Efficacy estimates of oral pre-exposure prophylaxis for HIV prevention in cisgender women with partial adherence.

Pre-exposure prophylaxis (PrEP) with tenofovir (TFV) disoproxil fumarate and emtricitabine administered orally daily is effective in preventing human immunodeficiency virus (HIV) acquisition in both men and women with sufficient adherence; however, the adherence-efficacy relationship in cisgender women has not been well established. We calculated the adherence-efficacy curve for cisgender women by using HIV incidence and plasma TFV concentration data from three trials (FEM-PrEP, VOICE and Partners PrEP). We imputed TFV diphosphate (TFV-DP) concentrations, a measure of long-term adherence, from TFV quantification by using data from the HIV Prevention Trials Network 082 study, which measured both TFV-DP and TFV concentrations. Two, four and seven pills per week reduced HIV incidence by 59.3% (95% credible interval (CrI) 29.9-95.8%), 83.8% (95% CI 51.7-99.8%) and 95.9% (95% CI 72.6-100%), respectively. Our adherence-efficacy curve can be validated and updated by HIV prevention studies that directly measure TFV-DP concentrations. The curve suggests that high adherence confers high protection in cisgender women. However, the lower efficacy with partial adherence highlights the need for new PrEP products and interventions to increase adherence.

Pharmacokinetic serum concentrations of VRC01 correlate with prevention of HIV-1 acquisition.

BACKGROUND: The phase 2b proof-of-concept Antibody Mediated Prevention (AMP) trials showed that VRC01, an anti-HIV-1 broadly neutralising antibody (bnAb), prevented acquisition of HIV-1 sensitive to VRC01. To inform future study design and dosing regimen selection of candidate bnAbs, we investigated the association of VRC01 serum concentration with HIV-1 acquisition using AMP trial data. METHODS: The case-control sample included 107 VRC01 recipients who acquired HIV-1 and 82 VRC01 recipients who remained without HIV-1 during the study. We measured VRC01 serum concentrations with a qualified pharmacokinetic (PK) Binding Antibody Multiplex Assay. We employed nonlinear mixed effects PK modelling to estimate daily-grid VRC01 concentrations. Cox regression models were used to assess the association of VRC01 concentration at exposure and baseline body weight, with the hazard of HIV-1 acquisition and prevention efficacy as a function of VRC01 concentration. We also compared fixed dosing vs. body weight-based dosing via simulations. FINDINGS: Estimated VRC01 concentrations in VRC01 recipients without HIV-1 were higher than those in VRC01 recipients who acquired HIV-1. Body weight was inversely associated with HIV-1 acquisition among both placebo and VRC01 recipients but did not modify the prevention efficacy of VRC01. VRC01 concentration was inversely correlated with HIV-1 acquisition, and positively correlated with prevention efficacy of VRC01. Simulation studies suggest that fixed dosing may be comparable to weight-based dosing in overall predicted prevention efficacy. INTERPRETATION: These findings suggest that bnAb serum concentration may be a useful marker for dosing regimen selection, and operationally efficient fixed dosing regimens could be considered for future trials of HIV-1 bnAbs. FUNDING: Was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) (UM1 AI068614, to the HIV Vaccine Trials Network [HVTN]; UM1 AI068635, to the HVTN Statistical Data and Management Center [SDMC], Fred Hutchinson Cancer Center [FHCC]; 2R37 054165 to the FHCC; UM1 AI068618, to HVTN Laboratory Center, FHCC; UM1 AI068619, to the HPTN Leadership and Operations Center; UM1 AI068613, to the HIV Prevention Trials Network [HPTN] Laboratory Center; UM1 AI068617, to the HPTN SDMC; and P30 AI027757, to the Center for AIDS Research, Duke University (AI P30 AI064518) and University of Washington (P30 AI027757) Centers for AIDS Research; R37AI054165 from NIAID to the FHCC; and OPP1032144 CA-VIMC Bill & Melinda Gates Foundation.

Development of a tool to assess HIV prevention readiness of adolescent girls and young women in HPTN 082 study.

BACKGROUND: African adolescent girls and young women (AGYW) represent a large proportion of new HIV infections, a priority population for pre-exposure prophylaxis (PrEP), but adherence remains a challenge. A reliable, valid readiness tool would help identify AGYW motivated to take PrEP who need adherence support. METHODS: In the HPTN 082 open-label PrEP study (2016-2019), South African and Zimbabwean women ages 16-25 were administered an HIV prevention readiness measure (HPRM). The 25 items in the HPRM included medication beliefs, connection with care, disclosure of PrEP use, social support, and housing stability using a 5-point Likert scale. Exploratory factor analysis (EFA) using polychoric correlations, scale reliability, and predictive validity were performed on data from 315 participants who responded to all items. We assessed the predictive value of HPRM scores with PrEP adherence, defined as tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots, as a continuous measure and dichotomized as high PrEP adherence (≥700 fmol/punch). RESULTS: EFA yielded 23 items with three subscales: self-efficacy (16 items), PrEP disclosure (4 items), and social support (3 items). Cronbach's α ranged from 0.71 to 0.92 for the overall scale and the subscales. The average overall scale and the subscales were predictive of 3-month PrEP adherence for TFV-DP concentrations: for each unit increase of the HPRM score, TFV-DP concentration increased by 103 fmol/punch (95% CI: 16, 189, p = 0.02); the highest HPRM score equated with 608 fmol/punch on average. For the self-efficacy subscale, TFV-DP increased by 90 fmol/punch (95% CI: 7, 172, p = 0.03); PrEP disclosure, 68 fmol/punch (95% CI: 19, 117 p = 0.01); and social support, 58fmol/punch (95% CI: 2, 113, p = 0.04). Higher PrEP disclosure suggests high adherence (OR 1.36, 95% CI: 1.00, 1.86, p = 0.05) and predicted persistent high adherence at both months three and six (OR: 1.50, 95% CI: 1.03, 2.21, p = 0.04). CONCLUSIONS: The HPRM scale overall and the subscales individually demonstrated good internal consistency among African young women. PrEP disclosure subscale exhibiting significant association with persistent high PrEP adherence is an important finding for PrEP adherence support programs. Future work will assess replicability and expand self-efficacy and social-support subscales after item revision. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

Impact of catch-up human papillomavirus vaccination on cervical cancer incidence in Kenya: A mathematical modeling evaluation of HPV vaccination strategies in the context of moderate HIV prevalence.

BACKGROUND: Cervical cancer incidence is high in Kenya due to HIV and limited access to cancer prevention services. Human papillomavirus (HPV) has been shown to increase HIV acquisition; however, the potential impact of HPV vaccination on HIV is unknown. We modeled the health impact of HPV vaccination in the context of the HIV epidemiology in Kenya. METHODS: Using a validated compartmental transmission model of HIV and HPV set in Kenya, we evaluated five scenarios of nonavalent HPV vaccination: single-age-vaccination of 10-year-old girls at 90% coverage; multi-age-cohort (MAC) vaccination of 10-14-year-old girls at 90% coverage; MAC plus moderate-coverage (50%) catch-up vaccination of 15-24-year-old women; MAC plus high-coverage (80%) catch-up of 15-24-year-old women; and MAC plus catch-up of 15-44-year-old women at 80% coverage (HPV-FASTER). We compared cervical cancer incidence, HIV prevalence, and cumulative cervical cancer and HIV cases averted after 50 years to a baseline scenario without vaccination. In all scenarios, we assumed the UNAIDS 90-90-90 goal for HIV treatment is attained by 2030. FINDINGS: In 2021, model-estimated cervical cancer incidence is 44/100,000 and HIV prevalence among women is 6·5%. In 2070, projected cancer incidence declines to 27/100,000 and HIV prevalence reaches 0·3% without vaccination. With single-age-vaccination, cancer incidence in 2070 is reduced by 68%, averting 64,529 cumulative cancer cases. MAC vaccination reduces cancer incidence by 75%, averting 206,115 cancer cases. Moderate and high-coverage catch-up and HPV-FASTER reduce cancer incidence by 80%, 82%, and 84%, averting 254,930, 278,690, and 326,968 cancer cases, respectively. In all scenarios, HIV prevalence in 2070 is reduced by a relative 8-11%, with 15,609-34,981 HIV cases averted after 50 years. INTERPRETATION: HPV vaccination can substantially reduce cervical cancer incidence in Kenya in the next 50 years, particularly if women up to age 24 are vaccinated. HIV treatment scale-up can also alleviate cervical cancer burden. However, HPV vaccination has modest additional impact on HIV when antiretroviral therapy coverage is high. FUNDING: National Institutes of Health, Bill and Melinda Gates Foundation.

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.

Assessing pregnancy and neonatal outcomes in Malawi, South Africa, Uganda, and Zimbabwe: Results from a systematic chart review.

A systematic chart review was performed to estimate the frequency of pregnancy outcomes, pregnancy complications and neonatal outcomes at facilities in Blantyre, Malawi; Johannesburg, South Africa; Kampala, Uganda; and Chitungwiza and Harare, Zimbabwe to provide comparisons with estimates from an ongoing clinical trial evaluating the safety of two biomedical HIV prevention interventions in pregnancy. A multi-site, cross-sectional chart review was conducted at Maternal Obstetric Units and hospitals where women participating in the ongoing clinical trial would be expected to deliver. All individuals delivering at the designated facilities or admitted for postpartum care within seven days of a delivery elsewhere (home, health clinic, etc.) were included in the review. Data were abstracted for pregnancy outcomes, pregnancy complications, maternal and neonatal death, and congenital anomalies. Data from 10,138 records were abstracted across all four sites (Blantyre n = 2,384; Johannesburg n = 1,888; Kampala n = 3,708; Chitungwiza and Harare n = 2,158), which included 10,426 pregnancy outcomes. The prevalence of preterm birth was 13% (range across sites: 10.4-20.7) and 4.1% of deliveries resulted in stillbirth (range: 3.1-5.5). The most commonly noted pregnancy complication was gestational hypertension, reported among 4.4% of pregnancies. Among pregnancies resulting in a live birth, 15.5% were low birthweight (range: 13.8-17.4) and 2.0% resulted in neonatal death (range:1.2-3.2). Suspected congenital anomalies were noted in 1.2% of pregnancies. This study provides systematically collected data on background rates of pregnancy outcomes, pregnancy complications and neonatal outcomes that can be used as a reference in support of ongoing HIV prevention studies. In addition, estimates from this study provide important background data for future studies of investigational products evaluated in pregnancy in these urban settings.

Use of the dapivirine vaginal ring and effect on cervical cytology abnormalities.

OBJECTIVE: We 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. DESIGN: Secondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE). METHODS: Data 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. RESULTS: Cervical 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). CONCLUSION: These 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.

Prediction of VRC01 neutralization sensitivity by HIV-1 gp160 sequence features.

The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.

Negative rumours about a vaginal ring for HIV-1 prevention in sub-Saharan Africa.

Rumours may influence health-related behaviours, including the uptake of and adherence to HIV prevention products. This study assessed the safety and effectiveness of a vaginal ring delivering the antiretroviral dapivirine for HIV prevention in Africa. We explored negative rumours about study participation and the vaginal ring amongst study participants and their communities in Malawi, Uganda, South Africa and Zimbabwe. In total 214 women participated in either single or serial in-depth interviews, or a focus group discussion. Three key findings emerged in the data. Firstly, rumours reflected fears concerning the ring and trial participation. Given the historical-political context of the countries in which the trial was conducted, the ring's investigational nature and its foreign origin, ring use was rumoured to cause negative health outcomes such as cancer and infertility and to be associated with practices such as witchcraft or Satanism. The salience of these rumours varied by country. Secondly, rumours reportedly affected participants' adherence to the ring, and other women's willingness to participate in the study. Finally, participants reported that participant engagement activities helped address rumours, resulting in enhanced trust and rapport between staff and participants.

Factors associated with bone mineral density in healthy African women.

UNLABELLED: There is a paucity of normative bone mineral density (BMD) data in healthy African women. Baseline total hip and lumbar spine BMD was measured in premenopausal women. BMD distribution was comparable to that of a reference population and was impacted by several factors including contraception and duration of lactation. INTRODUCTION: Normative data on bone mineral density (BMD) and the cumulative impact of lactation, contraceptive use, and other factors on BMD in healthy African women have not been well studied. OBJECTIVES: The objective of this study was to determine the factors associated with BMD in healthy premenopausal women in Uganda and Zimbabwe. METHODS: Baseline total hip (TH) and lumbar spine (LS) BMD was measured by dual x-ray absorptiometry in 518 healthy, premenopausal black women enrolling in VOICE, an HIV-1 chemoprevention trial, at sites in Uganda and Zimbabwe. Contraceptive and lactation histories, physical activity assessment, calcium intake, and serum vitamin D levels were assessed. Independent factors associated with BMD were identified using an analysis of covariance model. RESULTS: The study enrolled 331 women from Zimbabwe and 187 women from Uganda. Median age was 29 years (IQR 25, 32) and median body mass index (BMI) was 24.8 kg/m(2) (IQR 22.2, 28.6). In univariate analyses, lower TH BMD values were associated with residence in Uganda (p < 0.001), lower BMI (p < 0.001), and any use of and duration of depot-medroxyprogresterone acetate. Use of oral contraceptives, progestin-only implants, and higher physical activity levels were protective against reduced BMD. Similarly, lower LS BMD values were associated with these same factors but also higher parity and history of breastfeeding. In a multivariable analysis, lower TH and LS BMD values were associated with enrollment in Uganda, lower BMI, and lower physical activity level; contraceptive use was associated with lower spine BMD, and breastfeeding contributed to lower total hip BMD. CONCLUSIONS: Among healthy premenopausal women, TH and LS BMD was higher in Zimbabwe than Uganda. Additional factors independently associated with BMD included BMI, physical activity level, contraceptive use, and lactation.

Bacterial vaginosis and the risk of trichomonas vaginalis acquisition among HIV-1-negative women.

BACKGROUND: The vaginal microbiota may play a role in mediating susceptibility to sexually transmitted infections, including Trichomonas vaginalis (TV). METHODS: Data were analyzed from HIV-1-seronegative women participating in HIV Prevention Trials Network Protocol 035. At quarterly visits for up to 30 months, participants completed structured interviews and specimens were collected for genital tract infection testing. T. vaginalis was detected by saline microscopy. Bacterial vaginosis (BV) was characterized by Gram stain using the Nugent score (BV = 7-10; intermediate = 4-6; normal = 0-3 [reference group]). Cox proportional hazards models stratified by study site were used to assess the association between Nugent score category at the prior quarterly visit and TV acquisition. RESULTS: In this secondary analysis, 2920 participants from Malawi, South Africa, United States, Zambia, and Zimbabwe contributed 16,259 follow-up visits. Bacterial vaginosis was detected at 5680 (35%) visits, and TV was detected at 400 (2.5%) visits. Adjusting for age, marital status, hormonal contraceptive use, unprotected sex in the last week and TV at baseline, intermediate Nugent score, and BV at the prior visit were associated with an increased risk of TV (intermediate score: adjusted hazard ratio [aHR], 1.73; 95% confidence interval [CI], 1.21-2.19; BV: aHR, 2.40; 95% CI, 1.92-3.00). Sensitivity analyses excluding 211 participants with TV at baseline were similar to those from the full study population (intermediate score: aHR, 1.54; 95% CI, 1.10-2.14; BV: aHR, 2.23; 95% CI, 1.75-2.84). CONCLUSIONS: Women with a Nugent score higher than 3 were at an increased risk for acquiring TV. If this relationship is causal, interventions that improve the vaginal microbiota could contribute to reductions in TV incidence.