Introduction A vaginal ring containing dapivirine is effective for HIV prevention as pre‐exposure prophylaxis (Pr EP ). We evaluated the potential epidemiological impact and cost‐effectiveness of dapivirine vaginal ring Pr EP among 22‐ to 45‐year‐old women in KwaZulu‐Natal, South Africa. Methods Using mathematical modelling, we studied dapivirine vaginal ring Pr EP 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 infect ions, 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 Pr EP , implementation of dapivirine vaginal ring Pr EP , 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 Pr EP was modest (2% to 4% of people living with drug‐resistant HIV ). Over the lifetime horizon, dapivirine Pr EP implementation among female sex workers was cost‐saving, whereas incidence‐based Pr EP cost $1898 per life‐year gained, relative to Pr EP among female sex workers and $989 versus the reference scenario. In a scenario of 37% Pr EP effectiveness, Pr EP had less impact, but prioritization to female sex workers remained cost‐saving. In uncertainty analysis, female sex worker Pr EP was consistently cost‐saving; and over the lifetime horizon, Pr EP cost less than $6161 per life‐year gained in over 99% of simulations, whereas incidence‐ and age‐based Pr EP cost below $500 per life‐year gained in 61% and 49% of simulations respectively. Pr EP adherence and efficacy, and the effectiveness of antiretroviral therapy for HIV prevention, were the principal drivers of uncertainty in the cost‐effectiveness of Pr EP . ...

BackgroundAntiretroviral therapy (ART) is critical for ending the HIV epidemic. Tenofovir-containing ART is the first-line regimen in many countries including South Africa, with limited access to second-line ART. High levels of drug resistance have been reported among patients after virologic failure on tenofovir-containing first-line regimens (TenoRes Study, Lancet Infect Dis 2016). We assessed drug resistance at the population level using mathematical modeling.MethodsWe developed a stochastic individual-based model of the heterosexual HIV epidemic in KwaZulu-Natal South Africa, and compared drug resistance from scenarios of tenofovir-containing ART scale-up, either CD4-based (threshold < 500 cells/mL) or Fast-track (80% coverage by 2020). The model represents details of HIV transmission and disease progression, demography, sexual behavior, condom use, circumcision, treatment interventions and drug resistance dynamics including key mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using an initial population of 2.5 million, we performed 100 simulations from 1978 to 2030. We examined the prevalence of (majority) transmitted and acquired resistance by 2030.ResultsThe total resistance (proportion of HIV-infected persons with drug resistance) reached 34% from CD4-based ART by 2030, with 30% relative contribution from transmitted resistance and 70% from acquired resistance. In contrast, Fast-track ART reduced the total resistance to 22%; though, there was an increased relative contribution from transmitted resistance (~ 50%). In both scenarios, NNRTI mutations were the most prevalent, followed by M184V and K65R mutations. About 48% of persons with acquired drug- resistance harbored dual drug mutations, 44.7% had triple mutations and 7.3% just single mutations, from CD4-based ART. The respective estimates from Fast-track ART were similar; 49% for dual, 44.1% for triple and 6.9% for single mutations. In both scenarios, NNRTI mutations comprised about 80% of prevalent transmitted resistance.ConclusionCurrent WHO-recommended first-line ART could lead to substantial drug resistance. Effective surveillance for resistance transmission and access to second-line regimens would be crucial.Disclosures All authors: No reported disclosures.

Background Tenofovir-containing regimens comprise the preferred first-line antiretroviral therapy (ART) in many countries including South Africa, where utilization of second-line regimens is limited. Considerable HIV drug resistance has occurred among persons failing tenofovir-containing first-line ART. We evaluated drug resistance at the population level using mathematical modeling. Setting Heterosexual HIV epidemic in KwaZulu-Natal, South Africa. Methods We constructed a stochastic individual-based model and simulated scenarios of ART implementation, either CD4-based (threshold < 500 cells/mL) or Fast-track (81% coverage by 2020), with consideration of major drug-associated mutations (M184V, K65R and non-nucleoside reverse transcriptase inhibitor (NNRTI)). Using base case and uncertainty analyses, we assessed (majority) drug resistance levels. Results By 2030, the median total resistance (proportion of HIV-infected persons with drug resistance) is predicted to reach 31.4% (interquartile range (IQR): 16.5%-50.2%) with CD4-based ART, decreasing to 14.5% (IQR: 7.7%-25.8%) with Fast-track implementation. In both scenarios, we find comparably high prevalence (~80%) of acquired NNRTI-associated, M184V and K65R mutations. Over 48% of individuals with acquired resistance harbor dual, 44% triple and 7% just single drug mutations. Drug-resistant HIV is predicted to comprise 40% (IQR: 27%-50%) of incident infections, while 70% of prevalent transmitted resistance is NNRTI-associated. At 2018, the projected total resistance is 15% (IQR: 7.5%-25%), with 18% (IQR: 13%-24%) of incident infections from transmitted drug-resistant HIV. Conclusions WHO-recommended preferred first-line ART could lead to substantial drug resistance. Effective surveillance of HIV drug resistance and utilization of second-line as well as alternative first-line regimens is crucial.