A quantitative assessment of the consistency of projections from five mathematical models of the HIV epidemic in South Africa: a model comparison study.

BACKGROUND: Mathematical models are increasingly used to inform HIV policy and planning. Comparing estimates obtained using different mathematical models can test the robustness of estimates and highlight research gaps. As part of a larger project aiming to determine the optimal allocation of funding for HIV services, in this study we compare projections from five mathematical models of the HIV epidemic in South Africa: EMOD-HIV, Goals, HIV-Synthesis, Optima, and Thembisa. METHODS: The five modelling groups produced estimates of the total population, HIV incidence, HIV prevalence, proportion of people living with HIV who are diagnosed, ART coverage, proportion of those on ART who are virally suppressed, AIDS-related deaths, total deaths, and the proportion of adult males who are circumcised. Estimates were made under a "status quo" scenario for the period 1990 to 2040. For each output variable we assessed the consistency of model estimates by calculating the coefficient of variation and examining the trend over time. RESULTS: For most outputs there was significant inter-model variability between 1990 and 2005, when limited data was available for calibration, good consistency from 2005 to 2025, and increasing variability towards the end of the projection period. Estimates of HIV incidence, deaths in people living with HIV, and total deaths displayed the largest long-term variability, with standard deviations between 35 and 65% of the cross-model means. Despite this variability, all models predicted a gradual decline in HIV incidence in the long-term. Projections related to the UNAIDS 95-95-95 targets were more consistent, with the coefficients of variation below 0.1 for all groups except children. CONCLUSIONS: While models produced consistent estimates for several outputs, there are areas of variability that should be investigated. This is important if projections are to be used in subsequent cost-effectiveness studies.

Evaluation of the use of modelling in resource allocation decisions for HIV and TB.

INTRODUCTION: Globally, resources for health spending, including HIV and tuberculosis (TB), are constrained, and a substantial gap exists between spending and estimated needs. Optima is an allocative efficiency modelling tool that has been used since 2010 in over 50 settings to generate evidence for country-level HIV and TB resource allocation decisions. This evaluation assessed the utilisation of modelling to inform financing priorities from the perspective of country stakeholders and their international partners. METHODS: In October to December 2021, the World Bank and Burnet Institute led 16 semi-structured small-group virtual interviews with 54 representatives from national governments and international health and funding organisations. Interviews probed participants' roles and satisfaction with Optima analyses and how model findings have had been used and impacted resource allocation. Interviewed stakeholders represented nine countries and 11 different disease programme-country contexts with prior Optima modelling analyses. Interview notes were thematically analysed to assess factors influencing the utilisation of modelling evidence in health policy and outcomes. RESULTS: Common influences on utilisation of Optima findings encompassed the perceived validity of findings, health system financing mechanisms, the extent of stakeholder participation in the modelling process-including engagement of funding organisations, sociopolitical context and timeliness of the analysis. Using workshops can facilitate effective stakeholder engagement and collaboration. Model findings were often used conceptually to localise global evidence and facilitate discussion. Secondary outputs included informing strategic and financial planning, funding advocacy, grant proposals and influencing investment shifts. CONCLUSION: Allocative efficiency modelling has supported evidence-informed decision-making in numerous contexts and enhanced the conceptual and practical understanding of allocative efficiency. Most immediately, greater involvement of country stakeholders in modelling studies and timing studies to key strategic and financial planning decisions may increase the impact on decision-making. Better consideration for integrated disease modelling, equity goals and financing constraints may improve relevance and utilisation of modelling findings.

New HIV Infections Among Key Populations and Their Partners in 2010 and 2022, by World Region: A Multisources Estimation.

BACKGROUND: Previously, The Joint United Nations Programme on HIV/AIDS estimated proportions of adult new HIV infections among key populations (KPs) in the last calendar year, globally and in 8 regions. We refined and updated these, for 2010 and 2022, using country-level trend models informed by national data. METHODS: Infections among 15-49 year olds were estimated for sex workers (SWs), male clients of female SW, men who have sex with men (MSM), people who inject drugs (PWID), transgender women (TGW), and non-KP sex partners of these groups. Transmission models used were Goals (71 countries), AIDS Epidemic Model (13 Asian countries), Optima (9 European and Central Asian countries), and Thembisa (South Africa). Statistical Estimation and Projection Package fits were used for 15 countries. For 40 countries, new infections in 1 or more KPs were approximated from first-time diagnoses by the mode of transmission. Infection proportions among nonclient partners came from Goals, Optima, AIDS Epidemic Model, and Thembisa. For remaining countries and groups not represented in models, median proportions by KP were extrapolated from countries modeled within the same region. RESULTS: Across 172 countries, estimated proportions of new adult infections in 2010 and 2022 were both 7.7% for SW, 11% and 20% for MSM, 0.72% and 1.1% for TGW, 6.8% and 8.0% for PWID, 12% and 10% for clients, and 5.3% and 8.2% for nonclient partners. In sub-Saharan Africa, proportions of new HIV infections decreased among SW, clients, and non-KP partners but increased for PWID; elsewhere these groups' 2010-to-2022 differences were opposite. For MSM and TGW, the proportions increased across all regions. CONCLUSIONS: KPs continue to have disproportionately high HIV incidence.

Health and economic benefits of achieving contraceptive and maternal health targets in Small Island Developing States in the Pacific and Caribbean.

INTRODUCTION: Reducing unmet need for modern contraception and expanding access to quality maternal health (MH) services are priorities for improving women's health and economic empowerment. To support investment decisions, we estimated the additional cost and expected health and economic benefits of achieving the United Nations targets of zero unmet need for modern contraceptive choices and 95% coverage of MH services by 2030 in select Small Island Developing States. METHODS: Five Pacific (Kiribati, Samoa, Solomon Islands, Tonga and Vanuatu) and four Caribbean (Barbados, Guyana, Jamaica and Saint Lucia) countries were considered based on population survey data availability. For each country, the Lives Saved Tool was used to model costs, health outcomes and economic benefits for two scenarios: business-as-usual (BAU) (coverage maintained) and coverage-targets-achieved, which scaled linearly from 2022 (following COVID-19 disruptions) coverage of evidence-based family planning and MH interventions to reach United Nations targets, including modern contraceptive methods and access to complete antenatal, delivery and emergency care. Unintended pregnancies, maternal deaths, stillbirths and newborn deaths averted by the coverage-targets-achieved scenario were converted to workforce, education and social economic benefits; and benefit-cost ratios were calculated. RESULTS: The coverage-targets-achieved scenario required an additional US$12.6M (US$10.8M-US$15.9M) over 2020-2030 for the five Pacific countries (15% more than US$82.4M to maintain BAU). This additional investment was estimated to avert 126 000 (40%) unintended pregnancies, 2200 (28%) stillbirths and 121 (29%) maternal deaths and lead to a 15-fold economic benefit of US$190.6M (US$67.0M-US$304.5M) by 2050. For the four Caribbean countries, an additional US$17.8M (US$15.3M-US$22.4M) was needed to reach the targets (4% more than US$405.4M to maintain BAU). This was estimated to avert 127 000 (23%) unintended pregnancies, 3600 (23%) stillbirths and 221 (25%) maternal deaths and lead to a 24-fold economic benefit of US$426.2M (US$138.6M-US$745.7M) by 2050. CONCLUSION: Achieving full coverage of contraceptive and MH services in the Pacific and Caribbean is likely to have a high return on investment.

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa: results from five independent models.

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium.

Cost-effectiveness and impact of pre-exposure prophylaxis to prevent HIV among men who have sex with men in Asia: A modelling study.

INTRODUCTION: More than 70% of new HIV infections in Asia occurred in eight countries in 2020: Cambodia, China, India, Indonesia, Myanmar, Nepal, Thailand, and Vietnam-with a rising incidence among men who have sex with men (MSM). The World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) for those at risk of acquiring HIV, yet wide-scale implementation of PrEP, on a daily or event-driven basis, has been limited in Asia. METHODS: The Optima HIV model was applied to examine the impact of scaling-up PrEP over five-years to cover an additional 15% of MSM compared with baseline coverage, a target deemed feasible by regional experts. Based on behavioral survey data, we assume that covering 15% of higher-risk MSM will cover 30% of all sexual acts in this group. Scenarios to compare the impact of generic-brand daily dosing of PrEP with generic event-driven dosing (15 days a month) were modelled from the start of 2022 to the end of 2026. Cost-effectiveness of generic versus branded PrEP was also assessed for China, the only country with an active patent for branded, higher cost PrEP. The impact on new HIV infections among the entire population and cost per HIV-related disability-adjusted life year (DALY) averted were estimated from the beginning of 2022 to the end of 2031 and from 2022 to 2051. RESULTS: If PrEP were scaled-up to cover an additional 15% of MSM engaging in higher-risk behavior from the beginning of 2022 to the end of 2026 in the eight Asian countries considered, an additional 100,000 (66,000-130,000) HIV infections (17%) and 300,000 (198,000-390,000) HIV-related DALYs (3%) could be averted over the 2022 to 2031 period. The estimated cost per HIV-related DALY averted from 2022 to 2031 ranged from US$600 for event-driven generic PrEP in Indonesia to US$34,400 for daily branded PrEP in Thailand. Over a longer timeframe from 2022 to 2051, the cost per HIV-related DALY averted could be reduced to US$100-US$12,700. CONCLUSION: PrEP is a critical tool to further reduce HIV incidence in highly concentrated epidemics. Implementing PrEP in Asia may be cost-effective in settings with increasing HIV prevalence among MSM and if PrEP drug costs can be reduced, PrEP could be more cost-effective over longer timeframes.

Transmission reduction, health benefits, and upper-bound costs of interventions to improve retention on antiretroviral therapy: a combined analysis of three mathematical models.

BACKGROUND: In this so-called treat-all era, antiretroviral therapy (ART) interruptions contribute to an increasing proportion of HIV infections and deaths. Many strategies to improve retention on ART cost more than standard of care. In this study, we aimed to estimate the upper-bound costs at which such interventions should be adopted. METHODS: In this combined analysis, we compared the infections averted, disability-adjusted life-years (DALYs) averted, and upper-bound costs of interventions that improve ART retention in three HIV models with diverse structures, assumptions, and baseline settings: EMOD in South Africa, Optima in Malawi, and Synthesis in sub-Saharan African low-income and middle-income countries (LMICs). We modelled estimates over a 40-year time horizon, from a baseline of Jan 1, 2022, when interventions would be implemented, to Jan 1, 2062. We varied increment of ART retention (25%, 50%, 75%, and 100% retention), the extent to which interventions could be targeted towards individuals at risk of interrupting ART, and cost-effectiveness thresholds in each setting. FINDINGS: Despite simulating different settings and epidemic trends, all three models produced consistent estimates of health benefit (ie, DALYs averted) and transmission reduction per increment in retention. The range of estimates was 1·35-3·55 DALYs and 0·12-0·20 infections averted over the 40-year time horizon per additional person-year retained on ART. Upper-bound costs varied by setting and intervention effectiveness. Improving retention by 25% among all people receiving ART, regardless of risk of ART interruption, gave an upper-bound cost per person-year of US$2-6 in Optima (Malawi), $43-68 in Synthesis (LMICs in sub-Saharan Africa), and $28-180 in EMOD (South Africa). A maximally targeted and effective retention intervention had an upper-bound cost per person-year of US$93-223 in Optima (Malawi), $871-1389 in Synthesis (LMICs in sub-Saharan Africa), and $1013-6518 in EMOD (South Africa). INTERPRETATION: Upper-bound costs that could improve ART retention vary across sub-Saharan African settings and are likely to be similar to or higher than was estimated before the start of the treat-all era. Upper-bound costs could be increased by targeting interventions to those most at risk of interrupting ART. FUNDING: Bill & Melinda Gates Foundation.

Cost-effectiveness of easy-access, risk-informed oral pre-exposure prophylaxis in HIV epidemics in sub-Saharan Africa: a modelling study.

BACKGROUND: Approaches that allow easy access to pre-exposure prophylaxis (PrEP), such as over-the-counter provision at pharmacies, could facilitate risk-informed PrEP use and lead to lower HIV incidence, but their cost-effectiveness is unknown. We aimed to evaluate conditions under which risk-informed PrEP use is cost-effective. METHODS: We applied a mathematical model of HIV transmission to simulate 3000 setting-scenarios reflecting a range of epidemiological characteristics of communities in sub-Saharan Africa. The prevalence of HIV viral load greater than 1000 copies per mL among all adults (HIV positive and negative) varied from 1·1% to 7·4% (90% range). We hypothesised that if PrEP was made easily available without restriction and with education regarding its use, women and men would use PrEP, with sufficient daily adherence, during so-called seasons of risk (ie, periods in which individuals are at risk of acquiring infection). We refer to this as risk-informed PrEP. For each setting-scenario, we considered the situation in mid-2021 and performed a pairwise comparison of the outcomes of two policies: immediate PrEP scale-up and then continuation for 50 years, and no PrEP. We estimated the relationship between epidemic and programme characteristics and cost-effectiveness of PrEP availability to all during seasons of risk. For our base-case analysis, we assumed a 3-monthly PrEP cost of US$29 (drug $11, HIV test $4, and $14 for additional costs necessary to facilitate education and access), a cost-effectiveness threshold of $500 per disability-adjusted life-year (DALY) averted, an annual discount rate of 3%, and a time horizon of 50 years. In sensitivity analyses, we considered a cost-effectiveness threshold of $100 per DALY averted, a discount rate of 7% per annum, the use of PrEP outside of seasons of risk, and reduced uptake of risk-informed PrEP. FINDINGS: In the context of PrEP scale-up such that 66% (90% range across setting-scenarios 46-81) of HIV-negative people with at least one non-primary condomless sex partner take PrEP in any given period, resulting in 2·6% (0·9-6·0) of all HIV negative adults taking PrEP at any given time, risk-informed PrEP was predicted to reduce HIV incidence by 49% (23-78) over 50 years compared with no PrEP. PrEP was cost-effective in 71% of all setting-scenarios, and cost-effective in 76% of setting-scenarios with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%. In sensitivity analyses with a $100 per DALY averted cost-effectiveness threshold, a 7% per year discount rate, or with PrEP use that was less well risk-informed than in our base case, PrEP was less likely to be cost-effective, but generally remained cost-effective if the prevalence of HIV viral load greater than 1000 copies per mL among all adults was higher than 3%. In sensitivity analyses based on additional setting-scenarios in which risk-informed PrEP was less extensively used, the HIV incidence reduction was smaller, but the cost-effectiveness of risk-informed PrEP was undiminished. INTERPRETATION: Under the assumption that making PrEP easily accessible for all adults in sub-Saharan Africa in the context of community education leads to risk-informed use, PrEP is likely to be cost-effective in settings with prevalence of HIV viral load greater than 1000 copies per mL among all adults higher than 2%, suggesting the need for implementation of such approaches, with ongoing evaluation. FUNDING: US Agency for International Development, US President's Emergency Plan for AIDS Relief, and Bill & Melinda Gates Foundation.

Potential effects of disruption to HIV programmes in sub-Saharan Africa caused by COVID-19: results from multiple mathematical models.

BACKGROUND: The COVID-19 pandemic could lead to disruptions to provision of HIV services for people living with HIV and those at risk of acquiring HIV in sub-Saharan Africa, where UNAIDS estimated that more than two-thirds of the approximately 38 million people living with HIV resided in 2018. We aimed to predict the potential effects of such disruptions on HIV-related deaths and new infections in sub-Saharan Africa. METHODS: In this modelling study, we used five well described models of HIV epidemics (Goals, Optima HIV, HIV Synthesis, an Imperial College London model, and Epidemiological MODeling software [EMOD]) to estimate the effect of various potential disruptions to HIV prevention, testing, and treatment services on HIV-related deaths and new infections in sub-Saharan Africa lasting 6 months over 1 year from April 1, 2020. We considered scenarios in which disruptions affected 20%, 50%, and 100% of the population. FINDINGS: A 6-month interruption of supply of antiretroviral therapy (ART) drugs across 50% of the population of people living with HIV who are on treatment would be expected to lead to a 1·63 times (median across models; range 1·39-1·87) increase in HIV-related deaths over a 1-year period compared with no disruption. In sub-Saharan Africa, this increase amounts to a median excess of HIV deaths, across all model estimates, of 296 000 (range 229 023-420 000) if such a high level of disruption occurred. Interruption of ART would increase mother-to-child transmission of HIV by approximately 1·6 times. Although an interruption in the supply of ART drugs would have the largest impact of any potential disruptions, effects of poorer clinical care due to overstretched health facilities, interruptions of supply of other drugs such as co-trimoxazole, and suspension of HIV testing would all have a substantial effect on population-level mortality (up to a 1·06 times increase in HIV-related deaths over a 1-year period due to disruptions affecting 50% of the population compared with no disruption). Interruption to condom supplies and peer education would make populations more susceptible to increases in HIV incidence, although physical distancing measures could lead to reductions in risky sexual behaviour (up to 1·19 times increase in new HIV infections over a 1-year period if 50% of people are affected). INTERPRETATION: During the COVID-19 pandemic, the primary priority for governments, donors, suppliers, and communities should focus on maintaining uninterrupted supply of ART drugs for people with HIV to avoid additional HIV-related deaths. The provision of other HIV prevention measures is also important to prevent any increase in HIV incidence. FUNDING: Bill & Melinda Gates Foundation.