Conceived and designed the experiments: TBH JB RH CC. Performed the experiments: TBH. Analyzed the data: TBH RH JB CC. Wrote the first draft of the manuscript: TBH. Contributed to the writing of the manuscript: TBH JB RH RB GB IC SD GPG GG LJ JM HR CC. ICMJE criteria for authorship read and met: TBH JB RH RB GB IC SD GPG GG LJ JM HR CC. Agree with manuscript results and conclusions: TBH JB RH RB GB IC SD GPG GG LJ JM HR CC.
TBH has received consultancy fees from the Bill & Melinda Gates Foundation for work not directly related to the present work. GPG has in the past been a consultant in the field of Human Papilloma Virus research to Glaxo SmithKline and Merck, and has been a consultant in the field of stem cell transplantation to ViroPharma, but has no conflicts of interest in the HIV field. All other authors have declared that no competing interests exist.
Hallett et al use a mathematical model to examine the long-term impact and cost-effectiveness of different pre-exposure prophylaxis (PrEP) strategies for HIV prevention in serodiscordant couples.
Antiretrovirals have substantial promise for HIV-1 prevention, either as antiretroviral treatment (ART) for HIV-1–infected persons to reduce infectiousness, or as pre-exposure prophylaxis (PrEP) for HIV-1–uninfected persons to reduce the possibility of infection with HIV-1. HIV-1 serodiscordant couples in long-term partnerships (one member is infected and the other is uninfected) are a priority for prevention interventions. Earlier ART and PrEP might both reduce HIV-1 transmission in this group, but the merits and synergies of these different approaches have not been analyzed.
We constructed a mathematical model to examine the impact and cost-effectiveness of different strategies, including earlier initiation of ART and/or PrEP, for HIV-1 prevention for serodiscordant couples. Although the cost of PrEP is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. In some situations, highly effective PrEP could be cost-saving overall. To keep couples alive and without a new infection, providing PrEP to the uninfected partner could be at least as cost-effective as initiating ART earlier in the infected partner, if the annual cost of PrEP is <40% of the annual cost of ART and PrEP is >70% effective.
Strategic use of PrEP and ART could substantially and cost-effectively reduce HIV-1 transmission in HIV-1 serodiscordant couples. New and forthcoming data on the efficacy of PrEP, the cost of delivery of ART and PrEP, and couples behaviours and preferences will be critical for optimizing the use of antiretrovirals for HIV-1 prevention.
Every year, about 2.5 million people become infected with HIV, the virus that causes AIDS. HIV is usually transmitted through unprotected sex with an HIV-infected partner. It destroys immune system cells (including CD4 cells, a type of lymphocyte), leaving infected individuals susceptible to other infections. There is no cure for AIDS, although HIV can be held in check with antiretroviral therapy (ART), and there is no vaccine that protects against HIV infection. So, to halt the AIDS epidemic, other ways of preventing the spread of HIV are needed. Antiretroviral drugs could potentially be used in two ways to reduce HIV transmission. First, ART could be given to HIV-infected people before they need it for their own health to reduce their infectiousness; the World Health Organization currently recommends that HIV-positive people initiate ART when their CD4 count drops below 350 cells/µl blood but in many African countries ART is only initiated when CD4 counts fall below 200 cells/µl. Second, ART could be given to HIV-uninfected people to reduce acquisition of the virus. This approach—preexposure prophylaxis (PrEP)—has provided protection against HIV transmission in some but not all clinical trials.
Couples in long-term relationships where one partner is HIV-positive and the other is HIV-negative (HIV serodiscordant couples) are a priority group for prevention interventions. In sub-Saharan Africa, where most new HIV infections occur, 10%–20% of stable partnerships are serodiscordant and condom use is often low, not least because such couples may want children. Earlier ART or PrEP might reduce HIV transmission in this group but the merits of different approaches have not been analyzed. In this study, the researchers use a mathematical model to examine the long-term impact and cost-effectiveness of different PrEP and ART strategies for HIV prevention in serodiscordant couples.
The researchers constructed a model to simulate HIV infection and disease progression among hypothetical HIV serodiscordant stable heterosexual couples. The model incorporated data from South Africa on couple characteristics, disease progression, ART use, pregnancies, frequency of sex, and contact with other sexual partners, as well as estimates of the effectiveness of PrEP from clinical trials. The researchers used the model to compare the impact on HIV transmission, survival and quality of life, and the cost-effectiveness of no PrEP with four PrEP strategies—always use PrEP after diagnosis of HIV serodiscordancy, use PrEP up to and for a year after ART initiation by the HIV-infected partner (at a CD4 count of ≤200 cells/µl or ≤350 cells/µl), use PrEP only up to ART initiation by the infected partner, and use PrEP only while trying for a baby and during pregnancy. The model predicts, for example, that the cost per infection averted of PrEP used before ART initiation will be offset by future savings in lifelong treatment, particularly among couples with multiple partners, low condom use, and a high risk of transmission. To keep couples alive without the HIV-uninfected partner becoming infected, it could be more cost-effective to provide PrEP to the uninfected partner than to initiate ART earlier in the infected partner, provided the annual cost of PrEP is less than 40% of the annual cost of ART and PrEP is more than 70% effective. Finally, if PREP is 30%–60% effective, the most cost-effective strategy for couples could be to use PrEP in the uninfected partner prior to ART initiation in the infected partner at a CD4 count ≤350 cells/µl.
These findings suggest that the strategic use of PrEP and ART could cost-effectively reduce HIV transmission in HIV serodiscordant stable heterosexual couples in sub-Saharan Africa. The accuracy of these findings depends on the assumptions included in the mathematical model and on the data fed into it. In particular, the interpretation of these results is complicated by uncertainties in the likely cost of PrEP and the “real-world” effectiveness of PrEP. Nevertheless, these findings suggest that PrEP may become a valuable addition in some settings to existing approaches for HIV prevention such as condom promotion and male circumcision programs. Moreover, additional simulations with this mathematical model using more accurate information on the costs and effectiveness of PrEP could assist in future policy making decisions.
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Thirty years after HIV-1 was first recognized, the epidemic continues with 2.6 million people newly infected in the past year
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
ART reduces plasma and genital HIV-1 concentrations to undetectable levels in most treated individuals
A recent clinical trial of the pericoital use of topical 1% tenofovir gel among HIV-1–uninfected women
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
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 <350 or <500 cells/µl) in the HIV-1–infected partner be a more effective use of resources than providing PrEP to the uninfected partner?; and (iii) what is the best way to combine use of PrEP and ART to maximize impact and efficiency? To address each of these questions, we constructed an individual-based model describing HIV-1 serodiscordant couples in South Africa in which the use of PrEP and ART can be simulated and the effects on transmission and life-years saved can be quantified.
We constructed a microsimulation model of HIV-1 disease progression, transmission of infection, and treatment in stable HIV-1 serodiscordant heterosexual couples in South Africa. The model included the composition of couples (by sex, age, and current CD4 cell counts), ageing, disease progression, use of ART, conception and pregnancies, variations in coital frequency within stable partnerships and contact with other sexual partners. The model tracks each individuals' trajectories over time until they die. Each result presented is the mean for sets of 20,000 simulated couples. Key assumptions are summarized in
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 |
CD4 200–350: 1.59 | ||
CD4 0–200: 4.99 | ||
Mean time spent in CD4 cell count category (y) |
Infection to CD4 of 500: 2.4 | Pooled analysis of African observational cohort studies |
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 <350 cells/µl) | 0.08 | Cohorts of stable serodiscordant couples |
Mortality rates on ART (per year) | Multinational observational cohort studies |
|
ART initiation at CD4 500+: | 1.3% | |
ART initiation at CD4 350–500: | 2.5% | |
ART initiation at CD4 200–350: | 5% | |
ART initiation at CD4 0–200: | 10% | |
ART initiation at CD4 500+: | 1.3% | |
ART initiation at CD4 350–500: | 1.3% | |
ART initiation at CD4 200–350: | 2.5% | |
ART initiation at CD4 0–200: | 5% | |
Drop-out from ART (per year) | First year: 10%; subsequent years: 5% | Observational data from programs in Zambia |
PrEP effectiveness | 30%–80% (in |
Consistent with the ranges of effectiveness reported in a large trial of PrEP in serodiscordant couples |
Full cost per year of ART | US$450–US$800 (midpoint: US$625) | |
Full cost per year of PrEP | US$150 and US$250 (midpoint: US$200) |
|
Relative annual cost of PrEP compared to ART | 18%–56% (midpoint: 32%) | Calculated from values given above |
Mean time elapsed between entering category (CD4 cell count reaching value of upper bound) and exiting category (CD4 cell count drops below value of lower bound).
The parameter for the “effectiveness” of PrEP, which combines assumptions about the “intrinsic efficacy” of PrEP and levels of adherence to the regimen (
The cost of one person-year of PrEP was assumed to range between US$150 and US$250 on average (this includes lab testing, personnel, and drug costs), and the approximate costs of each additional person-year of ART was set at US$450–US$800
The model was analyzed by running a “baseline” scenario in which the only intervention was the initiation of ART for the infected partner, with initiation occurring when their CD4 cell count fell below 200 cells/µl (which until recently was the South African guideline for asymptomatic or nonpregnant HIV-infected individuals
These outcomes were chosen to capture the long-term impact on couples, so that the cumulative risk of transmission/death and total costs can be fully reflected. The latter two outcomes record the beneficial effects of these interventions on survival and quality of life, as well as HIV-1 transmission rates.
Three analyses were conducted to address the questions outlined above. In the first analysis, the impact of four different PrEP implementation strategies was examined (
Strategy | Description |
Baseline | No PrEP |
I | Always use PrEP after diagnosis of HIV-1 serodiscordancy in couples |
II | Use PrEP up to the initiation of ART for the stable HIV-1–infected partner, and during the first year of the partner's ART use |
III | Use PrEP up to the initiation of the stable HIV-1–infected partner on ART, then stop PrEP |
IV | Use PrEP only during periods of trying to conceive a pregnancy |
In strategies I–III, PrEP is initiated following HIV-1 testing of couples, and, in all strategies, PrEP is stopped immediately if the HIV-1–infected partner dies or the initially HIV-1–uninfected partner becomes HIV-1 infected.
In this and all other scenarios, it is assumed that ART is initiated promptly when the infected partner's CD4 cell count reaches 200 cells/µl.
An initial period of continued PrEP is allowed until viral load becomes suppressed after ART initiation in the HIV-1–infected partner. PrEP could reasonably be discontinued after an interval of less than 1 y, or be based on viral load monitoring of the infected partner instead.
In the model, pregnancies can be preceded by a period of “trying to conceive a pregnancy” during which the frequency of unprotected sex increases (see
The modelled impact of the four PrEP implementation strategies in the “partners in prevention” couples and “more typical couples” is shown in
(A, D) The proportion of infections averted by age 50 (relative to a baseline strategy with no PrEP intervention) for four PrEP strategies (see
The four PrEP strategies differed in the amount of PrEP used (
Costs per infection averted were calculated taking into account the lifetime costs of PrEP and ART for the initially uninfected individual who seroconverts. In the “partners in prevention” couples (
In the “more typical couples”, costs per infection averted were much lower (
For scenario III, the corresponding estimates of the costs per QALY saved are: for 30% effective PrEP, US$2,500–US$4,900 per QALY in “partners in prevention” couples or US$700–US$1,900 per QALY in “more typical couples” (depending on cost of PrEP); and for 80% effective PrEP, US$260–US$1,600 per QALY in “partners in prevention” couples or US$–200 (cost-saving) to US$500 per QALY in “more typical couples”. This result places PrEP among the more expensive public health interventions
The analyses were repeated in three other sets of couples with different types of behaviours (
We performed a comparison between an intervention that provides PrEP to the HIV-1–uninfected partner until the HIV-1–infected partner initiates ART at CD4<350 cells/µl (strategy III) and an intervention providing earlier ART initiation to the infected partner at a CD4 cell count of 500 cells/µl but no PrEP. Both interventions increase cost and reduce infections. The comparison metric was the number of couples “alive and HIV-1 free at age 50.”
The relative cost of PrEP to ART (vertical axis) and the effectiveness of PrEP (horizontal axis) are varied and the shaded region indicates the conditions where a PrEP intervention (PrEP used up to the moment that their infected partner starts treatment (at CD4<350 cells/µl)) is at least as cost-effective as earlier initiation of ART (at CD4<500 cells/µl) at allowing couples to be “alive and HIV-1 free at 50.” The dark shaded region corresponds to the “partners in prevention” assumptions about couples' behaviour and the lighter shaded region corresponds to “more typical couples” behaviour assumptions. Alternative analyses are presented where different assumptions about ART initiation and couples' behaviour are made (
A much broader range of PrEP effectiveness and cost values render PrEP at least as cost-effective as earlier ART if the behaviours characterizing the “more typical couples” are assumed (
We repeated these analyses in the context of earlier ART initiation, comparing PrEP use prior to ART initiation at CD4 cell counts below 200 cells/µl with earlier ART initiation at 350 cells/µl. The pattern is similar to the previous analysis and in “more typical couples”, PrEP with effectiveness of 50% could have an annual cost as much as 70% that of ART and be as cost-effective as earlier ART initiation for the HIV-1–infected partners. At the upper-bound of the estimate for relative PrEP-to-ART costs, PrEP would be as cost-effective as initiating ART in the HIV-1–infected partner at CD4<500 cells/µl if PrEP was more than 40% effective.
Both analyses were repeated using the QALY outcome (
An additional analysis quantified the influence of the assumed mortality and drop-out rates on infections averted for couples for whom ART is initiated at CD4 cell counts <500 cells/µl instead of CD4<200 cells/µl (
To determine the best overall strategies for the use of PrEP and ART among HIV serodiscordant couples, the impact (on couples being “alive and HIV free at 50”) and cost (net lifetime costs of treatment and PrEP to the couple) of the full range of possible different strategies were calculated. The strategies were: ART initiated by the HIV-1–infected partner at 200 cells/µl with no PrEP or with PrEP used by the uninfected partner until their partner initiates ART (with varying degrees of PrEP effectiveness: 30%, 60%, or 80%); with ART initiated at 350 cells/µl with no PrEP or with PrEP used by the uninfected partner until ART initiation by their partner (with the same values for PrEP effectiveness); and ART initiated at CD4 count of 500 cells/µl. The impact of all strategies were compared against no treatment. This information is summarized in “impact versus cost” plots (
For both types of couple modelled, in the absence of the option to use PrEP, earlier treatment initiation (up to treatment at CD4<500) could be the most efficient way, among these options, to spend resources in order to keep couples alive and HIV free (but not necessarily an optimal use of resources across a whole HIV program portfolio), although this would be associated with an increase in costs (additional cost compared to treatment at CD4<200: US$2,700 in “partners in prevention” couples and US$3,700 in “more typical couples”). However, if using PrEP were possible and the effectiveness was greater than 30%–40% (assuming the midpoint to high estimate for PrEP cost) then the overall most effective strategy for HIV prevention in higher risk (“more typical”) couples be to offer PrEP to the uninfected partners prior to their partners' treatment initiation.
The analysis provides three main results. First, PrEP used prior to ART initiation can prevent infections in HIV-1 serodiscordant couples and, although the initial costs are high, they are substantially offset by reduced future ART costs among HIV-1–uninfected partners who remain uninfected. In some circumstances (e.g., with effectiveness of 80% and used in couples that remain at high-risk), PrEP could be cost-saving overall. Second, PrEP in serodiscordant couples could be as cost-effective as earlier initiation of ART (compared to existing practice) if PrEP has a sufficiently high effectiveness (>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
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
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
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
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
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
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
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We are grateful to the Mark Dybul, Peter Piot, Stephen Becker, Blair Hanewall, Andy Hastings, Catherine Hankins, Kevin O'Reilly, Francois Venter, and Gesine Meyer-Rath for very useful discussions during the planning of the work and interpretation of the analyses.
antiretroviral treatment
pre-exposure prophylaxis
person-years at risk
quality-adjusted life-years