AFJOG

REVIEW African Journal of Obstetrics and Gynaecology | Volume 2 | Issue 3 | 2024 | Pre-Exposure Prophylaxis to prevent HIV infection during Pregnancy and Breast-feeding: A South African Perspective on the impact of oral PrEP on incidental pregnancy was planned to be collected during the IMPOWER-22 trial. This was a double- blind randomized controlled trial evaluating the safety and efficacy of oral islatravir administered monthly for prevention of HIV infection, among cis-gender women. Islatravir (MK8591) is a deoxyadenosine analogue that is converted intracellularly into its active form, islatravir triphosphate. It suppresses HIV- 1 replication through inhibition of reverse transcriptase. This drug falls under a group of novel drugs classified as Nucleoside Reverse Transcription Translocation Inhibitors (NRTTI). The trial was prematurely discontinued in September 2022 (44) . In December 2021, the Food and Drug Administration (FDA) placed a clinical hold on studies of islatravir for HIV treatment and prevention. This decision was based on reports of declining total lymphocyte and CD4 counts in some participants receiving islatravir (45,46) . MICROBICIDES/TOPICALFORMULATIONS: Microbicides are substances that can be used locally to reduce the risk of HIV infection through sexual exposure. Microbicides may be antiretroviral- (ARV) or non-ARV-based products. These products have been in development for more than 20 years. First-generation vaginal microbicides consisted of either surfactants that disrupted cell membranes, polyanions that prevent attachment to target cells in the vagina, or acid buffers that maintained vaginal pH. These products were not specific to HIV and showed no preventive effect (47) . Microbicides are manufactured in different forms (e.g gels, tablets, films, creams, lubricants, sponges and most importantly, rings) that may be applied vaginally or rectally. Microbicides offer a self-initiated and discreet HIV prevention tool that empowers women to take control of their sex events. Such products are crucial in the prevention of HIV acquisition, especially among AGYW. The Microbicide Trial Network (MTN), discontinued in 2021, evaluated the efficacy and safety of microbicides in diverse population groups (including PBFW) in four continents (48) . Vaginal Gels: ARV-based gels have been evaluated over the past decade, with promising results (49) . Pharmacokinetic studies have shown that TFV-based vaginal topical agents, in all their forms, dose vaginal tissues with high concentrations of TFV- diphosphate, the pharmacologically active drug (50) . A phase IIb clinical trial conducted in South Africa (CAPRISA 004) demonstrated a 39% reduction in acquisition of HIV with the use of a 1% TFV vaginal gel. A 54% reduction was observed in women who used the gel more than 80% of the time (51) . A similar phase III trial, also conducted in South Africa from 2011 - 2014 (FACTS 001), enrolled 2059 sexually active women (18-30yrs). The efficacy of peri-coital 1% TFV vaginal gel was compared to placebo. The study did not show any benefit of the gel relative to placebo and no product-related serious adverse events were reported (52) . The HIV incidence was reported at 4 per 100 women years in both groups. This was attributed to poor adherence to the gel. A sub-group analysis of the study demonstrated an estimated 52% protective effect among participants who used the gel as directed (HR 0·48, 95% CI 0·26–0·89) . The Vaginal and Oral Interventions to Control the Epidemic trial (VOICE; MTN 003), which assessed a daily rather than peri- coital regimen of tenofovir 1% gel, did not show a reduction in HIV infection in the daily TFV gel group, also as a result of poor adherence to use of the gel (53). VOICE was a randomised, placebo-controlled trial which assessed daily treatment with oral TDF, oral TDF/FTC, or 1% TFV vaginal gel. The study was conducted in women in South Africa, Uganda, and Zimbabwe, and enrolled 5029 HIV-uninfected women. The disappointing results on the efficacy of vaginal gels, as a result of poor adherence, has prompted the development of more acceptable and user-friendly products. Vaginal Rings: Newer forms of microbicides that contain long- acting ARV agents have shown promising results. Dapivirine ring (DVR), a monthly self-inserted vaginal ring containing the antiretroviral drug dapivirine (a non-nucleoside reverse transcriptace inhibitor; NNRTI) has been approved in some ESA countries and recommended by WHO for PrEP since 2021 (31) . In March 2022, the South African Health Products Regulatory Authority (SAHPRA) approved the use of the dapivirine ring in women aged ≥ 18 years (54) . This product has, however, not been approved in the United States of America (USA) and has only received a favorable opinion from the European Medicines Agency (55) , despite consistent evidence of safety and efficacy. ASPIRE (MTN-020) was a Phase III clinical trial that demonstrated the safety and efficacy of DVR in preventing new HIV infections. An exploratory analysis of the study data found that the monthly ring reduced the risk of HIV acquisition by at least 56% with consistent use (56) . The identical RING Study (IPM-027), conducted by the International Partnership for Microbicides (IPM) reported an overall risk reduction of 31% (57) . Both trials reported low systemic exposures to dapivirine, with little or no increased NNRTI-resistance mutations. The vaginal ring was generally well tolerated by participants. Data from ASPIRE indicated that younger women (aged 18–21 years) had no reduction in HIV-1 infection risk as a result of poor adherence to the product. In 2016, the follow-up HIV Open Label Prevention Extension (HOPE; MTN-025)) study was launched to evaluate safety and adherence to DVR, when participants were aware of the promising results of ASPIRE (58) . HOPE enrolled 1,456 former ASPIRE participants at 14 sites in Malawi, South Africa, Uganda and Zimbabwe. Women were given free-will to use the ring, and to discontinue use at any time during the study. The ring was well-tolerated, consistent with the safety profile seen in ASPIRE. Measures of adherence also indicated women’s uptake and use of the ring was higher. Furthermore, additional analysis suggested a lower than expected HIV transmission rate. The Dapivirine Ring Extended Access and Monitoring trial (DREAM; IPM-032) also assessed safety and adherence to DVR in women who participated in the RING and ASPIRE studies (59) . The feasibility of 3-monthly visits and HIV incidence were also assessed. DREAM was conducted in 5 South African sites and 1 site in Uganda. The study enrolled 1034 participants, with 848 completing the study. A 62% (95% CI = 1.1 - 2.6) overall risk reduction of HIV acquisition, with improved adherence was reported. The feasibility of 3-monthly visits, simulating a real- world environment, was also demonstrated. Women planning a pregnancy and PBFW were excluded from the study. Of concern, are the reported adherence challenges facing young women when using DVR (56,57) . The MTN-023 and IPM 030 trials evaluated the safety and tolerability of DVR in young girls under 18yrs in the United States (60,61) . The study enrolled 96 participants aged 15 -17yrs between July 2014 to July 2016. A monthly DVR was compared to a monthly placebo ring over a 6-month period. The study found no differences in safety outcomes between DVR and the placebo ring. Adherence to ring use was reported to be high. Forty-two percent of participants reported never having to remove the ring, except for monthly replacements and the ring was found to be highly acceptable. Ninety-five percent of participants found the ring easy to use and 74 percent African Journal of Obstetrics and Gynaecology | Volume 2 | Issue 3 | 2024 | 10