Introduction Thirty years after HIV-1 was first recognized, the epidemic continues with 2.6 million people newly infected in the past year [1]. Antiretroviral therapy (ART) can dramatically improve the survival of HIV-1–infected persons and is the cornerstone of strategies to prevent vertical HIV-1 transmission [2],[3]. 5.2 million people living with HIV-1 in low- and middle-income countries have been provided with life-saving ART [1]; however, reduced funding for AIDS programs as a result of the global economic crisis threatens these acheivements, and a sustainable response to the HIV-1 epidemic requires a large reduction in the numbers becoming infected [1],[4],[5]. Many different forms of interventions are used to help reduce the spread of HIV, and recently UNAIDS have proposed a framework that prioritises condom promotion, interventions for key populations, behaviour change programmes, male circumcision, prevention of mother-to-child transmssion, and treatment for people living with HIV as a basic set of program activities that should form the core of responses to the epidemic [6]. Recently, substantial scientific interest has developed in antiretroviral-based strategies for prevention of sexual HIV-1 transmission [7],[8]. In the past year, four clinical trials have closed confirming that antiretrovirals have the potential to be used as: (i) ART to reduce the infectiousness of HIV-1–infected persons [9], and (ii) oral or topical pre-exposure prophylaxis (PrEP) for uninfected persons to reduce acquisition [10]–[12]. Although there is much scientific enthusiasm about antiretroviral-based HIV-1 prevention, many questions remain about how best to marshal these tools to achieve the optimal impact [13],[14]. Here we aim to synthesize these new findings to understand how PrEP and ART could be used to reduce HIV transmission in stable HIV serodiscordant couples. ART reduces plasma and genital HIV-1 concentrations to undetectable levels in most treated individuals [15],[16], and observational studies, and a recent large multicentre clinical trial, have demonstrated large reductions in HIV-1 infectiousness (>90% reduction in transmission risk) in persons receiving ART [9],[17]–[21]. WHO guidelines currently recommend ART initiation at CD4 counts of 50% among those with high adherence to the intervention. Two further clinical trials testing the efficacy of daily oral tenofovir and oral emtricitabine-tenofovir in serodiscordant couples and heterosexual women have recently stopped, reporting a strong protective effect (>60%) of PrEP [11],[12]. These findings mirror those for daily oral PrEP in men who have sex with men (the iPrEX study) [28]. One trial (FemPrEP) testing the effect of oral daily emtricitabine tenofovir PrEP in heterosexual women [29] and the part of a large trial (the VOICE study) testing the effect of oral daily tenofovir in women [30] have also been stopped after interim reviews found that it was unlikely these studies would demonstrate benefit, and investigations in the likely causes for this are underway. High enthusiasm for antiretroviral-based HIV-1 prevention has been balanced by recognition of the need for strategies to efficiently deliver these expensive new prevention options [8]. It may be optimal and cost-effective in concentrated epidemics to preferentially deliver these interventions to those at highest risk of transmission, such as sex workers or individuals that inject drugs if benefit is observed on on-going trials [31]. However, in the generalized heterosexual epidemics in sub-Saharan Africa, most transmission occurs outside of such easily identified risk groups [1]. One group that has been identified as a high priority for HIV-1 prevention is uninfected individuals in long-term sexual partnerships with HIV-1–infected individuals, i.e., stable HIV-1 serodiscordant couples [32]–[35]. The proportion of stable partnerships in southern Africa that are serodiscordant has been estimated to be between 10% and 20% [36], and in the community mobilization work for the Partners in Prevention Study, 27% of couples tested at three South African sites (Cape Town, Orange Farm, and Soweto) were HIV-1 serodiscordant [37]. Condom use is typically low in stable partnerships [38], particularly during periods when couples desire pregnancy, during which the risk of HIV-1 acquisition and transmission is increased [39]. HIV-1 incidence can be high in these partnerships and, importantly, not all of the risk to the uninfected individual comes from their stable partner. By comparing the genetic sequence of the virus in serodiscordant couples where the HIV-1–uninfected partner became infected, it has been estimated that the HIV-1–infected partner was not the source of infection in approximately ∼30% of couples [40]. In these cases, PrEP—but not ART for the infected partner—could offer protection against infections that might arise from additional partners. Given the constrained resources for HIV-1 treatment and prevention in sub-Saharan Africa, many questions need to be considered regarding the relative benefits and costs of PrEP and earlier ART for HIV-1 prevention, specifically in potential target groups such as HIV-1 serodiscordant couples, including: (i) Is there any benefit of PrEP when ART is available and initiated promptly upon meeting CD4 criteria for the HIV-1–infected partner and, if there is, what patterns of PrEP use maximize this benefit?; (ii) when might earlier ART initiation (at either CD4 cell count 250 cells/µl and was not eligible for ART by national guidelines; we refer to this assumption as the “partners in prevention” scenario. HIV-1 seroincidence was relatively low (∼1.8/100 person-years at risk [pyar]) in the Partners in Prevention HSV/HIV Transmission Study cohort, which was likely owing to selecting couples willing to participate in an HIV-1 prevention clinical trial, frequent couples risk-reduction counselling, and resultant high condom use. Therefore, we constructed another set of assumptions, named “more typical couples”, in which 50% of the partnerships involved HIV-1–infected men (to correspond to the gender distribution of HIV-1 serodiscordancy in population-based studies in Africa [34]), condom use within the stable partnership was reduced to 75% of that reported in the partners in prevention cohort, 50% more of the HIV-1–uninfected partners in couples had external partners, and the frequency of unprotected sex with external partners was double that reported in the Partners in Prevention Study [41],[42]. The assumptions made in the “more typical couples” scenario were such that the overall incidence rate among these couples was consistent with other empirical measurements of HIV-1 incidence in serodiscordant couples (7.7/100 pyar in Zambia [43] and 9.2/100 pyar in Uganda [21]) and reflected the balance of infections from stable partners versus other partners implied by phylogenetic analysis of viral sequences in couples in Rakai, Uganda [44]. Three other sets of assumptions about couples' behaviour were also made and the results are shown in the supplementary materials (Text S1). 10.1371/journal.pmed.1001123.t001 Table 1 Key assumptions made in the model. Parameter Values Source Infectiousness of untreated individuals (relative to those with CD4 cell count ≥500 cells/µl) CD4 350–500: 1.00 Cohort of stable serodiscordant couples [20] CD4 200–350: 1.59 CD4 0–200: 4.99 Mean time spent in CD4 cell count category (y)a Infection to CD4 of 500: 2.4 Pooled analysis of African observational cohort studies [66] CD4 350–500: 2.4 CD4 200–350: 4.6 CD4 0–200: 2.6 Relative infectiousness of those on ART (relative to those untreated with CD4 cell count 70%) and low cost of delivery (<40% annual cost of ART). If used in couples that remain at high risk, PrEP could be as cost-effective as earlier ART even if PrEP had effectiveness of ∼40%. Third, in lower risk couples, earlier ART at CD4<500 may be the most cost-effective strategy, but, in couples that remain at high risk, PrEP and ART could be used together (PrEP in the uninfected individual prior to ART initiation for their HIV-1–infected partner) to deliver maximal benefit and best cost-effectiveness. We hope this might inform the choices that will be available for HIV prevention in couples. We note, however, that it is important that many other considerations besides cost-effectiveness should inform decision-making for HIV treatment initiation and provision of PrEP in couples, including equitable access and the preferences of the couples themselves. The principal determinants of the eventual use of PrEP among stable serodiscordant couples will be PrEP effectiveness, relative costs of PrEP and ART delivery, and couples' sexual behaviour. Using the model, we have defined a “target product profile,” the cost and effectiveness level for PrEP at which its use in a couple would to be at least as cost-effective as starting ART earlier in couples with different patterns of behaviour. The model shows that, if couples risk behaviour is reduced through risk reduction counselling, and becomes more like the behaviours reported by the “partners in prevention” clinical trial couples, then earlier initiation of ART is probably a more cost-effective way to manage infection and prevent HIV-1 infection (i.e., keeping couples “alive and HIV free”), unless PrEP in “real world” settings is at least as effective as indicated in recent trials among couples [11]. However, the model also shows that, in couples with risks similar to those recorded in observational studies (“more typical” behaviour assumptions [21],[43]), with a PrEP effectiveness similar to that observed in recent trials [11], and at a cost of delivery consistent with optimistic forecasts [53], PrEP use among the uninfected partner could be as cost-effective as earlier treatment, and even a cost-saving intervention in its own right. This outcome highlights how the behavioural profile of couples influences the potential utility of PrEP and illustrates the importance of maximizing efficiency by prioritizing interventions for highest risk couples. It also shows the need for further research into the behaviours of those in long-term serodiscordant couples, their responses to the counselling, and their preferences for these different forms of intervention, in order to develop responsive and appropriate programs. We note that although the feasibility of delivering ART is proven, the feasibility of PrEP is unknown and currently being investigated, so the information available about each option is not equal. Nonetheless, this analysis does support that PrEP could become one reasonable option that couples in this situation can be offered. And greater choices in HIV prevention should be welcomed as this can lead to increased uptake of services and better protection overall. These calculations should also inform decision making about investment in new technologies—for instance, by setting a limit on the cost for potential future longer-lasting PrEP formulations that may be more effective. All these considerations are, of course, influenced by the estimated cost of ART, which, through renegotiated drug supply contracts and task-shifting in clinics, might be expected to fall considerably in the coming years [54], which would tend to make earlier ART more cost-effective. We have explored these trade-offs using a detailed mathematical model that is parameterized and calibrated with data from stable serodiscordant heterosexual couples in South Africa, which included information on the sources of infection for those acquiring HIV-1 (i.e., whether infected by their stable partner or another partner). However, these couples may have lower risks of infection than HIV-1 serodiscordant couples in the general population due to study eligibility criteria and their participation in intensive HIV-1 prevention counselling during a clinical trial. Nonetheless, PrEP delivery programs would require initial HIV testing, and ideally will promote and provide couples HIV counselling and testing, so knowledge of serostatus and condom use will likely increase as has been reported among HIV serodiscordant couples in other studies [55],[56]. Sensitivity analyses were used to explore how differences in sexual behaviour affected the results. The data available from the Partners in Prevention trial [41],[42] cannot fully specify the long-term behaviour of couples in the model because couples were only followed for a 2-y period, whereas the model tracks individuals over their adult lifetimes. The use of the extended time-horizon of the simulation enabled the analysis to reflect the cumulative risk of transmission/death and total costs, whereas a short-term approach would not indicate whether infections in couples are averted or just delayed and would not capture the full cost implications of different strategies (e.g., because life-years saved and ART costs may follow many years after initial PrEP costs). The choice of outcome measure depends upon the relative value placed on preventing death and preventing HIV infection. The QALY approach emphasizes reduced deaths whereas the “alive and HIV free” metric gives more weight to HIV infection, which would often be survived with treatment. Giving more weight to averted infections also helps to implicitly reflect reduced risk of onward HIV transmission. If further data become available about the added clinical benefits to patients of ART initiation at higher CD4 cell counts rather than indicated in current national and international guidelines, then these should be used to update the model and revise this analysis. We also note that in the analysis the wider benefits of the intervention (or the cost of nonintervention), such as increased labour availability and economic growth, are not included in the calculations. Issues regarding the trade-offs between PrEP and ART for immediate clinical need, including the attendant ethical considerations, are important in the wider debate about resource allocation in HIV programs, but were not relevant here because we only investigated use of PrEP in couples after universal access to ART (at current national and international guidelines) has been achieved. Many countries aim to achieve this by 2015 [57], but we recognize that realistically this may not be achieved until many years later [1]. Many simplifying assumptions were made in the model, including not representing any change in risk behaviours during ART or PrEP use (i.e., potential “risk compensation” from feeling less at risk due to PrEP or ART use), the long-term interaction between PrEP and ART effectiveness through selection of resistant strains of virus [58],[59], or potential effects of sexually transmitted infections on the efficacy of ART or PrEP [60]. The model, and the chosen outcome measures, also do not capture the external sexual partner network so that, for instance, it does not account for the possibility that an averted infection terminates a chain of further infections [61], including averted infections among children. This factor may be expected to influence the estimated impact of ART and PrEP similarly (although further work is required to examine this) because, while ART reduces transmission to the infected individual's other partners, PrEP reduces the chance of infection and the subsequent risk of onward transmission to their partners, including during the initial highly infectious phase [25]. The model also does not reflect that the HIV-1 prevalence and infectiousness among external partners will be influenced by patterns of PrEP and ART use in the wider population [62],[63]. The impact of ART on the incidence of other diseases, particularly tuberculosis, was not explicitly captured and this could lead to an underestimation of the benefit of ART, although the CD4-level–specific mortality rates in untreated individuals and utility-weights in the QALY analysis should implicitly reflect the deterioration in health that is associated with advanced HIV-1 infection [64]. Interpretation of the results is further complicated by key uncertainties in the estimates of the cost of PrEP, which is inevitable given that PrEP delivery programs have not yet been implemented. However, the analyses presented here reflect these uncertainties and it is reassuring that our assumptions for the annual cost of PrEP (and the ratio of PrEP to ART costs) are similar to those independently derived by Pretorius et al. [63]. Although these results suggest that the use of PrEP in HIV-1 serodiscordant couples could be cost-effective and have a significant impact on HIV incidence for that group, there are still significant logistical challenges that are not captured in the model. The identification and retention of discordant couples in services varies from setting to setting, and has been shown to be particularly difficult in South Africa. In such settings the feasibility and cost of targeting discordant couples (and, in particular, couples in which the woman might be pregnant/trying to conceive) could make an intervention utilizing PrEP much more expensive. Lastly, although we hope that this model will assist in policy-making decisions, we recognize that other factors beyond effectiveness and cost will also influence the introduction of PrEP for certain groups. This analyses focuses on heterosexual HIV-1 serodiscordant couples in sub-Saharan Africa but similar questions could be asked for other groups such as men who have sex with men (MSM) in Africa and elsewhere. Different behavioural, biological, and program parameter values would be required for analyses in these different high risk groups reflecting for example the much higher risk of transmission per unprotected sex act [65] in MSM and the higher cost of treatment for MSM in developed countries. However, the same general principles would apply: the lower the cost and the higher the effectiveness of PrEP, the more likely it is that PrEP will be a cost-effective way to support serodiscordant couples. In summary, PrEP might become a valuable addition to combination approaches for HIV-1 prevention among stable serodiscordant couples in sub-Saharan Africa, in conjunction with ART. If PrEP is used by individuals that remain at high risk of infection prior to a partner's ART initiation, the additional cost per infection averted might be smaller than previously anticipated or the intervention could even be cost-saving, and the use of PrEP could be as cost-effective as earlier ART initiation. However, this outcome completely relies on the delivery cost of PrEP meeting current forecasts, and the “real-world” effectiveness of PrEP in couples being comparable to that found in the clinical trial [11]: if adherence to PrEP outside of trials is lower, or if PrEP is more expensive to deliver than expected, PrEP could be much less cost-effective. It is vital to understand these trade-offs as soon as possible so that programmatic decision making and implementation can quickly proceed. Supporting Information Figure S1 Incremental costs and impact of different PrEP implementation strategies for (A) “partners in prevention” couples and (B) “more typical couples”. In (A) and (B), the extra lifetime (discounted) cost of ART and PrEP (horizontal axis) and the numbers of couples in which an HIV infection is averted (by the age of 50) (vertical axis) are compared when PrEP is: (i) not used (baseline simulation, black star); (ii) always, purple polygon); (iii) up to ART initiation of partner and one year more, red polygon; (iv) up to ART initiation of partner, blue polygon (Table 2). The boundaries of the polygon are given by the ranges of PrEP efficacies and costs given in Table 1. The dot indicates the midpoint of the polygon and the black line connects the scenarios with the highest impacts (infections averted) at different levels of cost. (PDF) Click here for additional data file. Figure S2 The impact of different PrEP interventions in each of the three alternative types of couples (less condom use, more external partners, and more infected men) relative to the characteristics of the partners in prevention cohort. (A, C, E) The proportion of infections averted (relative to a baseline scenario with no PrEP intervention) for each of the four PrEP interventions (see Table 2). (B,D,F) The expected cost per infected averted for each of the four PrEP interventions: the pink and blue boxes reflect the lower and higher of the PrEP cost estimates and the higher and lower of the ART cost estimates, respectively. In (A–F), the boxes show a feasible range of results, which corresponds to a functional efficacy of PrEP ranging between 50% and 80%. (PDF) Click here for additional data file. Figure S3 Comparison of PrEP versus earlier ART initiation. This is the same analysis as shown in Figure 2 in the main text but with the frontiers shown for each of the five sets of couples assumptions [see Text S1]. In (A) and (B), the relative cost of PrEP to ART and the functional effectiveness of PrEP are varied. (A) The area to the right of the lines demarcates a region where PrEP use prior to partners' treatment at CD4 cell count below 200 would lead to more couples being “alive and HIV Free at 50” than an ART intervention of the same cost whereby the infected partner is initiated on treatment at CD4 cell count below 350. (B) The area to the right of the lines demarcates a region where PrEP use prior to partners' treatment at CD4 cell count below 350 would lead to more couples being “alive and HIV free at 50” than an ART intervention of the same cost whereby the infected partner is initiated on treatment at CD4 cell count below 500. The different lines show the frontier for the following assumptions about couples behaviour: “partners in prevention,” solid black line (as shown in Figure 2); “less condom use,” dashed blue line; “more extra partners,” dashed green line; “more men infected,” solid grey line; and “more typical couples”, dashed pink line (as shown in Figure 2). Cost is calculated as the total lifetime discounted cost of person-years on PrEP and ART of both partners in initially HIV-1 serodiscordant couples. (PDF) Click here for additional data file. Figure S4 Comparison of PrEP versus earlier ART initiation. This is the same analysis as shown in Figure S2 but with outcome defined as QALYs [see Text S1]. In (A) and (B), the relative cost of PrEP to ART and the functional effectiveness of PrEP are varied. (A) The area to the right of the lines demarks a region where PrEP use prior to partners' treatment at CD4 cell count below 200 would lead to a greater gain in QALYs than an ART intervention of the same cost whereby the infected partner is initiated on treatment at CD4 cell count below 350. (B) The area to the right of the lines demarcates a region where PrEP use prior to partners' treatment at CD4 cell count below 350 would lead to a greater gain in QALYs than an ART intervention of the same cost whereby the infected partner is initiated on treatment at CD4 cell count below 500. The different lines show the frontier for the following assumptions about couples' behaviour: “partners in prevention,” solid black line (as shown in Figure 2); “less condom use,” dashed blue line; “more extra partners,” dashed green line; “more men infected,” solid grey line; and “more typical couples”, dashed pink line (as shown in Figure 2). Cost is calculated as the total lifetime discounted cost of person-years on PrEP and ART of both partners in initially HIV-1 serodiscordant couples. (PDF) Click here for additional data file. Figure S5 The effect of drop-out and mortality assumptions on the impact of ART. Comparisons of the infections averted in couples (A) and the QALYs accrued by the couple with treatment initiated at CD4<200 (blue bars) or CD4<500 (red bars) making different sets of assumptions about mortality on ART and drop-out from ART. The assumptions about mortality and drop-out from ART are as follows: “default assumptions” uses the parameter values given in Table 1; “lower drop-out and mortality” uses mortality-rates that are 25% lower and drop-out rates that are 50% lower; “higher drop-out and mortality” used mortality-rates that are 25% higher and drop-out rates that are 50% higher.” (PDF) Click here for additional data file. Figure S6 Impact versus costs for combination strategies of ART and PrEP. (A) “Partners in prevention couples” and (B) “more typical couples.” The strategies depicted are: no intervention, purple star; ART initiated by the HIV-1–infected partner at 200 cells/µl with no PrEP, solid blue triangle or with PrEP used by the uninfected partner until their partner initiates ART (with varying degrees of PrEP effectiveness: open blue circle, 30%; open blue diamond, 60%; or open blue pentagram, 80%); with ART initiated at 350 cells/µl with no PrEP, solid red triangle, or with PrEP used by the uninfected partner until ART initiation by their partner (with the same values for PrEP effectiveness and respective shapes in red); and ART initiated at CD4 count of 500 cells/µl, solid black triangle. (PDF) Click here for additional data file. Text S1 Description of the model structure and all parameter values used in the model with detailed justifications and explanations. (PDF) Click here for additional data file.
