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AbstractIntroductionCurative therapies (CTx) to achieve durable remission of HIV disease without the need for antiretroviral therapy (ART) are currently being explored. Our objective was to model the long‐term health and cost outcomes of HIV in various countries, the impact of future CTx on those outcomes and the country‐specific value‐based prices (VBPs) of CTx.MethodsWe developed a decision‐analytic model to estimate the future health economic impacts of a hypothetical CTx for HIV in countries with pre‐existing access to ART (CTx+ART), compared to ART alone. We modelled populations in seven low‐and‐middle‐income countries and five high‐income countries, accounting for localized ART and other HIV‐related costs, and calibrating variables for HIV epidemiology and ART uptake to reproduce historical HIV outcomes before projecting future outcomes to year 2100. Health was quantified using disability‐adjusted life‐years (DALYs). Base case, pessimistic and optimistic scenarios were modelled for CTx+ART and ART alone. Based on long‐term outcomes and each country's estimated health opportunity cost, we calculated the country‐specific VBP of CTx.ResultsThe introduction of a hypothetical CTx lowered HIV prevalence and prevented future infections over time, which increased life‐years, reduced the number of individuals on ART, reduced AIDS‐related deaths, and ultimately led to fewer DALYs versus ART‐alone. Our base case estimates for the VBP of CTx ranged from $5400 (Kenya) up to $812,300 (United States). Within each country, the VBP was driven to be greater primarily by lower ART coverage, lower HIV incidence and prevalence, and higher CTx cure probability. The VBP estimates were found to be greater in countries where HIV prevalence was higher, ART coverage was lower and the health opportunity cost was greater.ConclusionsOur results quantify the VBP for future curative CTx that may apply in different countries and under different circumstances. With greater CTx cure probability, durability and scale up, CTx commands a higher VBP, while improvements in ART coverage may mitigate its value. Our framework can be utilized for estimating this cost given a wide range of scenarios related to the attributes of a given CTx as well as various parameters of the HIV epidemic within a given country.

AbstractIntroductionSome studies suggest that use of the injectable contraceptive depot medroxyprogesterone acetate (DMPA) may increase susceptibility to HIV infection. We aim to determine the influence that such an association could have had on the HIV epidemic in South Africa.MethodsWe simulate the heterosexual adult HIV epidemic in South Africa using a compartmental model stratified by age, behavioural risk group, sex, male circumcision status and contraceptive use. We model two possible scenarios: (1) The "With Effect" scenario assumes that DMPA increases susceptibility to HIV infection by 1.20‐fold (95% confidence interval 1.06 to 1.36) based on a combination of the results of a recent randomised controlled trial (ECHO trial) and a number of observational studies. (2) The "No Effect" scenario assumes that DMPA has no effect on HIV acquisition risk. We calculate the difference in HIV‐related outcomes between the With Effect and No Effect scenarios to determine the potential impact that DMPA use could have had on the HIV epidemic.ResultsA causal association between DMPA and HIV acquisition could have caused 430,000 (90% of model runs 160,000 to 960,000) excess HIV infections and 230,000 (90,000 to 470,000) AIDS deaths in South Africa from 1980 to 2017. These figures represent 4.3% (1.6% to 9.6%) and 6.9% (2.6% to 15.2%) of the total modelled estimates of HIV infections and AIDS deaths respectively in South Africa in that period. Of the additional infections, 36% (25% to 48%) would have occurred among men. If DMPA use continues at current levels, a potential causal association could cause an additional 130,000 (50,000 to 270,000) infections between 2018 and 2037. The excess infections would have required an additional 640,000 (190,000 to 1,660,000) years of ART from 1980 to 2017, and a further 2,870,000 (890,000 to 7,270,000) years of ART from 2018 to 2037.ConclusionsIf there is a causal association between DMPA use and HIV risk, it could have substantially increased the scale of the HIV epidemic in South Africa, affecting not only the users of DMPA, but also their partners and the wider population. The magnitude of this potential effect demands careful data collection and a careful consideration of policy choices for contraception in settings with large HIV epidemics.

AbstractIntroductionOral pre‐exposure prophylaxis (PrEP) is a new form of HIV prevention being considered for inclusion in national prevention portfolios. Many mathematical modelling studies have been undertaken that speak to the impact, cost and cost‐effectiveness of PrEP programmes. We assess the available evidence from mathematical modelling studies to inform programme planning and policy decision making for PrEP and further research directions.MethodsWe conducted a scoping review of the published modelling literature. Articles published in English which modelled oral PrEP in sub‐Saharan Africa, or non‐specific settings with relevance to generalized HIV epidemic settings, were included. Data were extracted for the strategies of PrEP use modelled, and the impact, cost and cost‐effectiveness of PrEP for each strategy. We define an algorithm to assess the quality and relevance of studies included, summarize the available evidence and identify the current gaps in modelling. Recommendations are generated for future modelling applications and data collection.Results and DiscussionWe reviewed 1924 abstracts and included 44 studies spanning 2007 to 2017. Modelling has reported that PrEP can be a cost‐effective addition to HIV prevention portfolios for some use cases, but also that it would not be cost‐effective to fund PrEP before other prevention interventions are expanded. However, our assessment of the quality of the modelling indicates cost‐effectiveness analyses failed to comply with standards of reporting for economic evaluations and the assessment of relevance highlighted that both key parameters and scenarios are now outdated. Current evidence gaps include modelling to inform service development using updated programmatic information and ex post modelling to evaluate and inform efficient deployment of resources in support of PrEP, especially among key populations, using direct evidence of cost, adherence and uptake patterns.ConclusionsUpdated modelling which more appropriately captures PrEP programme delivery, uses current intervention scenarios, and is parameterized with data from demonstration and implementation projects is needed in support of more conclusive findings and actionable recommendations for programmes and policy. Future analyses should address these issues, aligning with countries to support the needs of programme planners and decision makers for models to more directly inform programme planning and policy.

IntroductionThe new WHO guidelines recommend offering pre‐exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub‐Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape.MethodsWe use a model that was previously developed to capture subnational HIV transmission in sub‐Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub‐Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold.ResultsAt low‐to‐moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions.ConclusionsOur findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost‐effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost‐effective HIV response across Africa.

AbstractIntroductionSetting and monitoring progress towards targets for HIV control is critical in ensuring responsive programmes. Here, we explore how to apply targets for reduction in HIV incidence to local settings and which indicators give the strongest signal of a change in incidence in the population and are therefore most important to monitor.MethodsWe use location‐specific HIV transmission models, tailored to the epidemics in the counties and major cities in Kenya, to project a wide range of plausible future epidemic trajectories through varying behaviours, treatment coverage and prevention interventions. We look at the change in incidence across modelled scenarios in each location between 2015 and 2030 to inform local target setting. We also simulate the measurement of a library of potential indicators and assess which are most strongly associated with a change in incidence.ResultsConsiderable variation was observed in the trajectory of the local epidemics under the plausible scenarios defined (only 10 of 48 locations saw a median reduction in incidence of greater than or equal to an 80% target by 2030). Indicators that provide strong signals in certain epidemic types may not perform consistently well in settings with different epidemiological features. Predicting changes in incidence is more challenging in advanced generalized epidemics compared to concentrated epidemics where changes in high‐risk sub‐populations track more closely to the population as a whole. Many indicators demonstrate only limited association with incidence (such as "condom use" or "pre‐exposure prophylaxis coverage"). This is because many other factors (low effectiveness, impact of other interventions, countervailing changes in risk behaviours, etc.) can confound the relationship between interventions and their ultimate long‐term impact, especially for an intervention with low expected coverage. The population prevalence of viral suppression shows the most consistent associations with long‐term changes in incidence even in the largest generalized epidemics.ConclusionsTarget setting should be appropriate for the local epidemic and what can feasibly be achieved. There is no one universally reliable indicator to predict future HIV incidence across settings. Thus, the signature of epidemic control must contain indications of success across a wide range of interventions and outcomes.

AbstractIntroductionDue to the nature of funding, national planners and international donors typically balance budgets over short time periods when designing HIV programmes (˜5‐year funding cycles). We aim to explicitly quantify the cost of short‐term funding arrangements on the success of future HIV prevention programmes.MethodsUsing mathematical models of HIV transmission in Kenya, we compare the impact of optimized combination prevention strategies under different constraints on investment over time. Each scenario has the same total budget for the 30‐year intervention period but the pattern of spending over time is allowed to vary. We look at the impact of programmes with decreasing, increasing or constant spending across 5‐year funding cycles for a 30‐year period. Interventions are optimized within each funding cycle such that strategies take a short‐term view of the epidemic. We compare these with two strategies with no spending pattern constraints: one with static intervention choices and another flexible strategy with interventions changed in year ten.Results and DiscussionFor the same total 30‐year budget, greatest impact is achieved if larger initial prevention spending is offset by later treatment savings which leads to accumulating benefits in reduced infections. The impact under funding cycle constraints is determined by the extent to which greater initial spending is permitted. Short‐term funding constraints and funds held back to later years may reduce impact by up to 18% relative to the flexible long‐term strategy.ConclusionsEnsuring that funding arrangements are in place to support long‐term prevention strategies will make spending most impactful. Greater prevention spending now will bring considerable returns through reductions in new infections, greater population health and reductions in the burden on health services in the future.

AbstractIntroductionA strategic approach to the application of HIV prevention interventions is a core component of the UNAIDS Fast Track strategy to end the HIV epidemic by 2030. Central to these plans is a focus on high‐prevalence geographies, in a bid to target resources to those in greatest need and maximize the reduction in new infections. Whilst this idea of geographical prioritization has the potential to improve efficiency, it is unclear how it should be implemented in practice. There are a range of prevention interventions which can be applied differentially across risk groups and locations, making allocation decisions complex. Here, we use mathematical modelling to compare the impact (infections averted) of a number of different approaches to the implementation of geographical prioritization of prevention interventions, similar to those emerging in policy and practice, across a range of prevention budgets.MethodsWe use geographically specific mathematical models of the epidemic and response in 48 counties and major cities of Kenya to project the impact of the different geographical prioritization approaches. We compare the geographical allocation strategies with a nationally uniform approach under which the same interventions must be applied across all modelled locations.ResultsWe find that the most extreme geographical prioritization strategy, which focuses resources exclusively to high‐prevalence locations, may substantially restrict impact (41% fewer infections averted) compared to a nationally uniform approach, as opportunities for highly effective interventions for high‐risk populations in lower‐prevalence areas are missed. Other geographical allocation approaches, which intensify efforts in higher‐prevalence areas whilst maintaining a minimum package of cost‐effective interventions everywhere, consistently improve impact at all budget levels. Such strategies balance the need for greater investment in locations with the largest epidemics whilst ensuring higher‐risk groups in lower‐priority locations are provided with cost‐effective interventions.ConclusionsOur findings serve as a warning to not be too selective in the application of prevention strategies. Further research is needed to understand how decision‐makers can find the right balance between the choice of interventions, focus on high‐risk populations, and geographical targeting to ensure the greatest impact of HIV prevention.

IntroductionTo be used most effectively, pre‐exposure prophylaxis (PrEP) should be prioritized to those at high risk of acquisition and would ideally be aligned with time periods of increased exposure. Identifying such time periods is not always straightforward, however. Gaza Province in southern Mozambique is characterized by high levels of HIV transmission and circular labour migration to mines in South Africa. A strong seasonal pattern in births is observable, reflecting an increase in conception in December. Given the potential for increased HIV transmission between miners returning in December and their partners in Gaza Province, PrEP use by the latter would be a useful means of HIV prevention, especially for couples who wish to conceive.MethodsA mathematical model was used to represent population‐level adult heterosexual HIV transmission in Gaza Province. Increased HIV acquisition among partners of miners in December, coinciding with the miners' return from South Africa, is represented. In addition to a PrEP intervention, the scale‐up of treatment and recent scale‐up of male circumcision that have occurred in Gaza are represented.ResultsProviding time‐limited PrEP to the partners of migrant miners, as opposed to providing PrEP all year, would improve the cost per infection averted by 7.5‐fold. For the cost per infection averted to be below US$3000, at least 85% of PrEP users would need to be good adherers and PrEP would need to be cheaper than US$115 per person per year. Uncertainty regarding incidence of HIV transmission among partners of miners each year in December has a strong influence on estimates of cost per infection averted.ConclusionsProviding time‐limited PrEP to partners of migrant miners in Gaza Province during periods of increased exposure would be a novel strategy for providing PrEP. This strategy would allow for a better prioritized intervention, with the potential to improve the efficiency of a PrEP intervention considerably, as well as providing important reproductive health benefits.

AbstractIntroductionWeaknesses in care programmes providing anti‐retroviral therapy (ART) persist and are often instigated by late HIV diagnosis and poor linkage to care. We investigated the potential for a home‐based counselling and testing (HBCT) campaign to be improved through the optimal timing and enhancement of testing rounds to generate greater health outcomes at minimum cost.MethodsUsing a mathematical model of HIV care calibrated to longitudinal data from The Academic Model Providing Access To Healthcare (AMPATH) in Kenya, we simulated HBCT campaigns between 2016 and 2036, assessing the impact and total cost of care for each, for a further 20 years.ResultsWe find that simulating five equally spaced rounds averts 1.53 million disability‐adjusted life‐years (DALYs) at a cost of $1617 million. By altering the timing of HBCT rounds, a four‐round campaign can produce greater impact for lower cost. With "front‐loaded" rounds, the cost per DALY averted is reduced by 12% as fewer rounds are required ($937 vs. $1060). Furthermore, improvements to HBCT coverage and linkage to care avert over two million DALYs at a cost per DALY averted of $621 (41% less than the reference scenario).ConclusionsCountries implementing HBCT can reduce costs by optimally timing rounds and generate greater health outcomes through improving linkage, coverage, and retention. Tailoring HBCT campaigns to individual settings can enhance patient outcomes for minimal cost.

AbstractIntroductionThe HIV prevention cascade could be used in developing interventions to strengthen implementation of efficacious HIV prevention methods, but its practical utility needs to be demonstrated. We propose a standardized approach to using the cascade to guide identification and evaluation of interventions and demonstrate its feasibility for this purpose through a project to develop interventions to improve HIV prevention methods use by adolescent girls and young women (AGYW) and potential male partners in east Zimbabwe.DiscussionWe propose a six‐step approach to using a published generic HIV prevention cascade formulation to develop interventions to increase motivation to use, access to and effective use of an HIV prevention method. These steps are as follows: (1) measure the HIV prevention cascade for the chosen population and method; (2) identify gaps in the cascade; (3) identify explanatory factors (barriers) contributing to observed gaps; (4) review literature to identify relevant theoretical frameworks and interventions; (5) tailor interventions to the local context; and (6) implement and evaluate the interventions using the cascade steps and explanatory factors as outcome indicators in the evaluation design. In the Zimbabwe example, steps 1‐5 aided development of four interventions to overcome barriers to effective use of pre‐exposure prophylaxis (PrEP) in AGYW (15‐24 years) and voluntary medical male circumcision in male partners (15‐29). For young men, prevention cascade analyses identified gaps in motivation and access as barriers to voluntary medical male circumcision uptake, so an intervention was designed including financial incentives and an education session. For AGYW, gaps in motivation (particularly lack of risk perception) and access were identified as barriers to PrEP uptake: an interactive counselling game was developed addressing these barriers. A text messaging intervention was developed to improve PrEP adherence among AGYW, addressing reasons underlying lack of effective PrEP use through improving the capacity ("skills") to take PrEP effectively. A community‐led intervention (community conversations) was developed addressing community‐level factors underlying gaps in motivation, access and effective use. These interventions are being evaluated currently using outcomes from the HIV prevention cascade (step 6).ConclusionsThe prevention cascade can guide development and evaluation of interventions to strengthen implementation of HIV prevention methods by following the proposed process.

AbstractIntroductionSome observational data suggest that the progestogen injectable contraceptive depot medroxyprogesterone acetate (DMPA) may increase a woman's risk of HIV acquisition but a randomized clinical trial did not find a statistically significant increase in HIV risk for women using DMPA compared to two other methods. However, it could not rule out up to 30% increased HIV risk for DMPA users. We evaluate changes to contraceptive method mix in South Africa under different assumptions about the existence and strength of a possible undetected relationship between DMPA use and HIV risk.MethodsA mathematical model was developed to simulate the ongoing HIV epidemic and contraceptive method mix in South Africa to estimate how changes in method mix could impact HIV‐ and reproductive health‐related outcomes. We made different assumptions about the relationship between DMPA use and HIV risk, from no relationship to a 30% increase in HIV risk for women using DMPA. Scenario analyses were used to investigate the impact of switching away from DMPA predominance to new patterns of contraceptive use.ResultsIn South Africa, the HIV‐related benefits of reduced DMPA use could be as great as the harms of increased adverse reproductive health outcomes over 20 years, if DMPA did increase the risk of HIV acquisition by a relative hazard of infection of 1.1 or greater. A reduction in DMPA use among HIV‐positive women would have no benefit in terms of HIV infections, but would incur additional negative reproductive health outcomes. The most important driver of adverse reproductive health outcomes is the proportion of women who switch away from DMPA to no contraceptive method.ConclusionsIf there is any real increased HIV risk for DMPA users that has not been detected by the recent randomized trial, a reduction in DMPA use could reduce the ongoing number of new HIV infections. However, such a change would place more women at risk of adverse reproductive health effects. It is imperative that these effects are minimized by focusing on expanding access to safe, effective and acceptable alternative contraceptive methods for all women.