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.

The changing health impact of vaccines in the COVID-19 pandemic: A modeling study.

Much of the world's population had already been infected with COVID-19 by the time the Omicron variant emerged at the end of 2021, but the scale of the Omicron wave was larger than any that had come before or has happened since, and it left a global imprinting of immunity that changed the COVID-19 landscape. In this study, we simulate a South African population and demonstrate how population-level vaccine effectiveness and efficiency changed over the course of the first 2 years of the pandemic. We then introduce three hypothetical variants and evaluate the impact of vaccines with different properties. We find that variant-chasing vaccines have a narrow window of dominating pre-existing vaccines but that a variant-chasing vaccine strategy may have global utility, depending on the rate of spread from setting to setting. Next-generation vaccines might be able to overcome uncertainty in pace and degree of viral evolution.

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.

Understanding the Evolving Role of Voluntary Medical Male Circumcision as a Public Health Strategy in Eastern and Southern Africa: Opportunities and Challenges.

PURPOSE OF REVIEW: Voluntary male medical circumcision (VMMC) has been a cornerstone of HIV prevention in Eastern and Southern Africa (ESA) and is credited in part for declines in HIV incidence seen in recent years. However, these HIV incidence declines change VMMC cost-effectiveness and how it varies across populations. RECENT FINDINGS: Mathematical models project continued cost-effectiveness of VMMC in much of ESA despite HIV incidence declines. A key data gap is how demand generation cost differs across age groups and over time as VMMC coverage increases. Additionally, VMMC models usually neglect non-HIV effects of VMMC, such as prevention of other sexually transmitted infections and medical adverse events. While small compared to HIV effects in the short term, these could become important as HIV incidence declines. Evidence to date supports prioritizing VMMC in ESA despite falling HIV incidence. Updated modeling methodologies will become necessary if HIV incidence reaches low levels.

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.

Incremental costs of integrated PrEP provision and effective use counselling in community-based platforms for adolescent girls and young women in South Africa: an observational study.

INTRODUCTION: Adolescent girls and young women (AGYW) are a priority population for pre-exposure prophylaxis (PrEP), a highly effective HIV prevention method. However, effective PrEP use among AGYW has been low. Interventions to support PrEP effective use may improve pill-taking. Affordability of PrEP programs depends on their cost. We, therefore, evaluated the cost of community-based PrEP with effective use counselling. METHODS: Cost data from a randomized controlled trial were used to evaluate the cost of PrEP provision with effective use counselling offered to AGYW through community-based HIV testing platforms between November 2018 and November 2019. AGYW were randomized to receive (1) group-based community health club effective use counselling, (2) individualized effective use counselling or (3) community-based PrEP dispensary. Task shifting of effective use counselling from nurses to trained lay counsellors was implemented in groups 1 and 2. Personnel costs were estimated from time-and-motion observations and staff interviews. Expenditure and ingredients-based approaches were used to estimate costs for medical and non-medical supplies. RESULTS: In total, 603 AGYW initiated PrEP and accrued a total of 1280 months on PrEP. Average cost per person-month on PrEP with group-based community health club, individualized effective use counselling and community-based PrEP dispensary under the Department of Health scenario were similar and high (USD $55.32, $55.65 and $55.46, respectively) due to low PrEP client volume observed in the clinical trial. Increasing client volume (scaled Department of Health scenario) reduced cost per-person month estimates to USD $15.48, $26.40 and $13.99, respectively. CONCLUSIONS: As designed, individualized effective use counselling increased the cost of standard-of-care PrEP delivery by 89%, group-based community health effective use counselling increased the cost of standard-of-care PrEP delivery by 11%. These estimates can inform cost-effectiveness and budget impact analysis for PrEP provision with effective use counselling services.

The risks and benefits of providing HIV services during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic has caused widespread disruptions including to health services. In the early response to the pandemic many countries restricted population movements and some health services were suspended or limited. In late 2020 and early 2021 some countries re-imposed restrictions. Health authorities need to balance the potential harms of additional SARS-CoV-2 transmission due to contacts associated with health services against the benefits of those services, including fewer new HIV infections and deaths. This paper examines these trade-offs for select HIV services. METHODS: We used four HIV simulation models (Goals, HIV Synthesis, Optima HIV and EMOD) to estimate the benefits of continuing HIV services in terms of fewer new HIV infections and deaths. We used three COVID-19 transmission models (Covasim, Cooper/Smith and a simple contact model) to estimate the additional deaths due to SARS-CoV-2 transmission among health workers and clients. We examined four HIV services: voluntary medical male circumcision, HIV diagnostic testing, viral load testing and programs to prevent mother-to-child transmission. We compared COVID-19 deaths in 2020 and 2021 with HIV deaths occurring now and over the next 50 years discounted to present value. The models were applied to countries with a range of HIV and COVID-19 epidemics. RESULTS: Maintaining these HIV services could lead to additional COVID-19 deaths of 0.002 to 0.15 per 10,000 clients. HIV-related deaths averted are estimated to be much larger, 19-146 discounted deaths per 10,000 clients. DISCUSSION: While there is some additional short-term risk of SARS-CoV-2 transmission associated with providing HIV services, the risk of additional COVID-19 deaths is at least 100 times less than the HIV deaths averted by those services. Ministries of Health need to take into account many factors in deciding when and how to offer essential health services during the COVID-19 pandemic. This work shows that the benefits of continuing key HIV services are far larger than the risks of additional SARS-CoV-2 transmission.

Cost-effectiveness of point-of-care testing with task-shifting for HIV care in South Africa: a modelling study.

BACKGROUND: The number of people on antiretroviral therapy (ART) requiring treatment monitoring in low-resource settings is rapidly increasing. Point-of-care (POC) testing for ART monitoring might alleviate burden on centralised laboratories and improve clinical outcomes, but its cost-effectiveness is unknown. METHODS: We used cost and effectiveness data from the STREAM trial in South Africa (February, 2017-October, 2018), which evaluated POC testing for viral load, CD4 count, and creatinine, with task shifting from professional to lower-cadre registered nurses compared with laboratory-based testing without task shifting (standard of care). We parameterised an agent-based network model, EMOD-HIV, to project the impact of implementing this intervention in South Africa over 20 years, simulating approximately 175 000 individuals per run. We assumed POC monitoring increased viral suppression by 9 percentage points, enrolment into community-based ART delivery by 25 percentage points, and switching to second-line ART by 1 percentage point compared with standard of care, as reported in the STREAM trial. We evaluated POC implementation in varying clinic sizes (10-50 patient initiating ART per month). We calculated incremental cost-effectiveness ratios (ICERs) and report the mean and 90% model variability of 250 runs, using a cost-effectiveness threshold of US$500 per disability-adjusted life-year (DALY) averted for our main analysis. FINDINGS: POC testing at 70% coverage of patients on ART was projected to reduce HIV infections by 4·5% (90% model variability 1·6 to 7·6) and HIV-related deaths by 3·9% (2·0 to 6·0). In clinics with 30 ART initiations per month, the intervention had an ICER of $197 (90% model variability -27 to 863) per DALY averted; results remained cost-effective when varying background viral suppression, ART dropout, intervention effectiveness, and reduction in HIV transmissibility. At higher clinic volumes (≥40 ART initiations per month), POC testing was cost-saving and at lower clinic volumes (20 ART initiations per month) the ICER was $734 (93 to 2569). A scenario that assumed POC testing did not increase enrolment into community ART delivery produced ICERs that exceeded the cost-effectiveness threshold for all clinic volumes. INTERPRETATION: POC testing is a promising strategy to cost-effectively improve patient outcomes in moderately sized clinics in South Africa. Results are most sensitive to changes in intervention impact on enrolment into community-based ART delivery. FUNDING: National Institutes of Health.

Individual and community-level benefits of PrEP in western Kenya and South Africa: Implications for population prioritization of PrEP provision.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV and has the potential to significantly impact the HIV epidemic. Given limited resources for HIV prevention, identifying PrEP provision strategies that maximize impact is critical. METHODS: We used a stochastic individual-based network model to evaluate the direct (infections prevented among PrEP users) and indirect (infections prevented among non-PrEP users as a result of PrEP) benefits of PrEP, the person-years of PrEP required to prevent one HIV infection, and the community-level impact of providing PrEP to populations defined by gender and age in western Kenya and South Africa. We examined sensitivity of results to scale-up of antiretroviral therapy (ART) and voluntary medical male circumcision (VMMC) by comparing two scenarios: maintaining current coverage ("status quo") and rapid scale-up to meet programmatic targets ("fast-track"). RESULTS: The community-level impact of PrEP was greatest among women aged 15-24 due to high incidence, while PrEP use among men aged 15-24 yielded the highest proportion of indirect infections prevented in the community. These indirect infections prevented continue to increase over time (western Kenya: 0.4-5.5 (status quo); 0.4-4.9 (fast-track); South Africa: 0.5-1.8 (status quo); 0.5-3.0 (fast-track)) relative to direct infections prevented among PrEP users. The number of person-years of PrEP needed to prevent one HIV infection was lower (59 western Kenya and 69 in South Africa in the status quo scenario; 201 western Kenya and 87 in South Africa in the fast-track scenario) when PrEP was provided only to women compared with only to men over time horizons of up to 5 years, as the indirect benefits of providing PrEP to men accrue in later years. CONCLUSIONS: Providing PrEP to women aged 15-24 prevents the greatest number of HIV infections per person-year of PrEP, but PrEP provision for young men also provides indirect benefits to women and to the community overall. This finding supports existing policies that prioritize PrEP use for young women, while also illuminating the community-level benefits of PrEP availability for men when resources permit.

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.

Impact along the HIV pre-exposure prophylaxis "cascade of prevention" in western Kenya: a mathematical modelling study.

INTRODUCTION: Over one hundred implementation studies of HIV pre-exposure prophylaxis (PrEP) are completed, underway or planned. We synthesized evidence from these studies to inform mathematical modelling of the prevention cascade for oral and long-acting PrEP in the setting of western Kenya, one of the world's most heavily HIV-affected regions. METHODS: We incorporated steps of the PrEP prevention cascade - uptake, adherence, retention and re-engagement after discontinuation - into EMOD-HIV, an open-source transmission model calibrated to the demography and HIV epidemic patterns of western Kenya. Early PrEP implementation research from East Africa was used to parameterize prevention cascades for oral PrEP as currently implemented, delivery innovations for oral PrEP, and future long-acting PrEP. We compared infections averted by PrEP at the population level for different cascade assumptions and sub-populations on PrEP. Analyses were conducted over the 2020 to 2040 time horizon, with additional sensitivity analyses for the time horizon of analysis and the time when long-acting PrEP becomes available. RESULTS: The maximum impact of oral PrEP diminished by over 98% across all prevention cascades, with the exception of long-acting PrEP under optimistic assumptions about uptake and re-engagement after discontinuation. Long-acting PrEP had the highest population-level impact, even after accounting for possible delays in product availability, primarily because its effectiveness does not depend on drug adherence. Retention was the most significant cascade step reducing the potential impact of long-acting PrEP. These results were robust to assumptions about the sub-populations receiving PrEP, but were highly influenced by assumptions about re-initiation of PrEP after discontinuation, about which evidence was sparse. CONCLUSIONS: Implementation challenges along the prevention cascade compound to diminish the population-level impact of oral PrEP. Long-acting PrEP is expected to be less impacted by user uptake and adherence, but it is instead dependent on product availability in the short term and retention in the long term. To maximize the impact of long-acting PrEP, ensuring timely product approval and rollout is critical. Research is needed on strategies to improve retention and patterns of PrEP re-initiation.