Researchonline.lshtm.ac.uk
Title: Post-treatment effect of isoniazid preventive therapy on tuberculosis incidence in HIV-infected individuals on antiretroviral therapyAuthors: Sumner, T.1, Houben, RM.1, Rangaka, MX.2,3, Maartens, G.4,5, Boulle, A.6, Wilkinson, R.J.7,8,9,White, RG1.AffiliationsDepartment of Infectious Disease Epidemiology, TB Modelling Group, TB Centre, and Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, UKCentre for Infectious Disease Epidemiology, Department of Infection & Population Health, University College London, London, UKInstitute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, South AfricaDivision of Clinical Pharmacology, University of Cape Town, South Africa;?Tuberculosis?Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USACentre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, South Africa.Department of Medicine, Imperial College London W2 1PG, UKThe Francis Crick Institute Mill Hill Laboratory, London NW7 1AAInstitute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory 7925, South AfricaCorresponding Author: Tom Sumner, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK; Tel: +44(0)20 7927 2957; email: tom.sumner@lshtm.ac.ukKeywords: preventive therapy; IPT; HIV; South AfricaRunning Title: Post-treatment effect of INH on tuberculosisSummaryUsing mathematical modelling of trial data, we show IPT cures around one third of Mycobacterium tuberculosis infections in HIV-infected individuals on ART. These results are important for determining appropriate clinical guidelines for IPT use in varying epidemiological settings.Conflict of interestWe confirm that none of the authors has any conflict of interestWord count: 2848Abstract BackgroundIn HIV-uninfected individuals, isoniazid preventive therapy (IPT) has been associated with long-term protection against tuberculosis (TB). For HIV-infected/ART-na?ve individuals, high TB rates have been observed following completion of IPT, consistent with a lack of “cure” of infection. Recent trial data of IPT among HIV-infected individuals on ART in Khayelitsha, South Africa has suggested that the effect of IPT persisted following completion of IPT. MethodsUsing mathematical modelling we explored if this increased duration of protection may be due to an increased curative ability of IPT when given in combination with ART. The model was used to estimate the annual risk of infection (ARI) and proportion of individuals whose latent infection was “cured” by IPT, defined such that they must be re-infected to be at risk of disease. ResultsThe estimated ARI was 4.0% (2.6-5.8) and the estimated proportion of individuals whose latent infection (LTBI) was cured following IPT was 35.4% (2.4-76.4%), higher than that previously estimated for HIV-infected/ART- na?ve individuals. Our results suggest that IPT can cure LTBI in approximately one third of HIV-infected individuals on ART, and therefore provide protection beyond the period of treatment. ConclusionsAmong HIV-infected individuals on ART in low incidence settings, 12 months of IPT may provide additional long term benefit. Among HIV-infected individuals on ART in high incidence settings, the durability of this protection will be limited due to continued risk of re-infection, and continuous preventive therapy together with improved infection control efforts will be required to provide long-term protection against TB. IntroductionIsoniazid (INH) preventive therapy (IPT) has been shown to reduce the risk of tuberculosis (TB) in people living with HIV (PLHIV) ADDIN EN.CITE <EndNote><Cite><Author>Akolo</Author><Year>2010</Year><RecNum>62</RecNum><DisplayText>[1]</DisplayText><record><rec-number>62</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">62</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akolo, C.</author><author>Adetifa, I.</author><author>Shepperd, S.</author><author>Volmink, J.</author></authors></contributors><titles><title>Treatment of latent tuberculosis infection in HIV infected persons (Review)</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><volume>20</volume><number>1</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[1] and the WHO strongly recommends that PLHIV who do not have active TB disease should receive at least 6 months of IPT as part of HIV care ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2012</Year><RecNum>392</RecNum><DisplayText>[2]</DisplayText><record><rec-number>392</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">392</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors><tertiary-authors><author>WHO Press</author></tertiary-authors></contributors><titles><title>WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders</title></titles><dates><year>2012</year></dates><pub-location>Geneva</pub-location><publisher>WHO</publisher><urls></urls></record></Cite></EndNote>[2]. However evidence from clinical trials in high TB incidence settings has shown that the duration of protection following 6-12 months IPT is limited PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdrZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdrZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA [3-5] and that continuation of therapy (up to 36 months) provides increased protection against TB disease ADDIN EN.CITE <EndNote><Cite><Author>Samandari</Author><Year>2011</Year><RecNum>53</RecNum><DisplayText>[6]</DisplayText><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Samandari, T.</author><author>Agizew, T.</author><author>Nyirenda, S.</author><author>Tedla, Z.</author><author>Sibanda, T.</author><author>Shang, N.</author><author>Mosimaneotsile, B.</author><author>Motsamai, O.</author><author>Mozeman, L.</author><author>Davis, M.</author><author>Talbot, E.</author><author>Moeti, T.</author><author>Moffat, H.</author><author>Kilmarx, P.</author><author>Castro, K.</author><author>Wells, C.</author></authors></contributors><titles><title>6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>1588-1598</pages><volume>377</volume><dates><year>2011</year></dates><urls></urls></record></Cite></EndNote>[6]. This has led to the conditional recommendation that PLHIV in high TB transmission areas should take at least 36 months of INH ADDIN EN.CITE <EndNote><Cite><Author>WHO</Author><Year>2012</Year><RecNum>392</RecNum><DisplayText>[2]</DisplayText><record><rec-number>392</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">392</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>WHO</author></authors><tertiary-authors><author>WHO Press</author></tertiary-authors></contributors><titles><title>WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders</title></titles><dates><year>2012</year></dates><pub-location>Geneva</pub-location><publisher>WHO</publisher><urls></urls></record></Cite></EndNote>[2]. Following completion of a course of preventive therapy, TB disease can result from reactivation of a previous infection or through acquisition of a new infection. If, following therapy, INH results in lifelong protection against reactivation of existing infections (referred to here as “cure”) then reinfection must occur before individuals can progress to disease. If INH does not “cure”, then previously infected individuals will be at immediate risk of progressing to TB disease. In practice, TB disease observed following completion of therapy is likely due to a combination of these mechanisms.Evidence from trials in immunocompetent individuals suggests that a 9 month course of IPT is sufficient to “cure” infection in most individuals ADDIN EN.CITE <EndNote><Cite><Author>Comstock</Author><Year>1999</Year><RecNum>23</RecNum><DisplayText>[7]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Comstock, G.W.</author></authors></contributors><titles><title>How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults?</title><secondary-title>International Journal of Tuberculosis and Lung Disease</secondary-title></titles><periodical><full-title>International Journal of Tuberculosis and Lung Disease</full-title><abbr-1>Int. J. Tuberc. Lung Dis.</abbr-1><abbr-2>Int J Tuberc Lung Dis</abbr-2><abbr-3>International Journal of Tuberculosis & Lung Disease</abbr-3></periodical><pages>847-850</pages><volume>31</volume><number>10</number><dates><year>1999</year></dates><urls></urls><research-notes>6 months does not give optimal protection
9-10 months is optimal 
>12 months not necessary</research-notes></record></Cite></EndNote>[7]. In contrast, in a previous analysis of trial data from the pre-antiretroviral therapy (ART) era we found that the high rates of TB following completion of 6-12 months IPT in PLHIV were consistent with an almost complete lack of “cure” of latent M. tuberculosis infection (LTBI) ADDIN EN.CITE <EndNote><Cite><Author>Houben</Author><Year>2014</Year><RecNum>391</RecNum><DisplayText>[8]</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houben, R. M.</author><author>Sumner, T.</author><author>Grant, A. D.</author><author>White, R. G.</author></authors></contributors><auth-address>TB Modelling Group, Department of Infectious Disease Epidemiology, TB Centre, and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.</auth-address><titles><title>Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></periodical><alt-periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></alt-periodical><pages>5325-30</pages><volume>111</volume><number>14</number><dates><year>2014</year><pub-dates><date>Apr 8</date></pub-dates></dates><isbn>1091-6490 (Electronic)
0027-8424 (Linking)</isbn><accession-num>24706842</accession-num><urls><related-urls><url>;[8]. Mathematical modelling of a trial of community wide INH in South African gold mines reached similar conclusions about the effectiveness of IPT in PLHIV ADDIN EN.CITE <EndNote><Cite><Author>Vynnycky</Author><Year>2014</Year><RecNum>346</RecNum><DisplayText>[9]</DisplayText><record><rec-number>346</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">346</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vynnycky, E</author><author>Sumner, T.</author><author>Fielding, K. L.</author><author>Lewis, J. J.</author><author>Cox, A.P.</author><author>Hayes, R.J.</author><author>Corbett, E.L.</author><author>Churchyard, G. J.</author><author>Grant, A. D.</author><author>White, R. G.</author></authors></contributors><titles><title>Tuberculosis control in South African goldmines: mathematical modelling of a trial of community wide IPT</title><secondary-title>American Journal of Epidemiology</secondary-title></titles><periodical><full-title>American Journal of Epidemiology</full-title><abbr-1>Am. J. Epidemiol.</abbr-1><abbr-2>Am J Epidemiol</abbr-2></periodical><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[9]. This lack of cure from IPT in PLHIV not on ART suggests that regimens with better curative potential (for example containing rifampicin or rifapentine) ADDIN EN.CITE <EndNote><Cite><Author>Jereb</Author><Year>2011</Year><RecNum>393</RecNum><DisplayText>[10]</DisplayText><record><rec-number>393</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">393</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Jereb, J.A.</author><author>Goldberg, S.V.</author><author>Powell, K. </author><author>Villarino, M.E.</author><author>LoBue. P.</author></authors></contributors><titles><title>Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection</title><secondary-title>Morbidity and Mortality Weekly Report</secondary-title></titles><pages>1650</pages><volume>60</volume><dates><year>2011</year></dates><publisher>CDC</publisher><urls></urls></record></Cite></EndNote>[10] could be considered to reduce the risk of reactivation disease. However, these regimens carry increased risk of adverse effects and drug-drug interactions in individuals taking ART ADDIN EN.CITE <EndNote><Cite><Author>Maartens</Author><Year>2009</Year><RecNum>470</RecNum><DisplayText>[11]</DisplayText><record><rec-number>470</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">470</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maartens, G.</author><author>Decloedt, E.</author><author>Cohen, K.</author></authors></contributors><titles><title>Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries</title><secondary-title>Antiviral Therapy</secondary-title></titles><periodical><full-title>Antiviral Therapy</full-title><abbr-1>Antivir. Ther.</abbr-1><abbr-2>Antivir Ther</abbr-2></periodical><volume>14</volume><number>8</number><dates><year>2009</year></dates><urls></urls></record></Cite></EndNote>[11].ART provides additional protection against TB disease over IPT alone, in patients starting ART after, or during, a course of INH PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hbmRhcmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hbmRhcmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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 EN.CITE.DATA [6, 12-14]. Recently published data from a pragmatic trial of IPT conducted among people established on, or starting, ART in Khayelitsha, Cape Town, South Africa ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15], suggested that the protective effect of IPT persisted in the year following completion of IPT, longer than observed in trials in HIV-infected/ART- na?ve individuals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdrZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXdrZW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS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ADDIN EN.CITE.DATA [3, 4]. However this trial was not powered to determine the duration of benefit. Given the implementation of new criteria for starting ART earlier in HIV disease, it is important to explore the potential reasons for this apparent increased duration of protection of IPT with concomitant ART in high incidence TB settings. Quantifying the curative ability of IPT in HIV infected individuals on ART is a critical step in estimating the potential long-term individual and population level benefits of IPT in different epidemiological settings. In this paper we use an extension of the approach presented in ADDIN EN.CITE <EndNote><Cite><Author>Houben</Author><Year>2014</Year><RecNum>391</RecNum><DisplayText>[8]</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houben, R. M.</author><author>Sumner, T.</author><author>Grant, A. D.</author><author>White, R. G.</author></authors></contributors><auth-address>TB Modelling Group, Department of Infectious Disease Epidemiology, TB Centre, and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.</auth-address><titles><title>Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></periodical><alt-periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></alt-periodical><pages>5325-30</pages><volume>111</volume><number>14</number><dates><year>2014</year><pub-dates><date>Apr 8</date></pub-dates></dates><isbn>1091-6490 (Electronic)
0027-8424 (Linking)</isbn><accession-num>24706842</accession-num><urls><related-urls><url>;[8] to analyse data from the Khayelitsha trial ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15], to estimate the proportion of HIV infected individuals on ART that were “cured” by IPT. MethodsThe model is based on a previously published model ADDIN EN.CITE <EndNote><Cite><Author>Houben</Author><Year>2014</Year><RecNum>391</RecNum><DisplayText>[8]</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houben, R. M.</author><author>Sumner, T.</author><author>Grant, A. D.</author><author>White, R. G.</author></authors></contributors><auth-address>TB Modelling Group, Department of Infectious Disease Epidemiology, TB Centre, and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.</auth-address><titles><title>Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></periodical><alt-periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></alt-periodical><pages>5325-30</pages><volume>111</volume><number>14</number><dates><year>2014</year><pub-dates><date>Apr 8</date></pub-dates></dates><isbn>1091-6490 (Electronic)
0027-8424 (Linking)</isbn><accession-num>24706842</accession-num><urls><related-urls><url>;[8] and is similar in structure to a number of other TB models PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WeW5ueWNreTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WeW5ueWNreTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+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ADDIN EN.CITE.DATA [16, 17]. It describes the tuberculosis dynamics in a preventive therapy trial cohort of HIV infected individuals on ART after the cessation of IPT or placebo. The model structure is shown in figure 1.Following the completion of drug the population is divided between susceptible (never infected, S), recently infected (defined as infected for the first time in the previous 2 years, I), recently reinfected (again, in the last 2 years, R), latently infected (last (re)infected 2 or more years ago, L) and those cured by IPT (C). The model structure is the same for both placebo and INH trial arms and differs only in the initial conditions (see below).The proportion of the population that are cured following IPT (p) can only develop disease if they are reinfected with M. tuberculosis. Cured, susceptible and latent individuals are (re)infected at rate λ and move to the recently (re)infected classes. The risk of infection is assumed to be constant for the short duration of the trial. This is based on the assumption that the trial population mixes homogenously with the non-trial population and is consistent with data from Cape Town which suggests that the annual risk of infection (ARI) has been relatively constant over the last 15 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lcml0emluZ2VyPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lcml0emluZ2VyPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh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ADDIN EN.CITE.DATA [18].Recently infected, recently reinfected and latently infected individuals can progress to disease at rates dp, dn and dx respectively representing primary, endogenous (reactivation) and exogenous (reinfection) disease. The risk of disease following (re)infection is assumed to decline with time since (re)infection ADDIN EN.CITE <EndNote><Cite><Author>Vynnycky</Author><Year>1997</Year><RecNum>5</RecNum><DisplayText>[16]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vynnycky, E.</author><author>Fine, P.E.M.</author></authors></contributors><titles><title>The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection</title><secondary-title>Epidemiology and Infection</secondary-title></titles><periodical><full-title>Epidemiology and Infection</full-title><abbr-1>Epidemiol. Infect.</abbr-1><abbr-2>Epidemiol Infect</abbr-2><abbr-3>Epidemiology & Infection</abbr-3></periodical><pages>183-201</pages><volume>119</volume><dates><year>1997</year></dates><label>Modelling</label><urls></urls></record></Cite></EndNote>[16] ADDIN EN.CITE <EndNote><Cite><Author>Sutherland</Author><Year>1982</Year><RecNum>445</RecNum><DisplayText>[19]</DisplayText><record><rec-number>445</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">445</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sutherland, I.</author><author>Svandova, E.</author><author>Radhakrishna, S.</author></authors></contributors><titles><title>The development of clinical tuberculosis following infection with tubercle bacilli</title><secondary-title>Tubercle</secondary-title></titles><periodical><full-title>Tubercle</full-title><abbr-1>Tubercle</abbr-1><abbr-2>Tubercle</abbr-2></periodical><pages>255-68</pages><volume>62</volume><number>4</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>[19]. This is modelled by dividing the recently infected and recently reinfected compartments into 2 sub-compartments representing years since (re)infection with different risks of disease. After 2 years recently (re)infected individuals progress to the latent class where they experience a much reduced risk of progression to disease. The model equations are given in the supporting information.ART reduces the risk of TB in HIV-infected individuals. We assume that this effect is due only to related changes in CD4 count. Following Williams et al. ADDIN EN.CITE <EndNote><Cite><Author>Williams</Author><Year>2010</Year><RecNum>237</RecNum><DisplayText>[20]</DisplayText><record><rec-number>237</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">237</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Williams, B.G.</author><author>Granich, R.</author><author>De Cock, K.M.</author><author>Glaziou, P.</author><author>Sharma, A.</author><author>Dye, c.</author></authors></contributors><titles><title>Antiretroviral therapy for tuberculosis control in nine African countries</title><secondary-title>Proceedings of the National Academy of Sciences of the United States of America </secondary-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></periodical><pages>19485-19489</pages><volume>107</volume><number>45</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[20] we assume that the relative risk of TB increases exponentially with decreasing CD4 cell count at a rate α for each decline of 100 cells/μL. CD4 values in the model were taken from the trial data.The model is initialised to represent the population in the intervention and placebo arms at cessation of IPT. The proportions of individuals in each compartment at this time depend on the annual risk of infection (ARI), the proportion cured by IPT (p), the level of drug resistance (δ) in the population and the average age of the cohort (a). Expressions for the populations in each state are given in table 1. In our primary analysis, a 12 month course of INH is assumed to suppress recent infection (to a latent state) in all individuals completing therapy and to clear latent infection in a proportion, p. We also assume that INH can have no effect in individuals infected with INH resistant strains of TB. Results of a cross-sectional survey of adult clinic attendees in Khayelitsha found prevalence of isoniazid resistance of 10.4 and 15.7% in new and previously treated TB cases respectively ADDIN EN.CITE <EndNote><Cite><Author>Cox</Author><Year>2010</Year><RecNum>455</RecNum><DisplayText>[21]</DisplayText><record><rec-number>455</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">455</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cox, H.</author><author>McDermid, C.</author><author>Azevedo, V.</author><author>Muller, O.</author><author>Coetzee, D.</author><author>Simpson, J.</author><author>Barnard, M.</author><author>Coetzee, G.</author><author>van Cutsem, G.</author><author>Goemaere, E.</author></authors></contributors><titles><title>Epidemic levels of drug resistant tuberculosis (MDR and XDR-TB) in a high HIV prevalence setting in Khayelitsha, South Africa</title><secondary-title>PloS One</secondary-title></titles><periodical><full-title>PloS One</full-title><abbr-1>PLoS One</abbr-1><abbr-2>PLoS One</abbr-2></periodical><pages>e13901</pages><volume>5</volume><number>11</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[21]. Approximately 40% of the trial cohort had history of previous TB therefore we assumed a baseline prevalence of INH resistance of 12.5%. We do not allow for mixed infections in the model. The model was calibrated to the prevalence of LTBI in the placebo arm and the TB incidence rate observed in the placebo and INH arms during the post treatment period ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15]. Estimates of LTBI prevalence were based on analysis of a similar high incidence setting to the trial location ADDIN EN.CITE <EndNote><Cite><Author>Wood</Author><Year>2010</Year><RecNum>386</RecNum><DisplayText>[22]</DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wood, R.</author><author>Liang, H.</author><author>Wu, H.</author><author>Middelkoop, K.</author><author>Oni, T.</author><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Bekker, L. G.</author><author>Lawn, S. D.</author></authors></contributors><titles><title>Changing prevalence of TB infection with increasing age in high TB burden townships in South Africa</title><secondary-title>IJTLD</secondary-title></titles><periodical><full-title>IJTLD</full-title></periodical><pages>406-412</pages><volume>14</volume><number>4</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[22] which estimated prevalence of infection of 74.3% (61.2-87.4) in individuals of 35 years of age, the median age in the trial cohort ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15]. The prevalence of infection was assumed to be normally distributed with a mean and 95% confidence interval determined by the values presented in ADDIN EN.CITE <EndNote><Cite><Author>Wood</Author><Year>2010</Year><RecNum>386</RecNum><DisplayText>[22]</DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wood, R.</author><author>Liang, H.</author><author>Wu, H.</author><author>Middelkoop, K.</author><author>Oni, T.</author><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Bekker, L. G.</author><author>Lawn, S. D.</author></authors></contributors><titles><title>Changing prevalence of TB infection with increasing age in high TB burden townships in South Africa</title><secondary-title>IJTLD</secondary-title></titles><periodical><full-title>IJTLD</full-title></periodical><pages>406-412</pages><volume>14</volume><number>4</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[22].Model calibration was based on the Bayesian melding method ADDIN EN.CITE <EndNote><Cite><Author>Alkema</Author><Year>2007</Year><RecNum>365</RecNum><DisplayText>[23]</DisplayText><record><rec-number>365</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">365</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alkema, L.</author><author>Raftery, A.E.</author><author>Clark, S.J.</author></authors></contributors><titles><title>Probabilistic projections of HIV prevalence using Bayesian melding</title><secondary-title>The annals of applied statistics</secondary-title></titles><pages>229-248</pages><volume>1</volume><number>1</number><dates><year>2007</year></dates><urls></urls></record></Cite></EndNote>[23] implemented using a sampling/importance resampling algorithm ADDIN EN.CITE <EndNote><Cite><Author>Rubin</Author><Year>1988</Year><RecNum>447</RecNum><DisplayText>[24]</DisplayText><record><rec-number>447</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">447</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Rubin, D.</author></authors><secondary-authors><author>DeGroot, M.H.</author><author>Lindley, D.V.</author><author>Smith, A.F.M</author></secondary-authors></contributors><titles><title>Using the SIR algorithm to simulate posterior distributions</title><secondary-title>Bayesian Statistics 3</secondary-title></titles><pages>395-402</pages><dates><year>1988</year></dates><pub-location>Oxford</pub-location><publisher>OUP</publisher><urls></urls></record></Cite></EndNote>[24]. First we generated a large number of samples from the prior parameter distributions. Then the model was run for each parameter set and the likelihood calculated. The parameter sets were then resampled with replacement using the likelihood as weights. The following results are based on 100,000 model runs, a resample size of 200,000.Table S2 (supporting information) shows the prior distributions of the model parameters used in the calibration process. We used uniform priors for the ARI and proportion cured (p) as we have limited or no information on their values. The priors for risk of developing primary disease in the first year post infection and the protective effect of previous infection were based on earlier studies ADDIN EN.CITE <EndNote><Cite><Author>Vynnycky</Author><Year>1997</Year><RecNum>5</RecNum><DisplayText>[16]</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vynnycky, E.</author><author>Fine, P.E.M.</author></authors></contributors><titles><title>The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection</title><secondary-title>Epidemiology and Infection</secondary-title></titles><periodical><full-title>Epidemiology and Infection</full-title><abbr-1>Epidemiol. Infect.</abbr-1><abbr-2>Epidemiol Infect</abbr-2><abbr-3>Epidemiology & Infection</abbr-3></periodical><pages>183-201</pages><volume>119</volume><dates><year>1997</year></dates><label>Modelling</label><urls></urls></record></Cite></EndNote>[16] with wider uncertainly ranges to reflect potential differences between populations. These values, together with estimates of the relative risk of disease in subsequent years were used to calculate the risks of primary (dp), endogenous (dn) and exogenous disease (dx) (see supporting information for further details). CD4 values in HIV negative individuals and the increase in TB risk with declining CD4 were based on previous analysis of sub-saharan African populations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtczwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtczwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE.DATA [20, 25]Sensitivity analysis was conducted to explore the impact of assumptions about the prevalence of drug resistance and the efficacy of INH against drug resistant strains on the model results. We considered two alternative assumptions for the level of drug resistance: that all LTBI was drug susceptible (resistance 0%); the prevalence of resistance was based on the results of drug susceptibility testing of cases of active disease in the trial cohort (25 out of 34 cases were cultured; of these 6 (24%) were resistant to INH (2) or multiple drugs (4). We also explored the assumption that INH can not cure infections with resistant strains of M. tuberculosis but is effective in suppressing recent infections with such strains. Further details can be found in the supporting information.ResultsFigure 2 shows the fit of the model to the data. The model estimate of the prevalence of LTBI infection in the placebo was 75.2% (61.9-88.7) compared with empirical estimates of 74.3% (61.2-87.4) ADDIN EN.CITE <EndNote><Cite><Author>Wood</Author><Year>2010</Year><RecNum>386</RecNum><DisplayText>[22]</DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wood, R.</author><author>Liang, H.</author><author>Wu, H.</author><author>Middelkoop, K.</author><author>Oni, T.</author><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Bekker, L. G.</author><author>Lawn, S. D.</author></authors></contributors><titles><title>Changing prevalence of TB infection with increasing age in high TB burden townships in South Africa</title><secondary-title>IJTLD</secondary-title></titles><periodical><full-title>IJTLD</full-title></periodical><pages>406-412</pages><volume>14</volume><number>4</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[22] (figure 2a). The model captures the trends in incidence in the placebo and intervention arms observed in the trial during the follow-up period (figure 2b). In the placebo arm incidence declines over time consistent with an increase in time spent on ART by trial participants (and hence increasing CD4 counts) resulting in a reduced risk of TB. In the intervention arm the model predicts a lower incidence immediately after cessation of IPT compared to the placebo arm (as seen in the trial data). During the follow-up period the incidence rate increases to similar levels to those observed in the placebo arm. Table 2 shows the hazard ratios (HR) estimated from the model for different time periods following completion of treatment compared to the values observed during the trial. Model estimates were within the 95% CI observed in the trial.In the primary analysis the model estimated ARI was 4.0% (2.6-5.8) and the estimated proportion cured (p) was 35.4% (2.4-76.4%). The posterior distributions of these parameters are shown in figure 3 (posterior distributions of the other model parameters can be found in the supporting information). Table S4 (supporting information) compares the model predictions for the ARI and p under different assumptions about drug resistance. Model estimates of the ARI were similar across all scenarios. In the limiting case that all infections in the population were drug susceptible the estimate cure rate was lower at 23.2% (0.1-61.5%).In the placebo arm, 53.7% (32.4-66.2) of TB disease is estimated to be due to recent transmission (classed as occurring within 2 years of (re)infection). This is in line with empirical estimates from similar high HIV-prevalent settings in southern Africa ranging from 35% to 68% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJ2ZXI8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZXJ2ZXI8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS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ADDIN EN.CITE.DATA [26-30]. The model also allows us to look at the proportion of disease occurring via different routes over time in the intervention arm (see supplementary figure S3). Initially the majority of cases are due to reactivation in individuals who were not cured following IPT. Over time there is an increase in disease due to recent infection as individuals who were either cured by IPT or whose infection was suppressed to a latent state are reinfected. The cumulative proportion of disease that occurs in individuals cured by IPT, in the 2 years following completion of therapy, was estimated to be 7.8% (0.4-32.1).DiscussionOur results suggest that in HIV-infected persons on ART IPT may cure existing LTBI in approximately one third of individuals, although there is uncertainty in the estimated value. This is a consequence of the uncertainty observed in the trial results and the importance of reinfection in driving TB incidence following completion of IPT. Earlier analysis of trials from the pre-ART era suggested that INH was unlikely to result in cure of LTBI in ART naive individuals ADDIN EN.CITE <EndNote><Cite><Author>Houben</Author><Year>2014</Year><RecNum>391</RecNum><DisplayText>[8]</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Houben, R. M.</author><author>Sumner, T.</author><author>Grant, A. D.</author><author>White, R. G.</author></authors></contributors><auth-address>TB Modelling Group, Department of Infectious Disease Epidemiology, TB Centre, and Department of Clinical Research, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.</auth-address><titles><title>Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></periodical><alt-periodical><full-title>Proceedings of the National Academy of Sciences of the United States of America</full-title><abbr-1>Proc. Natl. Acad. Sci. U. S. A.</abbr-1><abbr-2>Proc Natl Acad Sci U S A</abbr-2></alt-periodical><pages>5325-30</pages><volume>111</volume><number>14</number><dates><year>2014</year><pub-dates><date>Apr 8</date></pub-dates></dates><isbn>1091-6490 (Electronic)
0027-8424 (Linking)</isbn><accession-num>24706842</accession-num><urls><related-urls><url>;[8]. Together, these findings are consistent with the hypothesis that INH requires a (better) functioning immune system to ‘cure’ existing infection PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc21haWw8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc21haWw8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS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 EN.CITE.DATA [31, 32]. The model outputs indicate that immediately following completion of therapy the majority of cases occur due to reactivation of ineffectively treated latent infection. While this is in part a consequence of our assumption that IPT is at least sufficient to suppress recent infections to a latent state in all individuals, it is interesting that this effect persists for approximately 50 weeks at which point disease due to reinfection starts to dominate. Several trials of IPT in PLHIV, including a comparison of 6m vs 36m IPT in Botswana PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hbmRhcmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYW1hbmRhcmk8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy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ADDIN EN.CITE.DATA [6, 12] and the THRio study in ART clinics in Brazil ADDIN EN.CITE <EndNote><Cite><Author>Golub</Author><Year>2015</Year><RecNum>437</RecNum><DisplayText>[33]</DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Golub, J. E.</author><author>Cohn, S.</author><author>Saraceni, V.</author><author>Cavalcante, J. P.</author><author>Pacheco, A.G.</author><author>Moulton, L. H.</author><author>Durovni, B.</author><author>Chaisson, R. E.</author></authors></contributors><titles><title>Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium burden tuberculosis setting: the TB/HIV in Rio (THRio) Study</title><secondary-title>CID</secondary-title></titles><periodical><full-title>CID</full-title></periodical><pages>639-645</pages><volume>60</volume><number>4</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>[33], have reported a significant increase in TB rates shortly after completion of therapy. Whether these cases are due to reactivation or reinfection is unclear. Our results strengthen the hypothesis ADDIN EN.CITE <EndNote><Cite><Author>Golub</Author><Year>2015</Year><RecNum>437</RecNum><DisplayText>[33]</DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Golub, J. E.</author><author>Cohn, S.</author><author>Saraceni, V.</author><author>Cavalcante, J. P.</author><author>Pacheco, A.G.</author><author>Moulton, L. H.</author><author>Durovni, B.</author><author>Chaisson, R. E.</author></authors></contributors><titles><title>Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium burden tuberculosis setting: the TB/HIV in Rio (THRio) Study</title><secondary-title>CID</secondary-title></titles><periodical><full-title>CID</full-title></periodical><pages>639-645</pages><volume>60</volume><number>4</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>[33] that the majority of TB occurring in HIV-infected individuals during the first year following completion of IPT is due to reactivation of existing infections. Our results also suggest that, while lack of cure is necessary to reproduce the TB incidence observed in the trial intervention arm, in the longer-term reinfection is responsible for the majority of TB disease. This may partly explain the differences observed in the duration of effect following completion of IPT between trials in high incidence settings (such as South Africa) where the effect was lost quickly and those conducted in lower incidence settings such as Brazil where the benefit persisted for longer ADDIN EN.CITE <EndNote><Cite><Author>Golub</Author><Year>2015</Year><RecNum>437</RecNum><DisplayText>[33]</DisplayText><record><rec-number>437</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">437</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Golub, J. E.</author><author>Cohn, S.</author><author>Saraceni, V.</author><author>Cavalcante, J. P.</author><author>Pacheco, A.G.</author><author>Moulton, L. H.</author><author>Durovni, B.</author><author>Chaisson, R. E.</author></authors></contributors><titles><title>Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium burden tuberculosis setting: the TB/HIV in Rio (THRio) Study</title><secondary-title>CID</secondary-title></titles><periodical><full-title>CID</full-title></periodical><pages>639-645</pages><volume>60</volume><number>4</number><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>[33]. Given that a significant proportion of TB disease is due to recent transmission it is likely that even with a preventive therapy regimen that did cure latent infection, the duration of protection would be limited due to the risk of re-exposure in such high incidence settings. In such circumstances the use of continuous IPT together with improved infection control efforts to reduce exposure to repeated Mycobacterium tuberculosis infections may be necessary to provide long term protection against TB disease.We have assumed that the effect of ART on TB risk is solely due to increases in CD4 cell counts. Differences in CD4 count, and hence risk of TB, between the control and intervention arms were based on trial observations and therefore differences in observed TB incidence due to different CD4 distributions are accounted for in the model. By controlling for the effect of different CD4 counts in this way we can exclude the possibility that the observed effect of IPT is derived from a confounding effect of ART. However it is possible that time on ART modifies disease risk in other ways independent of CD4 count which would not be captured in our model. Drop out (due to death, drug toxicity, or loss to follow-up) was modelled based on rates of drop out observed in the trial and was assumed to be independent of TB status in the model. If this was not the case, for example individuals were more likely to be lost to follow-up if they were at higher risk of disease, this may have influenced our findings. However, numbers of deaths, adverse events and other loss to follow-up were similar by trial arm ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15].The prevalence of drug resistant infections in the model was based on the numbers of drug resistant cases observed in individuals developing active disease in the same setting as the trial. It has been suggested that the use of IPT may select for INH resistance, although a systematic review of the risk of acquired INH resistance following IPT found no conclusive evidence for a link between INH resistance and the use of IPT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxjZWxsczwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxjZWxsczwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE.DATA [34]. We also assumed that INH had no effect in individuals infected with drug resistant strains. Evidence from treatment of active disease suggests that first line drugs, including high dose isoniazid, can be effective in treating drug resistance tuberculosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc3BpbmFsPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fc3BpbmFsPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48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ADDIN EN.CITE.DATA [35-37] but there is limited data on the efficacy of INH in individuals thought to be infected with drug resistant strains of TB ADDIN EN.CITE <EndNote><Cite><Author>van der Werf</Author><Year>2012</Year><RecNum>468</RecNum><DisplayText>[38]</DisplayText><record><rec-number>468</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">468</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van der Werf, M. J.</author><author>Langendam, M. W.</author><author>Sandgren, A.</author><author>Manissero, D.</author></authors></contributors><auth-address>KNCV Tuberculosis Foundation, The Hague, The Netherlands. vanderwerfm@kncvtbc.nl</auth-address><titles><title>Lack of evidence to support policy development for management of contacts of multidrug-resistant tuberculosis patients: two systematic reviews</title><secondary-title>Int J Tuberc Lung Dis</secondary-title><alt-title>The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease</alt-title></titles><periodical><full-title>International Journal of Tuberculosis and Lung Disease</full-title><abbr-1>Int. J. Tuberc. Lung Dis.</abbr-1><abbr-2>Int J Tuberc Lung Dis</abbr-2><abbr-3>International Journal of Tuberculosis & Lung Disease</abbr-3></periodical><pages>288-96</pages><volume>16</volume><number>3</number><keywords><keyword>Antitubercular Agents/*therapeutic use</keyword><keyword>Contact Tracing</keyword><keyword>Health Policy</keyword><keyword>Humans</keyword><keyword>*Policy Making</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Risk</keyword><keyword>Tuberculosis, Multidrug-Resistant/epidemiology/*prevention & control</keyword></keywords><dates><year>2012</year></dates><isbn>1815-7920 (Electronic)
1027-3719 (Linking)</isbn><accession-num>22640442</accession-num><urls><related-urls><url>;[38]. In sensitivity analysis we explored the impact of assuming zero drug resistance, equivalent to assuming INH is effective against drug resistant strains, and found a lower estimate of the proportion cured by INH. As a larger proportion of the latently infected population could potentially be cured by INH so a lower effective cure rate is required to result in the same number of individuals being protected. Conversely, if the prevalence of resistance in the INH arm was higher, the estimated proportion cured would be higher as a greater proportion of those with INH-susceptible infections would need to be successfully cured to produce the levels of TB incidence observed in the trial.ConclusionOur results suggest that IPT can cure LTBI in approximately one third of HIV infected persons also taking ART and therefore provide protection beyond the period of IPT. In low incidence settings, 12 months of IPT in combination with ART may provide additional long term benefit to HIV-infected persons. However the durability of this protection will be limited in high incidence settings where there is a continued risk of exposure to re-infection, and continuous preventive therapy together with improved infection control will be required to provide long-term protection against TB. Author contributions: TS, RMH, MXR, GM and RGW conceived and designed the study. TS and RMH constructed the model and carried out the analysis. MXR and AB analysed and prepared the primary data. TS, RMH, MXR, GM, AB, RJW and RGW wrote the paper.References ADDIN EN.REFLIST 1.Akolo, C., et al., Treatment of latent tuberculosis infection in HIV infected persons (Review). Cochrane Database Syst Rev, 2010. 20(1).2.WHO, WHO policy on collaborative TB/HIV activities: Guidelines for national programmes and other stakeholders, 2012, WHO: Geneva.3.Hawken, M.P., et al., Isoniazid preventive therapy for tuberculosis in HIV-1-infected adults: results of a randomized controlled trial. AIDS, 1997. 11(7): p. 875-82.4.Johnson, J.L., et al., Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS, 2001. 15(16): p. 2137-47.5.Churchyard, G.J., et al., A trial of mass isoniazid preventive therpay for tuberculosis control. NEJM, 2014. 370(4).6.Samandari, T., et al., 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet, 2011. 377: p. 1588-1598.stock, G.W., How much isoniazid is needed for prevention of tuberculosis among immunocompetent adults? International Journal of Tuberculosis and Lung Disease, 1999. 31(10): p. 847-850.8.Houben, R.M., et al., Ability of preventive therapy to cure latent Mycobacterium tuberculosis infection in HIV-infected individuals in high-burden settings. Proc Natl Acad Sci U S A, 2014. 111(14): p. 5325-30.9.Vynnycky, E., et al., Tuberculosis control in South African goldmines: mathematical modelling of a trial of community wide IPT. American Journal of Epidemiology, 2014.10.Jereb, J.A., et al., Recommendations for Use of an Isoniazid-Rifapentine Regimen with Direct Observation to Treat Latent Mycobacterium tuberculosis Infection, in Morbidity and Mortality Weekly Report2011, CDC. p. 1650.11.Maartens, G., E. Decloedt, and K. Cohen, Effectiveness and safety of antiretrovirals with rifampicin: crucial issues for high-burden countries. Antiviral Therapy, 2009. 14(8).12.Samandari, T., et al., Tuberculosis incidence after 36 months' isoniazid prophylaxis in HIV-infected adults in Botswana: a posttrial observational analysis. AIDS, 2015. 29: p. 351-359.13.Golub, J., et al., Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS, 2009. 23(5): p. 631-636.14.Golub, J., et al., The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007. 21(11): p. 1441-1448.15.Rangaka, M.X., et al., Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. Lancet, 2014. 384(9944): p. 682-690.16.Vynnycky, E. and P.E.M. Fine, The natural history of tuberculosis: the implications of age-dependent risks of disease and the role of reinfection. Epidemiology and Infection, 1997. 119: p. 183-201.17.Ziv, E., C.L. Daley, and S.M. Blower, Early therapy for latent tuberculosis infection. Am J Epidemiol, 2001. 153(4): p. 381-5.18.Kritzinger, F.E., et al., No decrease in annual risk of tuberculosis infection in endemic area in Cape Town, South Africa. Trop Med Int Health, 2009. 14(2): p. 136-42.19.Sutherland, I., E. Svandova, and S. Radhakrishna, The development of clinical tuberculosis following infection with tubercle bacilli. Tubercle, 1982. 62(4): p. 255-68.20.Williams, B.G., et al., Antiretroviral therapy for tuberculosis control in nine African countries. Proceedings of the National Academy of Sciences of the United States of America 2010. 107(45): p. 19485-19489.21.Cox, H., et al., Epidemic levels of drug resistant tuberculosis (MDR and XDR-TB) in a high HIV prevalence setting in Khayelitsha, South Africa. PloS One, 2010. 5(11): p. e13901.22.Wood, R., et al., Changing prevalence of TB infection with increasing age in high TB burden townships in South Africa. IJTLD, 2010. 14(4): p. 406-412.23.Alkema, L., A.E. Raftery, and S.J. Clark, Probabilistic projections of HIV prevalence using Bayesian melding. The annals of applied statistics, 2007. 1(1): p. 229-248.24.Rubin, D., Using the SIR algorithm to simulate posterior distributions, in Bayesian Statistics 3, M.H. DeGroot, D.V. Lindley, and A.F.M. Smith, Editors. 1988, OUP: Oxford. p. 395-402.25.Williams, B.G., et al., HIV infection, antiretroviral therapy, and CD4+ cell count distributions in African populations. J Infect Dis, 2006. 194(10): p. 1450-8.26.Verver, S., et al., Transmission of tuberculosis in a high incidence urban community in South Africa. International Journal of Epidemiology, 2004. 33(2): p. 351-357.27.Glynn, J.R., et al., The importance of recent infection with Mycobacterium tuberculosis in an area wuth high HIV prevalence: a long term molecular epidemiological study in Northern Malawi. JID, 2005. 192(3): p. 480-487.28.Lockman, S., et al., Molecular and conventional epidemiology of Mycobacterium tuberculiosis in Botswana: a population-based prospective study of 301 pulmonary tuberculosis patients. J. Clin. Microbiol, 2001. 39(3): p. 1042-1047.29.Houben, R.M., et al., Human immunodeficiency virus increases the risk of tuberculosis due to recent re-infection in individuals with latent infection. Int J Tuberc Lung Dis, 2010. 14(7): p. 909-15.30.Middelkoop, K., et al., Transmission of Tuberculosis in a South African Community With a High Prevalence of HIV Infection. JID, 2015. 211(1): p. 53-61.31.Esmail, H., C. Barry, and R.J. Wilkinson, Understanding latent tuberculosis: the key to improved diagnostic and novel treatment strategies. Drug Discovery Today, 2012. 17(9-10).32.Wilkinson, K.A., et al., Effect of treatment of latent tuberculosis infection on the T cell response to Mycobacterium tuberculosis antigens. The Journal of Infectious Diseases, 2006. 193(3): p. 354-359.33.Golub, J.E., et al., Long-term protection from isoniazid preventive therapy for tuberculosis in HIV-infected patients in a medium burden tuberculosis setting: the TB/HIV in Rio (THRio) Study. CID, 2015. 60(4): p. 639-645.34.Balcells, M.E., et al., Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis, 2006. 12(5): p. 744-51.35.Espinal, M.A., et al., Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA, 2000. 283(19): p. 2537-45.36.Katiyar, S.K., et al., A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis, 2008. 12(2): p. 139-45.37.Caminero, J.A., et al., Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis, 2010. 10(9): p. 621-9.38.van der Werf, M.J., et al., Lack of evidence to support policy development for management of contacts of multidrug-resistant tuberculosis patients: two systematic reviews. Int J Tuberc Lung Dis, 2012. 16(3): p. 288-96.TablesStatePlacebo Arm (p=0)INH ArmCuredC0(1-(1-ARI)a) p (1-δ)Never InfectedS(1-ARI)a(1-ARI)aRecently infectedIi=1,2((1-ARI)(a-i))(1-(1-ARI))((1-ARI)(a-i))(1-(1-ARI))(1-δ)Recently reinfectedRi=1,2(1-(1-ARI)(a-i))(1-(1-ARI))(1-(1-ARI)(a-i))(1-(1-ARI))(1-δ)Latently infectedL1-C-S-I-R1-C-S-I-RPrimary TBTp00Endogenous TBTn00Exogenous TBTx00Table 1 – Initial conditions in the model. ARI=Annual risk of infection; p=proportion cured following IPT; a=average age of the cohort; δ=proportion of individuals with drug resistance in the model population; i indicates time since infection (years). 0-11 months>12monthsTrial observations ADDIN EN.CITE <EndNote><Cite><Author>Rangaka</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText>[15]</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="sw9ae0rr5wzztker2s7pzp0w2p0tp22xpred">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rangaka, M.X.</author><author>Wilkinson, R. J.</author><author>Boulle, A.</author><author>Glynn, J. R.</author><author>Fielding, K.L.</author><author>van Custem, G.</author><author>Wilkinson, K. A.</author><author>Goliath, R.</author><author>Mathee, S.</author><author>Goemaere, E.</author><author>Maartens, G.</author></authors></contributors><titles><title>Isoniazid plus antiretroviral therpay to prevent tuberculosis: a randomised double-blind, placebo-controlled trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>682-690</pages><volume>384</volume><number>9944</number><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[15]0.61 (0.30-1.21)0.78 (0.39-2.0)Model0.48 (0.29-0.65)0.75 (0.53-0.92)Table 2 – Hazard Ratios. Comparison of model and observed hazard ratios at different trial time periods. Months are time after study drug course completion.Figure LegendsFigure 1 – Schematic of the model. The model structure is the same for placebo and INH trial arms but differs in initial conditions (see table 1). Dashed arrows indicate the distribution of cases at the start of the trial follow-up period (after IPT cessation) and represents the initial state of the model. The recently infected and recently reinfected compartments are subdivided into two stage but these are not shown here for clarityFigure 2 – Fit of the model to data. a) Fit to LTBI prevalence. Solid line shows data, dashed shows distribution from 200,000 re-sampled model runs. b) Fit to TB incidence. Points show incidence rate measured in the trial together with 95% confidence intervals (data points are offset to aid visualisation). Lines show the median model output and shaded regions the 95% credible interval calculated from the 200,000 re-sampled model runs.Figure 3 – Posterior distributions of the annual risk of infection (ARI) and proportion of LTBI cured following IPT (p). Uniform prior distributions shown by horizontal dotted lines. Posterior distributions are shown by the solid curves. Dashed vertical lines indicate the median values. 95% and 75% credible intervals (highest density probability) are shown by light and dark shaded areas respectively. Results are shown for the default scenario (resistance =12.5%).FiguresFigure 1b)a)Figure 2a)b)Figure 3 ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.