ONLINE ONLY MATERIAL



ONLINE ONLY MATERIAL

Methods

Section S1: Model representation of the natural history of HIV and other STIs and their interaction

HSV-2 natural history was categorised into primary ulcerative, early-latent, latent, and late-latent stages. After the primary ulcer, recurrent ulcers are modelled to occur in the early-latent and latent stages with decreasing frequency from time since infection. Per-contact male-to-female(MtoFtp) transmission probabilities for both HIV and HSV-2 were assumed to be twice those for female-to-male(FtoMtp)[1, 2]. HSV-2 transmission probabilities were assumed to be highest during primary HSV-2(MtoFtp= 0.29), and lower during periods of ulcer recurrence(MtoFtp= 0.20)[3]. Between ulcer recurrences, a very low HSV-2 transmission probability was assumed during the early-latent(MtoFtp= 0.01) and latent(MtoFtp= 0.005) stages to account for transmission that may occur during sub-clinical shedding[1, 4-13]. We assumed an HSV-2 transmission probability of zero during the late-latent stage.

HSV-2 ulcers increase HIV acquisition and transmission. The magnitude of the per-contact HSV-2 cofactor effects for HIV acquisition and transmission were chosen to be at the lower end of the estimated range for ulcers(3-300) to account for possible residual confounding[14, 15] and have been subject to sensitivity analyses[16]. The co-factor effect was assumed to be the same for acquisition and transmission and was taken as 25 for primary HSV-2 ulcers and 10 for recurrent HSV-2 ulcers. Although biologically plausible[17], no increase in the risk of HIV acquisition or transmission was assumed for the periods of sub-clinical shedding between ulcers, due to the lack of definitive data. We have previously shown that these co-factor effects give relative risks for the association of HIV and HSV-2 prevalence in line with the empirical data[18]. We assumed that frequency and duration of ulcerative recurrences were quadrupled during the symptomatic and AIDS stages of HIV infection[19, 20].

Other model parameter values, for the demography, sexual behaviour and natural history of the other STIs and their interaction with HIV were as reported in our previous publication[21], except that the mean survival time from HIV infection to death was increased from 10 to 11 years in line with the findings of a recent meta-analysis[22]. Cofactor effects of other STIs on HIV susceptibility and infectivity were assumed to be 25 for chancroid, 7.5 for primary syphilis, and 3 for Gonorrhoea and chlamydia infection. Lack-of-male-circumcision was assumed to double the per-contact probability of male acquisition of HIV, syphilis and chancroid[23]. In the model, in a sexual encounter in which there is more than one cofactor present, only the highest of the relevant cofactor effects is assumed to act on the probability of HIV transmission in that sexual act. Natural history parameters of all STIs were held constant across the cities. Simulated population composition and growth rate are determined in STDSIM by inputs relating to fertility, mortality and migration[21].

Section S2: Clinician initiated episodic therapy

Clinician initiated episodic therapy for HSV-2 was targeted at a proportion of symptomatic individuals who were simulated to recognize their ulcer, seek treatment and benefit from reduced ulcer duration. We proposed a low, medium and high value for each of these parameters. We assumed 10%, 20% and 60% of individuals recognised their ulcers, respectively. The medium estimate was based on a review by Brugha et al that found that in large-scale retrospective studies around 20% of HSV-2 infected individuals reported a history of symptomatic genital herpes[24] with the low estimate taken as the lower bound from an earlier study reporting similar findings[25]. Using these data we will tend to overestimate the proportion of individuals who recognise a particular ulcer episode because reported history of ulcers is a cumulative outcome. However, this overestimate will be countered to some extent because some individuals never experience a clinical episode. Our ‘high’ estimate was based on a study that found that after training, around 50% of women who initially reported no symptoms could be shown to accurately identify clinically recognisable genital lesions (calculated as 20%+80%(50%=60%)[26]. Of those recognising their ulcer, we assumed 39%(low scenario), 48%(medium scenario) and 72%(high scenario) of individuals sought treatment, based on data on treatment seeking from rural Tanzania in the 1990s[27] and from rural South Africa in 2003-4(pc Nuala McGrath Jan 2008). In treated individuals, we assumed the duration of primary HSV-2 ulcers was reduced by 20%(low scenario), 31%(medium scenario) and 37%(high scenario) respectively based on the minimum, mean and maximum estimates of the time until healing, after adjusting for treatment delays, from three studies[28-30]. We assumed the duration of recurrent HSV-2 ulcers was reduced by 0%(low scenario), 9%(medium scenario) and 21%(high scenario) respectively based on the minimum, mean and maximum estimates of the reduction in ulcer duration, after adjusting for treatment delays, from five studies[28, 29, 31-33].

Section S3: Patient initiated episodic therapy

Patient initiated episodic therapy for recurrent HSV-2 ulcers was targeted at a proportion of symptomatic individuals who were simulated to recognize their symptoms, self-treat and benefit from reduced ulcer duration. In this scenario we simulated clinician initiated episodic therapy for primary ulcers as above. For recurrent ulcers we assumed the same proportion recognised their symptoms as for clinic-based therapy, but assumed a higher proportion of those with recurrent ulcers received treatment, because of the less frequent need for clinic visits, and assumed a greater reduction in ulcer duration because of the earlier initiation of treatment. For recurrent ulcers we assumed 50%(low scenario), 70%(medium scenario) and 90%(high scenario) of symptomatic patients self-treated. The high estimate was based on adherence data from two patient initiated therapy trials[34, 35]. In the absence of other data, the low and medium estimate were assumed to be lower than this, but higher than for clinician initiated therapy. For recurrent ulcers we assumed that patient initiated episodic therapy reduced the duration of recurrent HSV-2 ulcers by 14%(low scenario), 29%(medium scenario) and 74%(high scenario) based on the minimum, mean and maximum point estimates from seven patient-initiated therapy studies[31, 34, 36-40].

Section S4: Suppresive therapy

Suppressive HSV-2 therapy was initiated in a proportion of HSV-2 infected individuals who were simulated to start therapy and stop after a finite period of time. Suppressive therapy was assumed to increase the interval between ulcers, reduce the duration of ulcers and reduce the infectiousness of HSV-2(but had no direct effect on HIV). We proposed a low, medium and high value for each of these parameters. We assumed that the interval between ulcers was increased by 350%, 575% or 700% based on the minimum, median and maximum point estimates from three RCTs of suppressive therapy[12, 41, 42]. We assumed suppressive therapy reduced the duration of ulcers by 14%, 29% and 74%, by assuming in the absence of multiple studies, that suppressive therapy should be at least as effective as patient initiated therapy and noting that our medium value is in line with the available empirical data(25% reduction)[41]. We assumed suppressive therapy reduced the infectiousness of HSV-2 by 65%, 81% and 96% based on the minimum, mean and maximum of data on the reduction in HSV-2 shedding days from seven studies in populations not in need of highly active anti-retroviral therapy(HAART)[12, 43-48]. We assumed that the effect on HSV-2 infectivity applied during the ulcerative and non-ulcerative periods of the primary, early latent and latent stages of HSV-2.

Section S5: Sensitivity analysis

We assessed the robustness of our findings to key baseline and intervention parameter values known to affect impact.

To explore the sensitivity of our results to our assumed baseline parameter values we modelled two scenarios in which we assumed a per-contact HIV cofactor effect between HSV-2 ulcers in both the early-latent and latent stages of 2.0 or 3.0(cofactor=1 in baseline scenario). In these scenarios, to avoid over-estimating the total impact of HSV-2 on HIV, the population attributable fraction(PAF) of HSV-2 for HIV transmission was refitted to the mean PAF in Cotonou and Kisumu over 2008-2012 in the baseline scenarios(40%), by reducing the magnitude of the cofactor effects assumed for primary and recurrent ulcers. We also simulated scenarios in which the assumed per-contact HIV cofactor effects for HSV-2 ulcers were doubled and halved. In these scenarios we refitted the HIV prevalence in 1997 by varying the HIV transmission probabilities. In all scenarios the biological parameter values were kept constant across the two cites. See figure footnotes for fitted parameter values in alternative scenarios.

To explore the sensitivity of our results to our assumed intervention parameter values we varied each intervention parameter in turn from its medium value to its high or low value. For episodic therapy we present this sensitivity analysis for clinician and patient initiated therapy in Cotonou and Kisumu. For suppressive therapy we present this sensitivity analysis for the scenario in which 50% of the general population is treated for life in Cotonou and Kisumu.

The impact of the intervention on HIV and HSV-2 incidence over 20 years was recalculated in each alternative scenario and compared with that predicted in the baseline scenarios.

References

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[39] Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Valaciclovir HSV Study Group. Arch Intern Med. 1996 Aug 12-26;156(15):1729-35.

[40] Ruhnek-Forsbeck M, Sandstrom E, Andersson B, Eriksson G, Hersle K, Lovhagen GB, et al. Treatment of recurrent genital herpes simplex infections with oral acyclovir. J Antimicrob Chemother. 1985 Nov;16(5):621-8.

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Results

Figure S1

Sensitivity analysis of the impact of episodic therapy to intervention parameter values For default parameter values see methods. Note difference in y-axis scale. ↑= increase; ↓= decrease; treat.= treatment; prim.= primary; recq.= recurrent;

| |Cotonou |Kisumu |

|Reductio|[pic] |[pic] |

|n in | | |

|HSV-2 | | |

|incidenc| | |

|e | | |

|over 20 | | |

|years | | |

|Reductio|[pic] |[pic] |

|n in HIV| | |

|incidenc| | |

|e | | |

|over 20 | | |

|years | | |

Figure S2

Sensitivity analysis of the impact of suppressive therapy to intervention parameter values. The default scenario show here is for 50% coverage of the general population with lifelong treatment duration. Note difference in y-axis scale. ↑= increase; ↓= decrease; int. bet. = interval between.

| |Cotonou |Kisumu |

|Reduction |[pic] |[pic] |

|in HSV-2 | | |

|incidence | | |

|over 20 | | |

|years | | |

|Reduction |[pic] |[pic] |

|in HIV | | |

|incidence | | |

|over 20 | | |

|years | | |

Figure S3

Sensitivity analysis of the impact of suppressive and episodic therapy to baseline parameter values. The default scenarios shown here are the ‘medium’ parameter sets for clinician and patient initiated episodic therapy and the ‘medium’ parameter set for the 50% coverage of the general population with lifelong treatment duration for suppressive therapy. Note difference in y-axis scale. B’tween ulcer cof= HSV-2 cofactor effect on HIV transmission between HSV-2 ulcers; Ulcer cofactor= HSV-2 ulcer cofactor effect on HIV transmission; Dbl = double. Fitted cofactor effect magnitudes were 17.86 for primary ulcers and 7.14 for recurrent ulcers in the between-ulcer cofactor = 2 scenario, and 6.96 for primary ulcers and 4.32 for recurrent ulcers in the between-ulcer cofactor = 3 scenario. Fitted mean per-contact HIV transmission probabilities were 0.392% from males to females and 0.196% from females to males in the ‘double’ HSV-2 cofactor scenario and 0.469% from males to females and 0.234% from females to males in the ‘half’ HSV-2 cofactor scenario.

| |Cotonou |Kisumu |

|Reduction |[pic] |[pic] |

|in HSV-2 | | |

|incidence | | |

|over 20 | | |

|years | | |

|Reduction |[pic] |[pic] |

|in HIV | | |

|inciednce | | |

|over 20 | | |

|years | | |

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