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Background: Persistent use of HIV prevention methods can be a challenge, particularly for some younger women. The long-acting, discreet, woman-centric dapivirine vaginal ring offers promise as a prevention method with less user burden, which could support continued use. We assessed dapivirine vaginal ring use to understand adherence patterns and identify characteristics influencing patterns., Setting: Participants enrolled in South Africa in the MTN-020/ASPIRE randomized placebo-controlled trial., Methods: We used group-based trajectory modeling to identify clusters of participants with similar longitudinal patterns of adherence in the last year of participation and potential predictors of group membership. Women with at least 1 year of follow-up were included (n = 626)., Results: Five adherence patterns were identified: (1) consistently high, 34%, (2) consistently moderate, 34%, (3) consistently low, 16%, (4) decreasing, 9%, and (5) increasing, 7%. Women younger than 22 years [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.0 to 3.0], using an intrauterine device (AOR 3.3, 95% CI: 1.4 to 7.8) or oral contraceptives (AOR 3.9, 95% CI: 1.7 to 8.9), experiencing menses (AOR 1.8, 95% CI: 1.1 to 3.0), and who reported inconsistent condom use (AOR 1.8, 95% CI: 1.0 to 3.3) were more likely to be classified as consistently low compared to consistently high (referent)., Conclusions: Most South African women successfully persisted with a moderate or high level of use. Encouraging ring replacement with completion of menses may help to decrease concerns about hygiene and improve persistence. Associations between contraception and persistent low adherence suggest efforts may be needed to ensure contraceptive method choice does not interfere with ring use., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women., Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564., Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported., Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women., Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support., Competing Interests: Declaration of interests PLA has received fees from Merck, ViiV Healthcare, and Gilead Sciences, and research support from Gilead Sciences paid to his institution. AR, WRS, and KS are employees of ViiV Healthcare. JFR is an employee of Gilead Sciences. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Placebo-controlled HIV-1 prevention trials of pre-exposure prophylaxis (PrEP) have not generally used concurrent measurement of adherence because of the potential risk of unblinding. However, several pre-exposure prophylaxis trials for HIV-1 prevention among women failed to show effectiveness because of low product adherence. Evaluation of product adherence objectively during a study provides the opportunity for strengthening adherence activities at sites having low adherence., Methods: During MTN-020/ASPIRE, a phase III, placebo-controlled trial of the dapivirine intravaginal ring, we implemented an adherence monitoring system. Monitoring began in quarter 1 (Q1) 2013 and continued through the conclusion of the trial. Blood plasma was collected quarterly and tested for dapivirine concentrations while maintaining blinding among study team members involved in participant management. Dapivirine concentrations >95 pg/mL, reflecting >8 hours of continuous use, were assessed as signaling product use. Study leadership monitored results on a monthly basis and provided feedback to site investigators. Experiences were shared across sites to motivate staff and counsel participants to strive toward higher adherence levels., Results: An upward trend in adherence was observed (P < 0.0001); the proportion of samples from subjects in the active arm with dapivirine >95 pg/mL increased from 63% in Q1 2013 to 84% by Q1 2015., Conclusions: Ongoing drug level testing as a marker of adherence in MTN-020/ASPIRE demonstrates the feasibility of real-time adherence monitoring while maintaining study blinding at the level of participants, sites, and study leadership. This approach is novel for large-scale effectiveness studies for HIV-1 prevention.

Background: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection., Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe., Results: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups., Conclusions: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

Objective: To develop and validate an HIV risk assessment tool to predict HIV acquisition among African women., Design: Data were analyzed from 3 randomized trials of biomedical HIV prevention interventions among African women (VOICE, HPTN 035, and FEM-PrEP)., Methods: We implemented standard methods for the development of clinical prediction rules to generate a risk-scoring tool to predict HIV acquisition over the course of 1 year. Performance of the score was assessed through internal and external validations., Results: The final risk score resulting from multivariable modeling included age, married/living with a partner, partner provides financial or material support, partner has other partners, alcohol use, detection of a curable sexually transmitted infection, and herpes simplex virus 2 serostatus. Point values for each factor ranged from 0 to 2, with a maximum possible total score of 11. Scores ≥5 were associated with HIV incidence >5 per 100 person-years and identified 91% of incident HIV infections from among only 64% of women. The area under the curve (AUC) for predictive ability of the score was 0.71 (95% confidence interval [CI]: 0.68 to 0.74), indicating good predictive ability. Risk score performance was generally similar with internal cross-validation (AUC = 0.69; 95% CI: 0.66 to 0.73) and external validation in HPTN 035 (AUC = 0.70; 95% CI: 0.65 to 0.75) and FEM-PrEP (AUC = 0.58; 95% CI: 0.51 to 0.65)., Conclusions: A discrete set of characteristics that can be easily assessed in clinical and research settings was predictive of HIV acquisition over 1 year. The use of a validated risk score could improve efficiency of recruitment into HIV prevention research and inform scale-up of HIV prevention strategies in women at highest risk.

A recent analysis from South Africa reported no association between age-disparate relationships and HIV-1 acquisition. We assessed the association between male partner age and HIV-1 acquisition among South African women participating in the VOICE trial. Of 4077 women enrolled, 3789 had complete data; 26% and 5% reported having a partner >5 and >10 years older at enrollment, respectively. Reporting a partner >5 years older (hazard ratio = 1.00; 95% confidence interval: 0.74 to 1.35) or >10 older (hazard ratio = 0.92; 95% confidence interval: 0.49 to 1.74) was not associated with HIV-1 acquisition. These data corroborate recent reports and may suggest a shift in local epidemiology of heterosexual HIV-1 transmission.

Background: Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition., Methods: We included data from South African women who used injectable contraception while participating in theVOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679., Findings: 3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%)solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence7·57 per 100 person-years, 95% CI 6·61–8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35–10·11) than among NET-EN users (5·67 per 100 person-years, 4·35–7·38;hazard ratio 1·53, 95% CI 1·12–2·08; p=0·007). This association persisted when adjusted for potential confoundingvariables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06–1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26–3·24) compared with 1·09 (0·78–1·52)for HSV-2-seronegative women (pinteraction=0·07)., Interpretation: Although moderate associations in observational analyses should be interpreted with caution, thesefi ndings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available., Funding: National Institutes of Health, Mary Meyer Scholars Fund, and the Ruth Freeman Memorial Fund.

Background: Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection., Methods: We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly., Results: Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events., Conclusions: None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).

BackgroundTwo phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation.MethodsWe did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037.FindingsBetween July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p

ObjectiveWe aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities.DesignSecondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE).MethodsData from ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of VOICE, a prior HIV-1 prevention trial conducted in a similar population.ResultsCervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6 versus 91.5%, ASC-US//LSIL: 7.8 versus 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7 versus 1.1%, P = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable with that of both dapivirine (P = 0.93) and placebo vaginal ring arms (P = 0.24).ConclusionThese findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of 2 years, is associated with development of cervical cytology abnormalities that could lead to precancerous or cancerous lesions.

Contraceptive adherence during acute and recent HIV-1 infection is important to maternal and child health given the elevated risk of vertical HIV-1 transmission and additional complications of pregnancy. Injectable contraception (IC) is the most common non-barrier modern contraception method used in sub-Saharan Africa (SSA). Adherence to IC after HIV-1 seroconversion is not well understood. We examined factors associated with IC discontinuation among women in SSA diagnosed with HIV-1 infection while participating in a clinical trial of biomedical HIV-1 prevention. After diagnosis with HIV-1 infection in the VOICE trial, 255 women from South Africa, Uganda, and Zimbabwe enrolled in a longitudinal observational study (MTN-015). Contraceptive method was assessed at MTN-015 baseline and at 3, 12, and 24 months post-seroconversion. Correlates of IC discontinuation were examined by Cox proportional hazard modeling. IC use was reported at baseline by 78% of women enrolled (198/255), of which 92% (182/198) completed at least one follow-up visit. Two-thirds of women (66%, 121/182) continued on IC during the follow-up period (median 24 months). Lower rates of IC discontinuation were observed in women who reported having had at least one child (HR 0.39, 95% CI 0.20-0.82) or earning a personal income (HR 0.51, 95% CI 0.30-0.87) at baseline. These findings suggest that many women with HIV-1 infection face complex decision-making regarding family planning in the years that follow seroconversion and highlight that some women may discontinue IC use despite on-site provision of family planning services. Understanding the broader context of family planning choices in recently seroconverted women may be key to more effective linkages between family planning services and HIV-1 testing and care.

ObjectiveTo develop and validate an HIV risk assessment tool to predict HIV acquisition among African women.DesignData were analyzed from 3 randomized trials of biomedical HIV prevention interventions among African women (VOICE, HPTN 035, and FEM-PrEP).MethodsWe implemented standard methods for the development of clinical prediction rules to generate a risk-scoring tool to predict HIV acquisition over the course of 1 year. Performance of the score was assessed through internal and external validations.ResultsThe final risk score resulting from multivariable modeling included age, married/living with a partner, partner provides financial or material support, partner has other partners, alcohol use, detection of a curable sexually transmitted infection, and herpes simplex virus 2 serostatus. Point values for each factor ranged from 0 to 2, with a maximum possible total score of 11. Scores ≥5 were associated with HIV incidence >5 per 100 person-years and identified 91% of incident HIV infections from among only 64% of women. The area under the curve (AUC) for predictive ability of the score was 0.71 (95% confidence interval [CI]: 0.68 to 0.74), indicating good predictive ability. Risk score performance was generally similar with internal cross-validation (AUC = 0.69; 95% CI: 0.66 to 0.73) and external validation in HPTN 035 (AUC = 0.70; 95% CI: 0.65 to 0.75) and FEM-PrEP (AUC = 0.58; 95% CI: 0.51 to 0.65).ConclusionsA discrete set of characteristics that can be easily assessed in clinical and research settings was predictive of HIV acquisition over 1 year. The use of a validated risk score could improve efficiency of recruitment into HIV prevention research and inform scale-up of HIV prevention strategies in women at highest risk.