Attitudes and perceptions towards developing a health educational video to enhance optimal uptake of malaria preventive therapy among pregnant women in Uganda: a qualitative study involving pregnant women, health workers, and Ministry of health officials.

BACKGROUND: Malaria in pregnancy remains a major global public health problem. Intermittent prophylaxis treatment of malaria in pregnancy with Sulphadoxine-pyrimethamine and co-trimoxazole is efficacious for prevention of malaria in pregnancy HIV negative and positive women, respectively. However, uptake of the recommended doses of therapies has remained suboptimal in Uganda, majorly due to inadequate knowledge among pregnant women. Therefore, this study aimed to explore attitudes and perceptions towards developing an educational video for malaria preventive therapy. METHODS: We conducted an exploratory study with qualitative methods among pregnant women attending antenatal care at Kisenyi Health Center IV (KHCIV), health workers from KHCIV, and officials from the Ministry of Health. The study was conducted at KHCIV from October 2022 to March 2023. Focus group discussions (FGD) were conducted among purposively selected pregnant women and key informant interviews (KII) among health workers and Ministry of Health officials. Data were analyzed using inductive and deductive thematic methods in atlas ti.8. RESULTS: A total of five FGDs comprising of 7-10 pregnant women were conducted; and KIIs were conducted among four mid-wives, two obstetricians, and two Ministry of Health officials. Generally, all respondents mentioned a need for interventions to improve malaria preventive knowledge among pregnant women; were positive about developing an educative video for malaria preventive therapy in pregnancy; and suggested a short, concise, and edutaining video focusing both the benefits of taking and risks of not taking malaria preventive therapy. They proposed that women may be encouraged to view the video as soon as they conceive and throughout the pregnancy. It also was suggested that the video may be viewed on television sets in maternal and reproductive health clinics and homes, and on smart phones. CONCLUSION: Pregnant women, health workers, and Ministry of Health officials were positive about the development of a short edutaining video on malaria preventive therapy that focuses on both benefits of taking and risks of not taking the malaria preventive therapy in pregnancy. This information guided the video development and therefore, in the development of health educative videos, client and stakeholder inputs may always be solicited.

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

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.

Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Couples' decision making regarding the use of multipurpose prevention technology (MPT) for pregnancy and HIV prevention.

We conducted a secondary analysis of discrete choice experiment (DCE) data from 395 couples enrolled in the Microbicide Trials Network (MTN)-045/CUPID study in Uganda and Zimbabwe to understand couple decision making around choice of multipurpose prevention technologies (MPTs) to prevent both HIV and pregnancy. Members of couples completed the same DCE, first separately then jointly, choosing between two hypothetical MPTs in a series of nine questions. Most couples either had similar preferences at the outset or had equal decision-making around MPTs (62%). Couples with male influence (17%) were more likely to use contraceptive pills with a male partner's knowledge and couples with female influence (21%) were less likely to have shared decision making about family planning. Males influenced discussion around MPT duration, side effects, menstrual changes, and how the vagina feels during sex. Decision making was relatively shared, though decisions around certain attributes were more likely to be dominated by male partners.

Correlates of Dapivirine Vaginal Ring Acceptance among Women Participating in an Open Label Extension Trial.

MTN-025/HOPE was an open-label trial of the dapivirine vaginal ring conducted in four African countries between 2016 and 2018. Women were first offered one ring monthly (at baseline, months 1 and 2), thereafter, transitioned to a more applicable real-world dispensation schedule, - 3 rings quarterly (at months 3, 6 and 9). Logistic regression analysis was used to assess correlates of ring acceptance at baseline and through follow-up. A total of 1456 women (median age 31 years) enrolled, 1342 (92.2%) accepted the ring at baseline and 1163 (79.9%) accepted the ring(s) at all visits. Changing ring dispensation from a monthly to a quarterly schedule had no negative effect on acceptance. Having a primary partner and him knowing about the ring being offered in HOPE, use of long-acting contraception (implants, injections, IUDs) or sterilization were associated with ring acceptance, along with prior strong intention to use the ring in the future. Efforts should consider these factors when rolling out the ring for HIV prevention.

Couples' Preferences for "2 in 1" Multipurpose Prevention Technologies to Prevent Both HIV and Pregnancy: Results of a Discrete Choice Experiment in Uganda and Zimbabwe.

End-user input early in biomedical product development may optimize design to support high uptake and adherence. We interviewed 400 couples (800 total participants) in Uganda and Zimbabwe to assess their preferences for multipurpose prevention technologies (MPTs) for HIV and pregnancy prevention. Using a discrete choice experiment, couples made a series of choices between hypothetical MPTs, including oral tablets and vaginal rings, inserts, and films and completed an interviewer-administered questionnaire assessing sociodemographic and behavioral measures. Most couples preferred presented MPTs over male condoms. Couples' MPT choices in both countries were influenced most by the combination of product form and dosing frequency, with monthly dosing preferred over daily. Analysis highlighted differences by country as to which side effects were most important: Ugandan couples placed greater importance on effects on the vaginal environment during sex, whereas Zimbabwean couples placed more importance on changes to menstruation and other side effects (headache, cramps). Couples' preferences signaled an openness to new product forms and more frequent dosing if preferred characteristics of other attributes were achieved.

Tenofovir Diphosphate Concentrations in Dried Blood Spots From Pregnant and Postpartum Adolescent and Young Women Receiving Daily Observed Pre-exposure Prophylaxis in Sub-Saharan Africa.

BACKGROUND: Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). METHODS: Directly observed PrEP was administered for 12 weeks in a pregnancy (14-24 weeks' gestation, n = 20) and postpartum (6-12 weeks postpartum, n = 20) group of AGYW aged 16-24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography-tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. RESULTS: Median age was 20 (IQR, 19-22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7-12) days in pregnancy and 17 (14-21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691-1166) in pregnancy versus 1406 fmol/punch (1053-1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667-1105) in pregnancy versus 1438 fmol/punch (1178-1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. CONCLUSIONS: TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Population-specific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. CLINICAL TRIALS REGISTRATION: NCT03386578.

Prevalence of undetectable and suppressed viral load in HIV-infected pregnant women initiating Option B+ in Uganda: an observational study nested within a randomized controlled trial.

BACKGROUND: Viral load (VL) testing is key in monitoring adherence to antiretroviral therapy (ART) and documenting HIV treatment response. As per HIV treatment guidelines in Uganda, the first VL test is recommended 6 months after initiation of ART. Undetectable VL (uVL) at ART initiation may be helpful in detecting elite controllers in the absence of previous ART use. We investigated viral suppression at ART initiation among a cohort of HIV-positive pregnant women enrolled in the Friends for Life Circles (FLC) for Option B+ randomized controlled trial (RCT). METHODS: Pregnant women ≥ 18 years of age testing positive for HIV at their first antenatal care visit and starting on ART Option B+ as per the National PMTCT Program guidelines were enrolled into the FLC for Option B+ RCT in urban Kampala and rural Mityana districts of Uganda. Each participant had whole blood samples collected at enrolment to assess baseline VL. Plasma HIV-1 RNA was quantified using COBAS Ampliprep /COBAS Taqman. Baseline VL below 400 RNA copies/ml was considered as viral suppression while baseline VL below 20 RNA copies/ml was considered uVL. RESULTS: The mean duration from the date of ART initiation to time of sample collection for baseline VL assessment was 4.4 days (SD 3.6). Of the 532 HIV-positive pregnant women enrolled in the FLC for Option B+ study and newly starting Option B+ without a self-reported history of prior ART use, 29 (5.5%) had uVL and 113 (21.4%) had suppressed VL at baseline. There was no association between participants' age, gravidity, marital status, mean monthly income, educational level, disclosure of HIV status to partner, and uVL or viral suppression at baseline. However, non-disclosure of HIV status to any other person was associated with decreased odds of viral suppression at baseline (OR 0.640; 0.416-0.982). CONCLUSION: Twenty-one percent of HIV-positive Ugandan pregnant women initiating ART (Option B+) showed virological suppression at baseline and were presumed to be "elite controllers" or to have misreported being ART-naive. Further studies are needed to better understand the biologic mechanisms of elite controllers among pregnant women as well as to differentiate elite controllers from concealed ART use. Trial Registration The trial was registered as NCT02515370 (04/08/2015) on Clinicaltrials.gov.

Ethical considerations for involving adolescents in biomedical HIV prevention research.

BACKGROUND: Involvement of adolescent girls in biomedical HIV research is essential to better understand efficacy and safety of new prevention interventions in this key population at high risk of HIV infection. However, there are many ethical issues to consider prior to engaging them in pivotal biomedical research. In Uganda, 16-17-year-old adolescents can access sexual and reproductive health services including for HIV or other sexually transmitted infections, contraception, and antenatal care without parental consent. In contrast, participation in HIV prevention research involving investigational new drugs requires adolescents to have parental or guardian consent. Thus, privacy and confidentiality concerns may deter adolescent participation. We describe community perspectives on ethical considerations for involving adolescent girls in the MTN 034 study in Uganda. METHODS: From August 2017 to March 2018, we held five stakeholder engagement meetings in preparation for the MTN 034 study in Kampala, Uganda (NCT03593655): two with 140 community representatives, two with 125 adolescents, and one with 50 adolescents and parents. Discussions were moderated by the study team. Proceedings were documented by notetakers. Summary notes described community perspectives of adolescent participation in HIV research including convergent, divergent or minority views, challenges, and proposed solutions. RESULTS: Most community members perceived parental or guardian consent as a principal barrier to study participation due to concerns about adolescent disclosure of pre-marital sex, which is a cultural taboo. Of 125 adolescent participants, 119 (95%) feared inadvertent disclosure of sexual activity to their parents. Community stakeholders identified the following critical considerations for ethical involvement of adolescents in HIV biomedical research: (1) involving key stakeholders in recruitment, (2) ensuring confidentiality of sensitive information about adolescent sexual activity, (3) informing adolescents about information to be disclosed to parents or guardians, (4) offering youth friendly services by appropriately trained staff, and (5) partnering with community youth organizations to maximize recruitment and retention. CONCLUSIONS: Stakeholder engagement with diverse community representatives prior to conducting adolescent HIV prevention research is critical to collectively shaping the research agenda, successfully recruiting and retaining adolescents in HIV clinical trials and identifying practical strategies to ensure high ethical standards during trial implementation.

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

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 .).

Tenofovir-based preexposure prophylaxis for HIV infection among African women.

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.).

DELIVER: A Safety Study of a Dapivirine Vaginal Ring and Oral PrEP for the Prevention of HIV During Pregnancy.

BACKGROUND: Pregnancy represents a period of high HIV acquisition risk. Safety data for the monthly dapivirine vaginal ring (DVR) during pregnancy are limited. Here, we report data from the first 2 cohorts of pregnant participants in MTN-042/DELIVER, a phase 3b, randomized, open-label safety trial of DVR and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). MTN-042 is being conducted in 3 cohorts beginning with later gestational ages when risks of drug exposure are less. METHODS: Eligible pregnant individuals aged 18-40 years in Malawi, South Africa, Uganda, and Zimbabwe were randomized 2:1 to monthly DVR or daily TDF/FTC. Participants in cohort 1 initiated product use between 36 weeks 0 days (36 0/7 weeks) and 37 6/7 weeks gestation; participants in cohort 2 initiated product use between 30 0/7 and 35 6/7 weeks gestation. All participants continued product use until delivery or 41 6/7 weeks gestation. Pregnancy outcomes and complications were assessed and summarized using descriptive statistics and compared with local background rates obtained through a separate chart review. RESULTS: One-hundred and fifty participants were enrolled into cohort 1 with 101 randomized to DVR and 49 to TDF/FTC. One-hundred and fifty-seven participants were enrolled into cohort 2 with 106 randomized to DVR and 51 to TDF/FTC. In both cohorts, pregnancy complications were rare and similar to local background rates. CONCLUSION: In this first study of a long-acting HIV prevention agent in pregnancy, adverse pregnancy outcomes and complications were uncommon when DVR and TDF/FTC were used in the third trimester of pregnancy, suggesting a favorable safety profile for both prevention products.

Enhanced peer-group strategies to support the prevention of mother-to-child HIV transmission leads to increased retention in care in Uganda: A randomized controlled trial.

INTRODUCTION: Despite the scale-up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at 6 weeks, 6, and and 24 months postpartum among pregnant women living with HIV and initiating Option B+. Women were randomized to a peer group support, community-based drug distribution and income-generating intervention called "Friends for Life Circles" (FLCs) versus the standard of care (SOC). Our secondary outcome was infant HIV status and HIV-free survival at 6 weeks and 18 months postpartum. METHODS: Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study at any gestational age. Participants were randomized 1:1 to the unblinded FLC intervention or SOC at enrolment and assessed for adherence to the prevention of mother-to-child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12, and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum and supported by plasma HIV-1 RNA viral load (VL) measured at the same time points, retention in care through the end of study, and HIV status and HIV-free survival of infants at 18 months postpartum. The FLC groups were formed during pregnancy within 4 months of enrollment and held monthly meetings in their communites, and were followed up until the last group participant reached 24 months post delivery. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm. RESULTS: There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p = 0.022. The adjusted HR of visit dropout was 2.4 times greater among participants randomized to SOC compared to FLC (aHR = 2.363, 95% CI: 1.199-4.656, p = 0.013). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6, and 24 months postpartum. Eight of the 431 infants tested at 18 months were HIV positive (1.9%), however, this was not statistically different among mothers enrolled in the FLC arm compared to those in the SOC arm. At 18 months, HIV-free survival of children born to mothers in the FLC arm was significantly higher than that of children born to mothers in the SOC arm. CONCLUSIONS: Our findings suggest that programmatic interventions that provide group support, community-based ART distribution, and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and ultimately, to the elimination of mother-to-child HIV transmission (EMTCT). TRIAL REGISTRATION: NCT02515370 (04/08/2015) on ClinicalTrials.gov.

Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Nevirapine given once-daily for the first 6, 14, or 28 weeks of life to infants exposed to HIV-1 via breastfeeding reduces transmission through this route compared with single-dose nevirapine at birth or neonatally. We aimed to assess incremental safety and efficacy of extension of such prophylaxis to 6 months. METHODS: In our phase 3, randomised, double-blind, placebo-controlled HPTN 046 trial, we assessed the incremental benefit of extension of once-daily infant nevirapine from age 6 weeks to 6 months. We enrolled breastfeeding infants born to mothers with HIV-1 in four African countries within 7 days of birth. Following receipt of nevirapine from birth to 6 weeks, infants without HIV infection were randomly allocated (by use of a computer-generated permuted block algorithm with random block sizes and stratified by site and maternal antiretroviral treatment status) to receive extended nevirapine prophylaxis or placebo until 6 months or until breastfeeding cessation, whichever came first. The primary efficacy endpoint was HIV-1 infection in infants at 6 months and safety endpoints were adverse reactions in both groups. We used Kaplan-Meier analyses to compare differences in the primary outcome between groups. This study is registered with ClinicalTrials.gov, number NCT00074412. FINDINGS: Between June 19, 2008, and March 12, 2010, we randomly allocated 1527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan-Meier analysis, 1·1% (95% CI 0·3-1·8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2·4% (1·3-3·6) of controls (difference 1·3%, 95% CI 0-2·6), equating to a 54% reduction in transmission (p=0·049). However, mortality (1·2% for nevirapine vs 1·1% for placebo; p=0·81) and combined HIV infection and mortality rates (2·3%vs 3·2%; p=0·27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups. INTERPRETATION: Nevirapine prophylaxis can safely be used to provide protection from mother-to-child transmission of HIV-1 via breastfeeding for infants up to 6 months of age. FUNDING: US National Institutes of Health.

Adherence and acceptability in MTN 001: a randomized cross-over trial of daily oral and topical tenofovir for HIV prevention in women.

We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94 %), but serum TFV concentrations indicated only 64 % of participants used tablets consistently. Most women in the U.S. (72 %) favored tablets over gel; while preferences varied at the African sites (42 % preferred gel and 40 % tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.

Enhanced Peer-Group strategies to support prevention of Mother-to-Child HIV transmission leads to increased retention in care in Uganda: A Randomized controlled trial.

Introduction: Despite scale up of Option B+, long-term retention of women in HIV care during pregnancy and the postpartum period remains an important challenge. We compared adherence to clinic appointments and antiretroviral therapy (ART) at different follow-up time points between enrolment and 24 months postpartum among pregnant women living with HIV and initiating Option B+ randomized to a peer group support, community-based drug distribution and income-generating intervention called "Friends for Life Circles" (FLCs) versus the standard of care (SOC). Methods: Between 16 May 2016 and 12 September 2017, 540 ART-naïve pregnant women living with HIV at urban and rural health facilities in Uganda were enrolled in the study. Participants were randomized 1:1 to the FLC intervention or SOC and assessed for adherence to prevention of mother to child HIV transmission (PMTCT) clinic appointments at 6 weeks, 12 and 24 months postpartum, self-reported adherence to ART at 6 weeks, 6 and 24 months postpartum validated by plasma HIV-1 RNA viral load (VL) measured at the same time points, and HIV status and HIV-free survival of infants at 18 months postpartum. We used Log-rank and Chi-Square p-values to test the equality of Kaplan-Meier survival probabilities and hazard rates (HR) for failure to retain in care for any reason by study arm. Results: There was no significant difference in adherence to PMTCT clinic visits or to ART or in median viral loads between FLC and SOC arms at any follow-up time points. Retention in care through the end of study was high in both arms but significantly higher among participants randomized to FLC (86.7%) compared to SOC (79.3%), p=0.022. The adjusted HR of visit dropout was 2.5 times greater among participants randomized to SOC compared to FLC (aHR=2.498, 95% CI: 1.417 - 4.406, p=0.002). Median VL remained < 400 copies/ml in both arms at 6 weeks, 6 and 24 months postpartum. Conclusions: Our findings suggest that programmatic interventions that provide group support, community based ART distribution and income-generation activities may contribute to retention in PMTCT care, HIV-free survival of children born to women living with HIV, and to the elimination of mother to child HIV transmission (MTCT).

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: a randomised, open-label, crossover trial.

BACKGROUND: Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. METHODS: MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16-21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. FINDINGS: From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17-19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. INTERPRETATION: Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences. FUNDING: National Institutes of Health.

Twenty years of Prevention of Mother to Child HIV Transmission: research to implementation at a national referral hospital in Uganda.

Background: Over 90% of new paediatric HIV infections are acquired through mother to child transmission. Prevention of mother to child HIV transmission (PMTCT) research in sub-Saharan Africa informed WHO guidelines which enabled implementation of PMTCT programs globally. Objectives: To describe Makerere University-Johns Hopkins University (MU-JHU) perinatal HIV prevention research and implementation of the Mulago National Referral Hospital (MNRH) PMTCT program. Methods: Perinatal HIV prevention studies conducted at MU-JHU between 1997-2016 were summarized. Program aggregated data was extracted and analyzed using STATA 15. Results: In 1999, the HIVNET 012 study demonstrated that single-dose nevirapine (sdNVP) to the mother at onset of labor and to her newborn, reduced MTCT by nearly 50%. In 2016, the PROMISE study documented the safety and efficacy of ART during pregnancy and breastfeeding period. Program implementation at MNRH started in 2000. Uptake of HIV testing increased from 70% to 99% from 2006 onwards. sd NVP was the initial ARV regimen but by 2012, MOH recommended Option B+(triple therapy). MTCT rates reduced from 16.9% in 2001 to 2.3% in 2020. Conclusion: Perinatal HIV prevention clinical trials conducted at MU-JHU provided evidence to inform WHO PMTCT guidelines. MNRH program evaluation demonstrated the significant decline in MTCT rates over the last two decades.

HIV genotypic resistance among pregnant women initiating ART in Uganda: a baseline evaluation of participants in the Option B+ clinical trial.

Background: Pre-treatment HIV drug resistance is a threat to elimination of mother to child HIV transmission and could lead to virological failure among HIV-positive pregnant women. We analysed genotypic HIV drug resistance (HIVDR) of baseline samples of participants enrolled in the Option B+ clinical trial in Uganda. Methods: HIV-infected pregnant women attending antenatal care were enrolled from Uganda's National Referral Hospital (Mulago) and Mityana District general hospital and surrounding health centers (HCs). Genotypic HIV testing was performed on blood samples from the first 135 enrolled women out of a subset of 136 participants (25%) who had a baseline VL>1000 copies/mL as one sample failed to amplify. Results: 159/540 (29.4%) had a VL < 1000 copies/ml and 381/540 (70.6%) had a VL >1,000 copies/ml. Of the women with VL>1000 copies/ml, 32 (23.7%) had resistance mutations including 29/135 (21.5%) NNRTI mutations, 6/135 (4.4%) NRTI mutations and 3/135 (2.2%) had both NNRTI and NRTI mutations. The most common NNRTI resistance mutations were: K103KN (5), K103N (5), V179T (4) and E138A (4). Conclusions: One quarter of the HIV-infected pregnant women in this trial at baseline had NNRTI genotypic resistance mutations. Our findings support new WHO guidelines for first-line ART that were changed to dolutegravir-based regimens.

Prevalent human papillomavirus infection increases the risk of HIV acquisition in African women: advancing the argument for human papillomavirus immunization.

OBJECTIVE: Vaccine-preventable human papillomavirus (HPV) infection is common, especially in sub-Saharan Africa where HIV risk is also high. However, unlike other sexually transmitted infections (STIs), HPV's role in HIV acquisition is unclear. We evaluated this relationship using data from MTN-003, a clinical trial of HIV chemoprophylaxis among cisgender women in sub-Saharan Africa. DESIGN: A case-control study. METHODS: We matched 138 women who acquired HIV (cases) to 412 HIV-negative controls. Cervicovaginal swabs collected within 6 months before HIV seroconversion were tested for HPV DNA. We estimated the associations between carcinogenic (high-risk) and low-risk HPV types and types targeted by HPV vaccines and HIV acquisition, using conditional logistic regression models adjusted for time-varying sexual behaviors and other STIs. RESULTS: Mean age was 23 (±4) years. Any, high-risk and low-risk HPV was detected in 84, 74 and 66% of cases, and 65, 55 and 48% of controls. Infection with at least two HPV types was common in cases (67%) and controls (49%), as was infection with nonavalent vaccine-targeted types (60 and 42%). HIV acquisition increased with any [adjusted odds ratio (aOR) 2.5, 95% confidence interval (95% CI) 1.3-4.7], high-risk (aOR 2.6, 95% CI 1.5-4.6) and low-risk (aOR 1.8, 95% CI 1.1-2.9) HPV. Each additional type detected increased HIV risk by 20% (aOR 1.2, 95% CI 1.1-1.4). HIV acquisition was associated with HPV types targeted by the nonavalent (aOR 2.1, 95% CI 1.3-3.6) and quadrivalent vaccines (aOR 1.9, 95% CI 1.1-3.2). CONCLUSION: HPV infection is associated with HIV acquisition in sub-Saharan African women. In addition to preventing HPV-associated cancers, increasing HPV vaccination coverage could potentially reduce HIV incidence.