PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. METHODS AND FINDINGS: HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. CONCLUSIONS: In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Metabolism of Long-Acting Rilpivirine After Intramuscular Injection: HIV Prevention Trials Network Study 076 (HPTN 076).

A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in human immunodeficiency virus (HIV) maintenance therapy. We previously characterized RPV metabolism after oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV after injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect 2 metabolites after intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV, and RPV N-glucuronide. Of the total of 80 individuals, 72 participants exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. In addition, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, four missense variants were detected for CYP3A4 whereas one missense variant and one frameshift variant were detected for CYP3A5. A total of eight missense variants of UGT1A4 were detected, whereas two variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to an overall understanding of metabolism after oral dosing versus injection. ClinicalTrials.gov Identifier: NCT02165202.

Acceptability of a long-acting injectable HIV prevention product among US and African women: findings from a phase 2 clinical Trial (HPTN 076).

INTRODUCTION: High HIV incidence and low adherence to daily oral PrEP among women underscore the need for more acceptable and easier to use HIV prevention products. Global demand for injectable contraception suggests that new, long-acting, injectable formulations could meet this need. We examine acceptability of a long-acting injectable PrEP among HIV-uninfected women in Zimbabwe, South Africa and two United States phase 2 trial sites. METHODS: Quantitative surveys were administered at the first, fourth and sixth injection visits. Focus group discussions (FGD) were conducted after the sixth injection visit. We compared the acceptability of injectable product attributes, prevention preferences and future interest in injectable PrEP by site and arm and ran longitudinal ordinal logistic regression models to identify determinants of future interest in injectable PrEP. RESULTS: Between April 2015 and February 2017, the trial enrolled 136 (100 African, 36 US) women with a median age of 31 years. Most participants (>75%) rated injectable attributes as very acceptable. While few reported rash or other side effects, 56% to 67% reported injection pain, with nonsignificant differences over time and between arms. During FGDs, participants described initial fear of the injectable and variable experiences with pain. Most US and African participants preferred injectable PrEP to daily oral pills (56% to 96% vs. 4% to 25%). Future interest in using injectable PrEP was associated with acceptability of product attributes and was higher in African than US sites. In FGDs, participants described multiple reasons for trial participation, including a combination of monetary, health-related and altruistic motivations. While associated with future interest in use in univariate models, neither altruistic nor personal motivations remained significant in the multivariate model. CONCLUSIONS: This study found that long-acting injectable PrEP is acceptable among African and US women experiencing product use. Acceptability of product attributes better predicted future interest in injectable use than experience of pain. This is reassuring as a single-dose regimen of a different product has advanced to phase 3 trials. Finally, the study suggests that future demand for an injectable PrEP by women may be greater in African than US settings, where the risk of HIV is highest.

CoQ10 in progressive supranuclear palsy: A randomized, placebo-controlled, double-blind trial.

OBJECTIVE: An investigator-initiated, multicenter, randomized, placebo-controlled, double-blind clinical trial to determine whether coenzyme Q10 (CoQ10) is safe, well tolerated, and effective in slowing functional decline in progressive supranuclear palsy (PSP). METHODS: Sixty-one participants received CoQ10 (2,400 mg/d) or placebo for up to 12 months. Progressive Supranuclear Palsy Rating Scale (PSPRS), Unified Parkinson's Disease Rating Scale, activities of daily living, Mini-Mental State Examination, the 39-item Parkinson's Disease Questionnaire, and 36-item Short Form Health Survey were monitored at baseline and months 3, 6, 9, and 12. The safety profile of CoQ10 was determined by adverse events, vital signs, and clinical laboratory values. Primary outcome measures were changes in PSPRS and Unified Parkinson's Disease Rating Scale scores from baseline to month 12. RESULTS: CoQ10 was well tolerated. No statistically significant differences were noted between CoQ10 and placebo groups in primary or secondary outcome measures. A nonsignificant difference toward slower clinical decline in the CoQ10 group was observed in total PSPRS among those participants who completed the trial. Before the final study visit at 12 months, 41% of participants withdrew because of travel distance, lack of perceived benefit, comorbidities, or caregiver issues. CONCLUSIONS: High doses of CoQ10 did not significantly improve PSP symptoms or disease progression. The high withdrawal rate emphasizes the difficulty of conducting clinical trials in patients with PSP. CLINICALTRIALSGOV IDENTIFIER: NCT00382824. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CoQ10 does not significantly slow functional decline in PSP. The study lacks the precision to exclude a moderate benefit of CoQ10.

Community Cultural Norms, Stigma and Disclosure to Sexual Partners among Women Living with HIV in Thailand, Brazil and Zambia (HPTN 063).

BACKGROUND: Serostatus disclosure may facilitate decreased HIV transmission between serodiscordant partners by raising risk awareness and heightening the need for prevention. For women living with HIV (WLWH), the decision to disclose may be influenced by culturally determined, community-level stigma and norms. Understanding the impact of community HIV stigma and gender norms on disclosure among WLWH in different countries may inform intervention development. METHODS: HPTN063 was a longitudinal, observational study of sexually active HIV-infected individuals, including heterosexual women, in care in Zambia, Thailand and Brazil. At baseline, a questionnaire measuring community HIV stigma and gender norms, anticipated stigma, demographic, partner/relationship characteristics, and intimate partner violence was administered. Longitudinal HIV disclosure to sexual partners was determined via audio-computer assisted self-interview (ACASI) at the baseline and quarterly during the one year following up. Logistic regression was conducted to identify the predictors of disclosure. RESULTS: Almost half (45%) of women living with HIV acknowledged perceived community HIV stigma (the belief that in their community HIV infection among women is associated with sex work and multiple sexual partners). Many women (42.9%) also acknowledged perceived community gender norms (the belief that traditional gender norms such as submissiveness to husbands/male sexual partners is necessary and that social status is lost if one does not procreate). HIV disclosure to current sex partners was reported by 67% of women. In multivariate analysis, among all women, those who were older [OR 0.16, 95%CI(0.06,0.48)], reported symptoms of severe depression [OR 0.53, 95%CI(0.31, 0.90)], endorsed anticipated stigma [OR 0.30, 95%CI(0.18, 0.50)], and were unmarried [OR 0.43, 95%CI(0.26,0.71)] were less likely to disclose to current partners. In an analysis stratified by marital status and cohabitation, unmarried [OR 0.41, 95%CI(0.20,0.82)] and non-cohabiting women [OR 0.31, 95%CI(0.13,0.73)] who perceived community HIV stigma were less likely to disclose to their sex partners. CONCLUSIONS: Perceived community level HIV stigma, along with individual level factors such as anticipated stigma, depressive symptoms, and older age, predict non-disclosure of HIV status to sexual partners among WLWH in diverse geographic settings. Interventions to promote disclosure among women in serodiscordant relationships should incorporate community-level interventions to reduce stigma and promote gender equality.

Computational gene expression modeling identifies salivary biomarker analysis that predict oral feeding readiness in the newborn.

OBJECTIVE: To combine mathematical modeling of salivary gene expression microarray data and systems biology annotation with reverse-transcription quantitative polymerase chain reaction amplification to identify (phase I) and validate (phase II) salivary biomarker analysis for the prediction of oral feeding readiness in preterm infants. STUDY DESIGN: Comparative whole-transcriptome microarray analysis from 12 preterm newborns pre- and postoral feeding success was used for computational modeling and systems biology analysis to identify potential salivary transcripts associated with oral feeding success (phase I). Selected gene expression biomarkers (15 from computational modeling; 6 evidence-based; and 3 reference) were evaluated by reverse-transcription quantitative polymerase chain reaction amplification on 400 salivary samples from successful (n = 200) and unsuccessful (n = 200) oral feeders (phase II). Genes, alone and in combination, were evaluated by a multivariate analysis controlling for sex and postconceptional age (PCA) to determine the probability that newborns achieved successful oral feeding. RESULTS: Advancing PCA (P < .001) and female sex (P = .05) positively predicted an infant's ability to feed orally. A combination of 5 genes, neuropeptide Y2 receptor (hunger signaling), adneosine-monophosphate-activated protein kinase (energy homeostasis), plexin A1 (olfactory neurogenesis), nephronophthisis 4 (visual behavior), and wingless-type MMTV integration site family, member 3 (facial development), in addition to PCA and sex, demonstrated good accuracy for determining feeding success (area under the receiver operator characteristic curve = 0.78). CONCLUSIONS: We have identified objective and biologically relevant salivary biomarkers that noninvasively assess a newborn's developing brain, sensory, and facial development as they relate to oral feeding success. Understanding the mechanisms that underlie the development of oral feeding readiness through translational and computational methods may improve clinical decision making while decreasing morbidities and health care costs.