission. As a result, exposed children are not receiving necessary follow-up screening and treatment leaving them susceptible to the damaging effects of HCV later in life. New treatments approved for HCV-infected children under 12 years old are currently in clinical trials, therefore making this deficiency even more relevant than before. Simple interventions such as improved communication between obstetricians, pediatricians, and patients and data collection quality control have the potential to help ameliorate the large gap in medical care to HCV-exposed children nationwide. bibliographyADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Alter, M. J., Kruszon-Moran, D., Nainan, O. V, McQuillan, G. M., Gao, F., Moyer, L. A., … Margolis, H. S. (1999). The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. [pii]\n10.1056/NEJM199908193410802Armstrong, G. L., Wasley, A., Simard, E. P., McQuillan, G. M., Kuhnert, W. L., & Alter, M. J. (2006). The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. [pii]Azzari, C., Moriondo, M., Indolfi, G., Betti, L., Gambineri, E., de Martino, M., & Resti, M. (2008). Higher risk of hepatitis C virus perinatal transmission from drug user mothers is mediated by peripheral blood mononuclear cell infection. J Med Virol. , C., Resti, M., Moriondo, M., Ferrari, R., Lionetti, P., & Vierucci, A. (2000). Vertical transmission of HCV is related to maternal peripheral blood mononuclear cell infection. Blood.Babik, J. M., Cohan, D., Monto, A., Hartigan-O’Connor, D. J., & McCune, J. M. (2011). The human fetal immune response to hepatitis C virus exposure in utero. The Journal of Infectious Diseases. , C. L., Grove, J., Meredith, L. W., Hu, K., Syder, A. J., Flores, M. V., … McKeating, J. A. (2011). Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission. Journal of Virology. , E. B., Chou, R., Wasson, N., Rahman, B., & Guise, J. M. (2013). Reducing risk for mother-to-infant transmission of hepatitis C virus: A systematic review for the U.S. preventive services task force. Annals of Internal Medicine. , C., Carbonne, B., Heim, N., Berkane, N., Petit, J. C., Uzan, S., & Grange, J. D. (1999). Detection of hepatitis C virus RNA (HCV RNA) in amniotic fluid: a prospective study. J Hepatol. (99)80031-2 [pii]Delgado-Borrego, A., Smith, L., Jonas, M. M., Hall, C. A., Negre, B., Jordan, S. H., … Chung, R. T. (2012). Expected and actual case ascertainment and treatment rates for children infected with hepatitis c in florida and the united states: Epidemiologic evidence from statewide and nationwide surveys. Journal of Pediatrics, 161(5), 915–921. , E., Thorlund, K., Wu, P., Kanters, S., Yaya, S., Cooper, C. L., & Mills, E. J. (2013). Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis. Clinical Infectious Diseases?: An Official Publication of the Infectious Diseases Society of America. , L. B., Bartolini, B., Capobianchi, M. R., & Pistello, M. (2016). Hepatitis C virus: life cycle in cells, infection and host response, and analysis of molecular markers influencing the outcome of infection and response to therapy. Clinical Microbiology and Infection?: The Official Publication of the European Society of Clinical Microbiology and Infectious Diseases, 22(10), 826–832. , M. A. (2016). Hepatitis C Viral Infection in Children: Updated Review. Pediatric Gastroenterology, Hepatology & Nutrition. Association for the Study of the Liver. (2017). EASL Recommendations on Treatment of Hepatitis C 2016. Journal of Hepatology, 66(1), 153–194. , N., Towers, C. V., Wolfe, L., Hennessy, M. D., Weitz, B., & Porter, S. (2016). Sharing of Snorting Straws and Hepatitis C Virus Infection in Pregnant Women. Obstetrics and Gynecology. , a, Bacq, Y., Bernuau, J., Martinot, M., Auperin, a, Boyer, N., … Marcellin, P. (2000). Decrease in serum ALT and increase in serum HCV RNA during pregnancy in women with chronic hepatitis C. Journal of Hepatology.Hattori, Y., Orito, E., Ohno, T., Sugauchi, F., Suzuki, S., Sugiura, M., … Mizokami, M. (2003). Loss of hepatitis C virus RNA after parturition in female patients with chronic HCV infection. J Med Virol. , M. H., & Thimme, R. (2014). Innate and adaptive immune responses in HCV infections. Journal of Hepatology, 61(1), S14–S25. , J., Prasad, M., & Walker, C. (2012). Broadened virus-specific T-cell responses are associated with postpartum declines in hepatitis C viremia. In: Infectious Diseases Society of America Annual Meeting. San Diego, CA.Hughes, B. L., Page, C. M., & Kuller, J. A. (2017). Hepatitis C in pregnancy: screening, treatment, and management. American Journal of Obstetrics and Gynecology, 217(5), B2–B12. , C. W., Golden-Mason, L., Brocato, M., Krull, M., Narkewicz, M. R., & Rosen, H. R. (2010). Innate immune function in placenta and cord blood of hepatitis C--seropositive mother-infant dyads. PLoS One. , G., & Resti, M. (2009). Perinatal transmission of hepatitis C virus infection. Journal of Medical Virology. Versalovic, Karen C. Carroll, Guido Funke, James H. Jorgensen, Marie Louise Landry, D. W. W. (2011). Manual of Clinical Microbiology, 10th edition. Manual of Clinical Microbiology, 10th edition. , R. M., & Shahul, S. (1998). Role of breast-feeding in transmission of hepatitis C virus to infants of HCV-infected mothers. Journal of Hepatology. (98)80003-2Kuncio, D. E., Newbern, E. C., Johnson, C. C., & Viner, K. M. (2016). Failure to Test and Identify Perinatally Infected Children Born to Hepatitis C Virus-Infected Women. Clinical Infectious Diseases, 62(8), 980–985. Campion, A., Larouche, A., Fauteux-Daniel, S., & Soudeyns, H. (2012). Pathogenesis of hepatitis C during pregnancy and childhood. Viruses. , H. H., & Kao, J. H. (2000). Hepatitis C virus load during pregnancy and puerperium. BJOG?: An International Journal of Obstetrics and Gynaecology.Lin, H. H., Kao, J. H., Hsu, H. Y., Ni, Y. H., Chang, M. H., Huang, S. C., … Chen, D. S. (1995). Absence of infection in breast-fed infants born to hepatitis C virus-infected mothers. The Journal of Pediatrics. (95)70356-XMack, C. L., Gonzalez-Peralta, R. P., Gupta, N., Leung, D., Narkewicz, M. R., Roberts, E. A., … Schwarz, K. B. (2012). NASPGHAN Practice guidelines: Diagnosis and management of hepatitis c infection in infants, children, and adolescents. Journal of Pediatric Gastroenterology and Nutrition, 54(6), 838–855. , E. E., Hwang, L.-Y., Seto, D. S. Y., Nolte, F. S., Nainan, O. V, Wurtzel, H., & Alter, M. J. (2005). Risk factors for perinatal transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. The Journal of Infectious Diseases, 192(February), 1880–1889. , P. G., Tosh, K., & McGuire, W. (2006). Caesarean section versus vaginal delivery for preventing mother to infant hepatitis C virus transmission. Cochrane Database of Systematic Reviews. , G. D., D’Agaro, P., Ansaldi, F., Ciana, G., Fertz, C., Alberico, S., & Campello, C. (2002). Mother-to-infant transmission of hepatitis C virus: Rate of infection and assessment of viral load and IgM anti-HCV as risk factors. Journal of Medical Virology. , A., Arshad, M., Qiang, G., Bradrick, S., & Jhaveri, R. (2012). Examining cells of trophoblastic origin for permissiveness for hepatitis C virus replication.Murphy, D. G., Sablon, E., Chamberland, J., Fournier, E., Dandavino, R., & Tremblay, C. L. (2015). Hepatitis C virus genotype 7, a new genotype originating from Central Africa. Journal of Clinical Microbiology. Institute of Health. (2017). Home - . U.S. National Library of Medicine.Nattermann, J. (2011). NK cells in acute hepatitis C. Journal of Hepatology. , Q. H., Gao, L. H., Cheng, Y. Q., Huang, X. F., Zhang, Y. F., Luo, X. D., … Wang, Y. Y. (2012). Hepatitis C virus infection of human cytotrophoblasts cultured in vitro. J Med Virol. Health Authority Opioid Overdose and Misuse: Public Health Division. (n.d.). Prescribing and Overdose Data for Oregon. Retrieved August 16, 2017, from , D. M., Santarossa, C., Grella, P., Pal?, G., Baldo, V., Boccagni, P., & Floreani, A. (2001). Viral load in HCV RNA-positive pregnant women. American Journal of Gastroenterology. (01)02697-1Patrick, S. W., Bauer, A. M., Warren, M. D., Jones, T. F., & Wester, C. (2017). Hepatitis C Virus Infection Among Women Giving Birth — Tennessee and United States, 2009–2014. MMWR. Morbidity and Mortality Weekly Report, 66(18), 470–473. , B. A., & Grobman, W. A. (2005). Routine hepatitis C virus screening in pregnancy: A cost-effectiveness analysis. In American Journal of Obstetrics and Gynecology. , C. B., Shah, S. N., Johnson, K. E., & Gupta, A. (2007). Impact of maternal HIV coinfection on the vertical transmission of hepatitis C virus: a meta-analysis. Clin Infect Dis. , M. R., & Honegger, J. R. (2013). Hepatitis C virus in pregnancy. Am J Perinatol, 30(2), 149–159. , D. B., Bukh, J., Kuiken, C., Muerhoff, A. S., Rice, C. M., Stapleton, J. T., & Simmonds, P. (2014). Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: Updated criteria and genotype assignment web resource. Hepatology. , E. M. (2017). Direct-acting antivirals for paediatric HCV: we got there. Nature Reviews Gastroenterology &Amp; Hepatology, 14, 452. Retrieved from , J. D., Latt, N., Beeby, P. J., Collins, E., Saunders, J. B., McCaughan, G. W., & Cossart, Y. E. (1997). Transmission of hepatitis C virus to infants of human immunodeficiency virus-negative intravenous drug-using mothers: Rate of infection and assessment of risk factors for transmission. Journal of Viral Hepatitis. , C., Kundi, M., Jatzko, G., Kiss, H., Lischka, A., & Holzmann, H. (2003). Increased Risk of Mother‐to‐Infant Transmission of Hepatitis C Virus by Intrapartum Infantile Exposure to Maternal Blood. The Journal of Infectious Diseases. , J. M., Stamataki, Z., Jennings, A., Hu, K., Farquhar, M. J., Harris, H. J., … McKeating, J. A. (2008). Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralizing antibodies. Hepatology. . Department of Health and Human Services, Centers for Disease Control and Prevention, Division of Viral Hepatitis (CDC). (2016). HCV FAQs for Health Professionals.U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC). (2016). Statistics and Surveillance.US Food & Drug Administration. (n.d.). Highlights of prescribing information for SOVALDI? (sofosbuvir) tablets, for oral use. Retrieved June 24, 2018, from National Library of Medicine. (n.d.). Drug label information: Ribasphere-ribavirin tablet. Retrieved June 23, 2018, from . Preventive Services Task Force. (2016). Final Recommendation Statement: Hepatitis C: Screening. Retrieved July 16, 2018, from , M. L. (2010). Antiviral therapy for hepatitis C: why are so few patients being treated? The Journal of Antimicrobial Chemotherapy. , R., Widell, A., & Norkrans, G. (1998). HCV-RNA levels increase during pregnancy in women with chronic hepatitis C. Scandinavian Journal of Infectious Diseases.Werner, J. M., Heller, T., Gordon, A. M., Sheets, A., Sherker, A. H., Kessler, E., … Rehermann, B. (2013). Innate immune responses in hepatitis C virus-exposed healthcare workers who do not develop acute infection. Hepatology. , S. (2012). Current treatment options and response rates in children with chronic hepatitis C. World Journal of Gastroenterology. , S., Rosenthal, P., Gonzalez-Peralta, R. P., Jonas, M. M., Balistreri, W. F., Lin, C. H., … Schwarz, K. B. (2017). Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection. Hepatology. Health Organization. (2017). Global hepatitis report, 2017. Who. 978-92-4-156545-5Zuure, F. R., Urbanus, A. T., Langendam, M. W., Helsper, C. W., Van Den Berg, C. H. S. B., Davidovich, U., & Prins, M. (2014). Outcomes of hepatitis C screening programs targeted at risk groups hidden in the general population: A systematic review. BMC Public Health, 14(1), 1–29. ................
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