Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in Kenya

A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV preexposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum1 dose/day)emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a ‘‘relaxed’’ definition (accounting for off-prescription dosing) and 40 % per a ‘‘strict’’ definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP

Utility of Different Adherence Measures for PrEP: Patterns and Incremental Value

Measuring PrEP adherence remains challenging. In 2009–2010, the International AIDS Vaccine Initiative randomized phase II trial participants to daily tenofovir disoproxil fumarate/emtricitabine or placebo in Uganda and Kenya. Adherence was measured by electronic monitoring (EM), self-report (SR), and drug concentrations in plasma and hair. Each adherence measure was categorised as low, moderate, or high and also considered continuously; the incremental value of combining measures was determined. Forty-five participants were followed over 4 months. Discrimination for EM adherence by area under receiver operating curves (AROC) was poor for SR (0.53) and best for hair (AROC 0.85). When combining hair with plasma or hair with self-report, discrimination was improved (AROC > 0.9). Self-reported adherence was of low utility by itself. Hair level was the single best PK measure to predict EM-assessed adherence; the other measurements had lower discrimination values. Combining short-term (plasma) and long-term (hair) metrics could be useful to assess patterns of drug-taking in the context of PrEP

Willingness to participate in future HIV vaccine trials among men who have sex with men and female sex workers living in Nairobi, Kenya.

OBJECTIVE: To evaluate factors associated with willingness to participate in future HIV vaccine trials among men who have sex with men and female sex workers living in Nairobi, Kenya. BACKGROUND: Working with 'key populations', those at elevated risk of HIV acquisition, is important to conduct efficient HIV prevention trials. In Nairobi Kenya, HIV infection is higher in men who have sex with men (MSM) and female sex workers (FSW) than in the general adult population, hence the need to establish if they would be willing to participate in future HIV vaccine trials. METHODS: We administered a structured questionnaire to MSM and FSW enrolled in a simulated vaccine efficacy trial (SiVET). The SiVET was an observational study designed to mimic the rigors of a clinical trial to assess HIV risk characteristics at baseline. After 12-15 months of follow-up, a structured questionnaire was administered to evaluate hypothetical willingness to participate in future HIV vaccine trials. RESULTS: Of 250 persons (80% MSM by design) enrolled in SiVET, 214 attended the final study visit and 174 (81%) of them expressed hypothetical willingness to participate in future HIV vaccine trials. These were 82% of MSM and 80% of FSW of those who attended the final study visit. Having a very good experience in the SiVET trial predicted willingness to participate in future HIV vaccine trials. Motivating factors for participation included a desire to receive education about HIV (59%) and to receive healthcare (57%). CONCLUSIONS: Our data demonstrate high willingness among key populations in Kenya, to participate in future HIV vaccine trials after completing participation in a SiVET. The findings suggest that these groups might be a reliable target population for consideration in future HIV vaccine trials. Assessment of willingness to participate in these populations provides important information that may help to inform future education and recruitment efforts for vaccine trials. Improving the research experience for members of key populations could impact their willingness to participate in HIV vaccine trials

Feasibility of conducting HIV prevention trials among key populations in Nairobi, Kenya

OBJECTIVE: To assess the feasibility of conducting HIV prevention trials among key populations in Nairobi, Kenya. BACKGROUND: HIV prevention trials require the inclusion of those at high risk of HIV infection and their informed decision to take part and remain in the clinical trial to the end is crucial. In Kenya key populations including men who have sex with men (MSM) and female sex workers (FSW) are, disproportionately, at high risk of HIV infection when compared to the general population. Few trials testing biomedical prevention products against HIV have enrolled Kenyan FSW and MSM. METHODS: We performed simulated vaccine efficacy trial (SiVET) using licensed hepatitis B vaccines as substitutes for a HIV vaccine candidate and included randomization for those immune to hep B. The SiVET was an observational study designed to mimic the rigors of a clinical trial; we assessed HIV risk, provided risk counselling and prevention tools and performed HIV testing at baseline and periodically until the end of the trial. MSM and FSW were enrolled at a ratio of 4:1. Volunteers were assigned to either hepatitis B vaccine or placebo. RESULTS: Recruitment took approximately 24 months between Sep 2015 and Sep 2017. Of the 368 volunteers screened, 250 (200 MSM and 50 FSW) were enrolled. Reasons for exclusion at screening included: being positive for HIV (n = 7), hepatitis (n = 14), other pre-existing medical conditions (n = 41), eligible but chose not to enrol (n = 47). Most of the volunteers adhered to study procedures and attended their study visits within the study window. These include volunteers who received the second vaccination 244 (98%), the third vaccination 228 (91%) and, the final study visit 217 (87%). The reasons volunteers discontinued from the study early included: relocation and loss to follow up (n = 14). A total of 8 cases of HIV infection were observed in 174.5 Person Years at Risk (PYAR), all among MSM, including 5 seroconversions identified at the last study visit, for a HIV incidence of 4.58 cases/ 100 PYAR, among MSM enrolled in the study. CONCLUSION: Our findings suggest that it is possible to conduct HIV prevention trials among key populations in Nairobi with a good adherence to a vaccine efficacy trial schedule. Despite HIV prevention efforts, we also noted a high incidence of HIV infection. This demonstrates the need for effective HIV prevention products in these populations

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa.

BACKGROUND: We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. METHODS AND FINDINGS: In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d'Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant's last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. CONCLUSIONS: Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. TRIAL REGISTRATION: ClinicalTrials.gov NCT02564523

Safety and Adherence to Intermittent Pre-Exposure Prophylaxis (PrEP) for HIV-1 in African Men Who Have Sex with Men and Female Sex Workers

Background Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW). Methods/Principal Findings MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2:1:2:1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a onemonth recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen. Conclusions/Significance Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens</p

Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection.

Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines

CLSI-Derived Hematology and Biochemistry Reference Intervals for Healthy Adults in Eastern and Southern Africa

BACKGROUND: Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial. METHODS AND FINDINGS: Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S. -derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials. CONCLUSIONS: To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa