Background: Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1 uninfected women who became pregnant while participating in MTN-020/ASPIRE. Methods: ASPIRE was a randomized, double-blind, placebo controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18–45 from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included: pregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, congenital anomalies), and infant growth. Results: Of 2,629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio=0.93; 95% CI 0.68–1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm. Conclusion: Dapivirine use in the periconception period does not appear to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.
Introduction Effective, long-acting prevention approaches are needed to reduce HIV incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa. Methods CAPRISA 012A was a randomised, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into nine groups and assessed safety, tolerability, pharmacokinetics, neutralization activity and anti-drug antibody levels. Pharmacokinetic modelling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals. Results VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations following 20mg/kg doses were 9.65μg/ml and 3.86μg/ml at 16 and 24 weeks. The median week 8 concentration following the 10mg/kg PGT121 dose was 8.26μg/ml. Modelling of PGT121 at 20mg/kg showed median concentrations of 1.37μg/ml and 0.22μg/ml at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity post administration and no anti-drug antibodies were detected. Discussion Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention.
IntroductionYoung African women bear a disproportionately high risk for HIV acquisition. HIV technologies that empower women to protect themselves are needed. Safe, potent antiretroviral agents such as tenofovir alafenamide (TAF), formulated as long-acting subdermal implants, offer an innovative solution.Methods and analysisCAPRISA 018 is a phase I/II trial to evaluate the safety, acceptability, tolerability and pharmacokinetics (PKs) of a TAF free base subdermal silicone implant containing 110 mg of TAF with an anticipated 0.25 mg/day release rate.The phase I trial (n=60) will assess the safety of one implant inserted in six participants (Group 1), followed by dose escalation components (Groups 2 and 3) assessing the safety, tolerability and PK of one to four TAF 110 mg implants releasing between 0.25 mg and 1 mg daily in 54 healthy women at low risk for HIV infection. Data from this phase I trial will be used to determine the dosing, implant location and implant replacement interval for the phase II trial.The phase II component (Group 4) will assess extended safety, PK, tolerability and acceptability of the implant in 490 at risk women, randomised in a 1:1 ratio to the TAF implant and placebo tablet or to the placebo implant and an oral pre-exposure prophylaxis tablet. Safety will be assessed by calculating the percentage change in creatinine clearance from baseline at weeks 4, 12, 24, 36, 72, 96 and 120, compared with the percentage change in the control group.Ethics and disseminationThe South African Health Products Regulatory Authority and the University of KwaZulu-Natal’s Biomedical Research Ethics Committee have approved the trial. Results will be disseminated through open access peer reviewed publications, conference presentations, public stakeholder engagement and upload of data into the clinical trials registry.Trial registration numberPACTR201809520959443.
We evaluated the acceptability of the 25 mg dapivirine vaginal ring (DVR) as an HIV prevention intervention and its influence on DVR adherence in the MTN-020/ASPIRE phase III trial. Acceptability measures were captured using ACASI at month 3 and end of product use (median 24 months, IQR 15–30). Monthly returned rings were classified as nonadherent if dapivirine release rate was ≤ 0.9 mg/month. Associations between acceptability measures and nonadherence were estimated using Poisson regression models with robust standard errors. At month 3 (N = 2334), 88% reported DVR was comfortable, 80% were unaware of it during daily activities, and 74% never felt it during sex. At exit, 66% were ‘very likely’ to use DVR in the future. Acceptability was found to differ significantly by country across several measures including wearing the ring during sex, during menses, partner acceptability, impact on sexual pleasure and willingness to use the ring in the future. Risk of nonadherence at month 12 was elevated if DVR was felt during sex at month 3 (aRR 1.67, 95% CI 1.26, 2.23). Risk of nonadherence in the last year of study participation was elevated if, at exit, participants minded wearing during sex (aRR 2.08, 95% CI 1.52, 2.85), during menses (aRR 1.57, 95% CI 1.06, 2.32), reported a problematic change to the vaginal environment (aRR 1.57, 95% CI 1.12, 2.21), and were not “very likely” to use DVR in the future (aRR 1.31, 95% CI 1.02, 1.68). DVR acceptability was overall high yet varied by country. Addressing perceived ring interference with sex, menses, or problematic changes to the vaginal environment in future interventions could help improve adherence, as could embracing sex-positive messaging related to ring use and increased pleasure.Trial Registration ClinicalTrials.gov Identifier: NCT01617096.
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