Efficient regulatory approval of two novel HIV prevention interventions in a resource-limited setting: experiences from Zimbabwe

The global burden of HIV remains unacceptably high despite significant progress made in HIV treatment and prevention. There is an urgent need to scale up the comprehensive HIV prevention strategies that include pre-exposure prophylaxis (PrEP). Oral PrEP is highly effective in preventing HIV acquisition when taken regularly, but this remains a challenge for some at-risk individuals. Therefore, there is a need for other HIV prevention options. The dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA) are novel biomedical interventions that are safe and efficacious for HIV pre-exposure prophylaxis, as demonstrated in recently completed clinical trials. Timely roll-out and scalability of efficacious interventions depend on the registration process with the national medicine regulatory authorities (NMRAs). The Medicines Control Authority of Zimbabwe (MCAZ) was the first NMRA globally to approve the DVR in July 2021 and the first in Africa to approve CAB-LA for HIV prevention in July 2022. The regulatory review process for DVR and CAB-LA by MCAZ took 4.5 and 5.5 months, respectively. This efficient review process of the two interventions by MCAZ, a regulatory body in a resource-limited setting, provides important lessons to shorten timelines between the completion of the clinical development process and the registration of essential medicines

Efficient regulatory approval of two novel HIV prevention interventions in a resource-limited setting: experiences from Zimbabwe.

The global burden of HIV remains unacceptably high despite significant progress made in HIV treatment and prevention. There is an urgent need to scale up the comprehensive HIV prevention strategies that include pre-exposure prophylaxis (PrEP). Oral PrEP is highly effective in preventing HIV acquisition when taken regularly, but this remains a challenge for some at-risk individuals. Therefore, there is a need for other HIV prevention options. The dapivirine vaginal ring (DVR) and long-acting injectable cabotegravir (CAB-LA) are novel biomedical interventions that are safe and efficacious for HIV pre-exposure prophylaxis, as demonstrated in recently completed clinical trials. Timely roll-out and scalability of efficacious interventions depend on the registration process with the national medicine regulatory authorities (NMRAs). The Medicines Control Authority of Zimbabwe (MCAZ) was the first NMRA globally to approve the DVR in July 2021 and the first in Africa to approve CAB-LA for HIV prevention in July 2022. The regulatory review process for DVR and CAB-LA by MCAZ took 4.5 and 5.5 months, respectively. This efficient review process of the two interventions by MCAZ, a regulatory body in a resource-limited setting, provides important lessons to shorten timelines between the completion of the clinical development process and the registration of essential medicines

Estimated costs for the delivery of safer conception strategies for HIV-discordant couples in Zimbabwe: a cost analysis.

BackgroundIn recent years, safer conception strategies have been developed to help HIV-serodiscordant couples conceive a child without transmitting HIV to the seronegative partner. The SAFER clinical trial assessed implementation of these strategies in Zimbabwe.MethodsAs a part of the SAFER study, we estimated the costs (in 2017 $US) associated with individual and combination strategies, in the trial setting and real-world practice, from a healthcare system perspective. Safer conception strategies included: 1) ART with frequent viral load testing until achieving undetectable viral load (ART-VL); 2) daily oral pre-exposure prophylaxis (PrEP); 3) semen-washing with intrauterine insemination; and 4) manual self-insemination at home. For costs in the trial, we used a micro-costing approach, including a time and motion study to quantify personnel effort, and estimated the cost per couple for individual and combination strategies for a mean of 6 months of safer services. For real-world practice, we modeled costs for three implementation scenarios, representing differences from the trial in input prices (paid by the Ministry of Health and Child Care [MOHCC]), intervention intensity, and increments to current HIV prevention and treatment practices and guidelines. We used one-way sensitivity analyses to assess the impact of uncertainty in input variables.ResultsIndividual strategy costs were$769-$1615 per couple in the trial;$185-$563 if using MOHCC prices. Under the target intervention intensity and using MOHCC prices, individual strategy costs were$73-$360 per couple over and above the cost of current HIV clinical practices. The cost of delivering the most commonly selected combination, ART-VL plus PrEP, ranged from$166-$517 per couple under the three real-world scenarios. Highest costs were for personnel, lab tests, and strategy-specific consumables, in variable proportions by clinical strategy and analysis scenario. Total costs were most affected by uncertainty in the price of PrEP, number of semen-washing attempts, and scale-up of semen-washing capacity.ConclusionsSafer conception methods have costs that may be affordable in many low-resource settings. These cost data will help implementers and policymakers add safer conception services. Cost-effectiveness analysis is needed to assess value for money for safer conception services overall and for safer strategy combinations.Trial registrationRegistry Name: Clinicaltrials.gov.Trial registration numberNCT03049176 . Registration date: February 9, 2017

Cost-effectiveness of safer reproduction strategies to prevent HIV in Zimbabwe

Background: HIV discordance in stable couples is a major driver of new infections, and discordant couples trying to conceive may be particularly at risk. Strategies that can reduce the risk of HIV transmission in these couples include antiretroviral therapy with adequate viral load suppression (ART/VL), oral pre-exposure prophylaxis (PrEP), artificial vaginal insemination (AVI), and semen washing (SW). Understanding the cost-effectiveness of these strategies is important, particularly in HIV endemic settings. Leveraging the ongoing SAFER study in Zimbabwe, we examined the cost-effectiveness of offering these strategies compared to current practice. Methods: The SAFER study is an observational cohort of discordant couples who are trying to conceive. SAFER participants are given a package of safer reproduction services, including counselling and a choice of one or more HIV prevention strategies: ART/VL, PrEP, AVI, or SW. We developed decision models to simulate the use of these strategies and to estimate their cost-effectiveness individually and in combination. Patient uptake of strategies was based on SAFER data. Total net costs and outcomes were assessed over a 30-year horizon from a health system perspective. Costs were derived from SAFER activities using micro-costing, including time and motion observations, and from published literature. Health outcomes were estimated using published literature and were measured in terms of disability-adjusted life-years (DALYs) associated with HIV infection. Incremental cost-effectiveness ratios (ICERs) were calculated using discounted total net health-care costs associated with each safer strategy versus current practice, and discounted DALYs for the seronegative partner and infant. Findings: Providing safer reproduction counselling and a choice of strategies is cost-effective compared with current practice, per the WHO standard of annual gross domestic product (GDP) per capita (US$1008 in Zimbabwe), and remains cost-effective up to 97$875 per DALY averted. Both AVI and ART/VL are cost-saving for couples with an HIV-positive woman, and ART/VL and SW were the most cost-effective strategies for couples with an HIV-positive man. Interpretation: Modelling suggests that offering safer reproduction counselling and services to HIV-discordant couples trying to conceive is likely to be highly cost-effective for HIV prevention. Our findings may inform implementation of these strategies in Zimbabwe, and sub-Saharan Africa. Funding: None

Preventing HIV and achieving pregnancy among HIV sero-different couples: Pilot study of a safer conception intervention in Zimbabwe.

Safer conception services are needed to minimize HIV transmission among HIV sero-different couples desiring pregnancy. Few studies have evaluated the choices couples make when offered multiple safer conception methods or real-world method acceptability and effectiveness. We piloted a comprehensive safer conception program (Clintrials.gov identifier: NCT03049176) for HIV sero-different couples planning pregnancy in Zimbabwe to measure feasibility, method uptake, acceptability, pregnancy outcome, and HIV transmission. This study was not designed to compare rates of HIV transmission by safer conception method choice but rather to understand choices couples make when seeking to minimize risk of HIV transmission and maximize likelihood of pregnancy. Couples in this prospective, non-randomized study were given a choice of one or more currently available safer conception methods: antiretroviral therapy (ART) with monthly viral load (VL) monitoring for the HIV-positive partner (ART/VL), pre-exposure prophylaxis (PrEP) for the HIV-negative partner, vaginal insemination (VI) for couples with an HIV-positive woman, and semen washing (SW) for couples with an HIV-positive man. Couples were followed monthly for up to 12 months of pregnancy attempts, quarterly during pregnancy, and 12 weeks post-partum. At each visit, data on method use, urine for pregnancy testing, and blood for HIV antibody testing, or viral load if HIV-positive, were obtained. Infants born to HIV-positive women were tested for HIV at 6 and 12 weeks. Between March 2017 and June 2019, 46 individuals from 23 HIV sero-different partnerships were enrolled and followed. At enrollment, all couples chose ART/VL, and all couples chose at least one additional method; 74% chose PrEP, 36% chose SW, and 25% chose VI. During pre-pregnancy follow-up visits, three couples discontinued SW, and one couple discontinued VI; all four of these couples opted for ART/VL plus PrEP. Satisfaction with safer conception methods was high among those who chose ART/VL and PrEP. Twelve couples achieved pregnancy. There were no cases of HIV transmission to partners, and no infants tested positive for HIV. This safer conception program is feasible and acceptable, allowing sero-different couples to safely achieve pregnancy. Sero-different couples in Zimbabwe seek a combination of HIV prevention methods, particularly ART/VL plus PrEP. Trial Registration: Clintrials.gov, NCT03049176