Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting ...assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.
We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel 40 mg, or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).
Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy.
ClinicalTrials.gov NCT00592124.
Abstract
Background
In South Africa, 60% of female sex workers (FSW) are living with HIV, many of whom experience structural and individual barriers to antiretroviral therapy (ART) initiation and ...adherence. Community-based decentralized treatment provision (DTP) may mitigate these barriers. To characterize optimal implementation strategies, we explored preferences for DTP among FSW living with HIV in Durban, South Africa.
Methods
Thirty-nine semi-structured in-depth interviews were conducted with FSW living with HIV (
n
= 24), and key informants (
n
= 15) including HIV program implementers, security personnel, and brothel managers. Participants were recruited using maximum variation and snowball sampling. Interviews were conducted in English or isiZulu between September–November 2017 and analyzed using grounded theory in Atlas.ti 8.
Results
DTP was described as an intervention that could address barriers to ART adherence and retention, minimizing transport costs, time and wage loss from clinic visits, and act as a safety net to address FSW mobility and clinic access challenges. Respondents highlighted contextual considerations for DTP and suggested that DTP should be venue-based, scheduled during less busy times and days, and integrate comprehensive health services including psychological, reproductive, and non-communicable disease services. ART packaging and storage were important for community-based delivery, and participants suggested DTP should be implemented by sex work sensitized staff with discrete uniform and vehicle branding.
Conclusions
Incorporating FSW preferences may support implementation optimization and requires balancing of tensions between preferences and feasibility. These data suggest the potential utility of DTP for FSW as a strategy to address those most marginalized from current ART programs in South Africa.
In South Africa, 62% of female sex workers (FSW) are estimated to be living with HIV. Qualitative research indicates that FSW share antiretroviral therapy (ART) with peers to surmount treatment ...barriers. We quantitatively described ART sharing, its correlates, and its relationship with viral suppression (VS) among FSW living with HIV in eThekwini, South Africa. Among FSW on ART (n = 890), 30% ever shared (gave and/or received) ART. Sharing ART was more likely among those with higher levels of alcohol use, illicit drug use, depression severity, and physical/sexual violence in the adjusted model. There was a positive, dose-response relationship between number of pills given to peers in the last 30 days and VS likelihood (aPR: 1.05, 95% CI: 1.02, 1.08; p < 0.01). Giving pills may strengthen peer relationships, which may facilitate ART adherence. ART distribution through peer networks holds promise as a context-appropriate intervention for improving ART adherence among FSW in this setting.
In South Africa >60% of female sex workers (FSW) are living with HIV, the majority of whom are not virally suppressed. Identifying multi-level determinants of viral suppression is central to ...developing implementation strategies to promote retention in HIV care and viral suppression among FSW with unmet treatment needs. Adult cisgender FSW living with HIV for ≥6 months, conducting sex work as their primary source of income, and residing in Durban (South Africa) were enrolled into the Siyaphambili Study, a sequential multiple assignment randomized trial. Baseline viral load and CD4 were assessed, and an interviewer-administered survey was conducted, capturing socio-demographic, reproductive and sexual history and behaviors, vulnerabilities, substance use, mental health, and stigma. We assessed baseline determinants of viral suppression (<50 copies/mL) using bivariate and multivariable robust poisson regression, considering associations across the individual, network, environmental and macrostructural levels. From June 2018 -March 2020, 1,644 women were screened, with 1,391 eligible FSW living with HIV enrolled. The analyses were conducted among the 1,373 participants with baseline data. Overall, 65% (889/1,373) of participants were reported to be on antiretroviral therapy and 38% (520/1,373) were virally suppressed. In the multivariable model, FSW who experienced a lack of housing in the prior six months were less likely to be virally suppressed (aPR: 0.72, 95%CI 0.56-0.91), while older FSW (aPR: 1.46 95%CI: 1.16-1.83 for 30-39 years old vs. 18-29 years old; aPR: 2.15 95%CI: 1.64-2.80 for 40+ years vs. 18-29 years old) and FSW reporting hormonal or long-acting contraception use were more likely to be virally suppressed (aPR: 1.19 95% CI: 1.00-1.43). We found vulnerability to be high among FSW living with HIV in South Africa and identified individual and structural determinants associated with viral suppression. Taken together these results suggest optimizing HIV treatment outcomes necessitates supporting younger sex workers and addressing housing instability. Trial registration: NCT03500172.
Expansion of tuberculous preventive therapy (TPT) is essential to curb TB incidence and mortality among people with HIV (PWH), yet implementation has been slow. Innovative strategies to ...operationalize TPT are urgently needed. Here we present an evaluation of community-based identification and referral of PWH on completion of a six-month course of isoniazid in a highly prevalent region in rural South Africa. Using a community-based TB/HIV intensive case finding strategy, a team of nurses and lay workers identified community members with HIV who were without fever, night sweats, weight loss, or cough and referred them to the government primary care clinics for daily oral isoniazid, the only available TPT regimen. We measured monthly adherence and six-month treatment completion in the community-based identification and referral (CBR) group compared to those already engaged in HIV care. Adherence was measured by self-report and urine isoniazid metabolite testing. A multivariable analysis was performed to identify independent predictors of TPT completion. Among 240 participants, 81.7% were female, median age 35 years (IQR 30-44), and 24.6% had previously been treated for TB. The median CD4 count in the CBR group was 457 (IQR 301-648), significantly higher than the clinic-based comparison group median CD4 of 344 (IQR 186-495, p<0.001). Independent predictors of treatment completion included being a woman (aOR 2.41, 95% 1.02-5.72) and community-based identification and referral for TPT (aOR 2.495, 95% 1.13-5.53). Among the CBR group, treatment completion was 90.0%, an absolute 10.8% higher than the clinic-based comparison group (79.2%, p = 0.02). Adherence was significantly greater in the CBR group than the clinic-based comparison group, as measured by self-report (p = 0.02) and urine isoniazid testing (p = 0.01). Among those not on ART at baseline, 10% of eligible PWH subsequently initiated ART. Community members living with HIV in TB endemic regions identified and referred for TPT demonstrated higher treatment completion and adherence compared to PWH engaged for TPT while receiving clinic-based care. Community-based identification and referral is an innovative adjunctive strategy to facilitate implementation of TB preventive therapy in people living with HIV.
South Africa, with its scientific capacity, good infrastructure and high HIV incidence rates, is ideally positioned to conduct large-scale HIV prevention trials. The HIV Prevention Research Unit of ...the South African Medical Research Council conducted four phase III and one phase IIb trials of women-initiated HIV prevention options in KwaZulu-Natal between 2003 and 2009. A total of 7046 women participated, with HIV prevalence between 25% and 45% and HIV incidence ranging from 4.5-9.1% per year. Unfortunately none of the interventions tested had any impact on reducing the risk of HIV acquisition; however, extremely valuable experience was gained, lessons learned and capacity built, while the communities gained associated benefits.
Our experience in conducting these trials ranged from setting up community partnerships to developing clinical research sites and dissemination of trial results. Community engagement included setting up community-based research sites with approval from both political and traditional leaders, and developing community advisory groups to assist with the research process. Community-wide education on HIV/sexually transmitted infection prevention, treatment and care was provided to over 90,000 individuals. Myths and misconceptions were addressed through methods such as anonymous suggestion boxes in clinic waiting areas and intensive education and counselling. Attempts were made to involve male partners to foster support and facilitate recruitment of women. Peer educator programmes were initiated to provide ongoing education and also to facilitate recruitment of women to the trials. Recruitment strategies such as door-to-door recruitment and community group meetings were initiated. Over 90% of women enrolled were retained. Community benefits from the trial included education on HIV prevention, treatment and care and provision of ancillary care (such as Pap smears, reproductive health care and referral for chronic illnesses). Social benefits included training of home-based caregivers and sustainable ongoing HIV prevention education through peer educator programmes.
Several challenges were encountered, including manipulation by participants of their eligibility criteria in order to enroll in the trial. Women attempted to co-enroll in multiple trials to benefit from financial reimbursements and individualised care. The trials became ethically challenging when participants refused to take up referrals for care due to stigma, denial of their HIV status and inadequate health infrastructure. Lack of disclosure of HIV status to partners and family members was particularly challenging. Some of the ethical dilemmas put to the test our responsibility as researchers and our obligation to provide health care to research participants.
Conducting these five trials in a period of six years provided us with invaluable insights into trial implementation, community participation, recruitment and retention, provision of care and dissemination of trial results. The critical mass of scientists trained as clinical trialists will continue to address the relentless HIV epidemic in our setting and ensure our commitment to finding a biomedical HIV prevention option for women in the future.
This study assesses risk factors of loss to follow-up (LTFU) and estimates mortality risk among female sex workers (FSW) with HIV in Durban, South Africa, in 2018–2021.
We used data from the ...Siyaphambili trial, which evaluated strategies for improved viral suppression. FSW with HIV aged ≥ 18 years with viral load ≥ 50 copies/mL were followed up for 18 months. LTFU was defined as absence from study or intervention visits for 6 months. We traced LTFU participants by calling/in-person visit attempts to ascertain their vital status. We used Cox regression to determine risk factors of LTFU and inverse probability of tracing weights to correct mortality risk.
Of 777 participants, 10 (1.3%) had died and 578 (74.4%) were initially LTFU. Among those LTFU, 36.3% (210/578) were traced successfully, with 6 additional deaths ascertained. Recent physical and sexual violence, and non-viral suppression were associated with increased LTFU. The unweighted and weighted 18-month mortality risks were 2.4% (95% CI: 0.8%−3.9%) and 3.7% (95% CI: 1.8%−5.9%), respectively.
LTFU is common among FSW with HIV in South Africa with additional investigation of vital status demonstrating under-ascertained mortality. These data suggest the need for comprehensively addressing risks for mortality among FSW.
ABSTRACT
In South Africa, 60% of female sex workers are estimated to be living with human immunodeficiency virus (HIV). Many of these women face structural and individual‐level barriers to ...initiating, accessing, and adhering to antiretroviral therapy (ART). While data are limited, it is estimated that less than 40% of sex workers living with HIV achieve viral suppression, leading to suboptimal clinical outcomes and sustained risks of onward sexual and vertical HIV transmission. Siyaphambili, a NINR/NIH‐funded study, focuses on studying optimal implementation strategies for meeting HIV treatment needs among cisgender female sex workers living with HIV who are not virally suppressed. Here, we present the study protocol of this sequential multiple assignment randomized trial. In total, 800 viremic female sex workers will be enrolled into an 18‐month adaptive implementation study to 1) compare the effectiveness and durability of a nurse‐led decentralized ART treatment program versus an individualized case management approach, in isolation or in combination to achieve viral suppression and 2) estimate incremental cost‐effectiveness of interventions and combinations of interventions. The primary outcome is a combined intention‐to‐treat outcome of retention in ART care and viral suppression at 18 months with secondary implementation outcomes. Siyaphambili aims to inform the implementation of and scale‐up of HIV treatment services for female sex workers by determining the minimal package of services needed to achieve viral suppression and by characterizing individuals in need of more intensive HIV treatment approaches.
Expansion of tuberculous preventive therapy (TPT) is essential to curb TB incidence and mortality among people with HIV (PWH), yet implementation has been slow. Innovative strategies to ...operationalize TPT are urgently needed. Here we present an evaluation of community-based identification and referral of PWH on completion of a six-month course of isoniazid in a highly prevalent region in rural South Africa. Using a community-based TB/HIV intensive case finding strategy, a team of nurses and lay workers identified community members with HIV who were without fever, night sweats, weight loss, or cough and referred them to the government primary care clinics for daily oral isoniazid, the only available TPT regimen. We measured monthly adherence and six-month treatment completion in the community-based identification and referral (CBR) group compared to those already engaged in HIV care. Adherence was measured by self-report and urine isoniazid metabolite testing. A multivariable analysis was performed to identify independent predictors of TPT completion. Among 240 participants, 81.7% were female, median age 35 years (IQR 30-44), and 24.6% had previously been treated for TB. The median CD4 count in the CBR group was 457 (IQR 301-648), significantly higher than the clinic-based comparison group median CD4 of 344 (IQR 186-495, p<0.001). Independent predictors of treatment completion included being a woman (aOR 2.41, 95% 1.02-5.72) and community-based identification and referral for TPT (aOR 2.495, 95% 1.13-5.53). Among the CBR group, treatment completion was 90.0%, an absolute 10.8% higher than the clinic-based comparison group (79.2%, p = 0.02). Adherence was significantly greater in the CBR group than the clinic-based comparison group, as measured by self-report (p = 0.02) and urine isoniazid testing (p = 0.01). Among those not on ART at baseline, 10% of eligible PWH subsequently initiated ART. Community members living with HIV in TB endemic regions identified and referred for TPT demonstrated higher treatment completion and adherence compared to PWH engaged for TPT while receiving clinic-based care. Community-based identification and referral is an innovative adjunctive strategy to facilitate implementation of TB preventive therapy in people living with HIV.
PDF
