Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial.

BACKGROUND: Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring. METHODS: Plasma collected on the visit at which seroconversion was detected was tested by next-generation sequencing with unique molecular identifiers for non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRM) present at ≥1% frequency. Bulk-cloned plasma-derived recombinant HIV was phenotyped in a TZM-bl-based assay for susceptibility to DPV and other NNRTI. HIV-1 RNA was retrospectively quantified in plasma samples collected before HIV seroconversion. RESULTS: Among 38 participants who seroconverted in HOPE, 7 (18%) had NNRTI DRM detected by next-generation sequencing with unique molecular identifiers including A98G, K103N, V106M, E138A, and V179D. Six of 7 samples with NNRTI DRM had <3-fold reduction in susceptibility to DPV. Only 1 sample with K103N and V179I polymorphism had 9-fold reduction in susceptibility to DPV, but this genotype occurred in an individual who did not use DPV ring, likely indicating transmitted resistance. Detection of NNRTI resistance was not higher in individuals who remained on DPV ring >3 months after acquiring HIV infection. CONCLUSIONS: NNRTI resistance among women who seroconverted during HOPE was infrequent and selection of DPV-specific mutations was not detected. DPV ring is considered a safe and effective option for HIV prevention in women.

Dapivirine vaginal ring for HIV prevention: modelling health outcomes, drug resistance and cost-effectiveness.

INTRODUCTION: A vaginal ring containing dapivirine is effective for HIV prevention as pre-exposure prophylaxis (PrEP). We evaluated the potential epidemiological impact and cost-effectiveness of dapivirine vaginal ring PrEP among 22- to 45-year-old women in KwaZulu-Natal, South Africa. METHODS: Using mathematical modelling, we studied dapivirine vaginal ring PrEP implementation, either unprioritized, or prioritized based on HIV incidence (≥3% per year), age (22 to 29 years) or female sex worker status, alongside the implementation of voluntary medical male circumcision and antiretroviral therapy scaled-up to UNAIDS Fast-Track targets. Outcomes over the intervention (2019 to 2030) and lifetime horizons included cumulative HIV infections, life-years lived, costs and cost-effectiveness. We assessed the incremental cost-effectiveness ratios against the revealed willingness to pay ($500) and the standard (2017 per capita gross domestic product; $6161) cost-effectiveness thresholds for South Africa. RESULTS: Compared to a reference scenario without PrEP, implementation of dapivirine vaginal ring PrEP, assuming 56% effectiveness and covering 50% of 22 to 29-year-old or high-incidence women, prevented 10% or 11% of infections by 2030 respectively. Equivalent, unprioritized coverage (30%) prevented fewer infections (7%), whereas 50% coverage of female sex workers had the least impact (4%). Drug resistance attributable to PrEP was modest (2% to 4% of people living with drug-resistant HIV). Over the lifetime horizon, dapivirine PrEP implementation among female sex workers was cost-saving, whereas incidence-based PrEP cost $1898 per life-year gained, relative to PrEP among female sex workers and $989 versus the reference scenario. In a scenario of 37% PrEP effectiveness, PrEP had less impact, but prioritization to female sex workers remained cost-saving. In uncertainty analysis, female sex worker PrEP was consistently cost-saving; and over the lifetime horizon, PrEP cost less than $6161 per life-year gained in over 99% of simulations, whereas incidence- and age-based PrEP cost below $500 per life-year gained in 61% and 49% of simulations respectively. PrEP adherence and efficacy, and the effectiveness of antiretroviral therapy for HIV prevention, were the principal drivers of uncertainty in the cost-effectiveness of PrEP. CONCLUSIONS: Dapivirine vaginal ring PrEP would be cost-saving in KwaZulu-Natal if prioritized to female sex workers. PrEP's impact on HIV prevention would be increased, with potential affordability, if prioritized to women by age or incidence.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa.

BACKGROUND: Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear. METHODS: We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. RESULTS: Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing $10 880-$19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing $298-$1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<$1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEP's 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEP's costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEP's cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. CONCLUSIONS: Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.