HIV Prevention Trials Research Articles

Likelihood-based inferences for active-arm trial with counterfactual incidence based on recency assay

Abstract Objectives The approach of using HIV recency assay to estimate the counterfactual incidence rate is being used as the primary efficacy method in a few ongoing large-scale HIV pre-exposure prophylaxis (PrEP) trials, and the current available approach for the inference is based on the Wald method that leverages the asymptotic distribution of the estimators. One issue with the Wald test is that it does not work well when the number of HIV infections are small in the active arm, and it fails to work when there are zero HIV infections. As future long-acting PrEP products are becoming more efficacious, it is very likely that a small or zero number of infections will be observed in HIV prevention trials, especially for subgroup analyses or interim analyses, hence there is a pressing need to develop inference methods that work under such scenarios. Methods It is well known that when the sample size is small to moderate, likelihood ratio tests are more reliable than Wald tests in terms of actual error probabilities coming close to matching nominal levels. In this manuscript we derive the likelihood ratio test and the likelihood-based confidence intervals for HIV prevention trials based on recency assays. Results Compared with the Wald test, the proposed method works when there are zero infections. Additionally, unlike the Wald test, the p-value from the likelihood ratio test is an increasing function with respect to the number of infections, which is a desirable property as otherwise it will cause confusions. Conclusions For HIV PrEP trials based on recency assay, the likelihood-based p-value and confidence interval can be preferable to the Wald based inference methods when the number of HIV infections is expected to be small.

Congregation leader and member discussions in a church-based family strengthening, mental health promotion and HIV prevention trial: Intervention.

Collaboration with African religious congregations can promote psychosocial well-being with greater accessibility. Effective collaboration requires studying congregations as unique intervention contexts. This study explored how an intervention in western Kenya fit within and altered congregational discussion patterns. We conducted a cluster-randomized trial of a church-based intervention to improve family relationships, mental health and sexual health. For each intervention topic covered, we describe baseline and post-intervention changes in church leaders' beliefs and communication as well as discussion frequency between leaders and members and among members. Mixed-effects logistic regression assessed pre-post change in member-reported discussion frequency. At baseline, members and leaders reported already discussing family, parenting, and emotions frequently and sexuality and finances less frequently. Leaders generally felt they should discuss all topics but were less comfortable and knowledgeable about sexuality and finances than other topics. After the intervention, leader comfort and knowledge increased and discussion frequency increased for nearly all topics, especially those discussed less initially. Good fit between the desires and activities of church members and leaders suggests the potential for further collaboration, especially on mental health and family well-being. Increased discussion of sensitive topics underscores the potential of community-level interventions to affect social norms.

Posttraumatic Stress Disorder Symptoms and Incarceration: The Impact on Sexual Risk-Taking, Sexually Transmitted Infections, and Depression Among Black Sexual Minority Men in HIV Prevention Trials Network (HPTN) 061.

Black men and people belonging to sexual minority groups are disproportionately impacted by criminal legal involvement and sexually transmitted infections (STIs). Traumatic experiences are often associated with later criminal legal involvement, depression symptoms, sexual risk behavior, and STIs. Research on the joint influence of trauma and incarceration on STI risk among racial and/or sexual minority people is limited. This study tested the association between post-traumatic stress disorder (PTSD) symptoms and incarceration on sexual risk behavior and STI among Black sexual minority men, a population that may be at higher risk for contracting STIs. Using data from the HIV Prevention Trials Network 061 Study, a longitudinal study of adult Black sexual minority men in six U.S. cities (N = 855), we tested associations between past six-month incarceration and subsequent sexual risk behavior, STI, and depression symptoms, for those with and without pre-incarceration PTSD symptoms. PTSD symptoms were elevated among participants who reported Hispanic ethnicity, having sex with both men and women, and previous incarceration. Although there were not significant differences between recent incarceration and sexual risk for those with and without PTSD, incarceration was linked to some sexual risk behaviors regardless of PTSD symptoms. Among people with PTSD symptoms, there was a higher prevalence of sexual risk and depression symptoms, regardless of incarceration. These findings suggest a potentially compounding influence of PTSD symptoms and incarceration on sexual risk and infection among Black sexual minority men.

The "3 Ps" of EmPowerment, Partnership and Protection - Stakeholder Perceptions of Beneficial Outcomes of Engagement in HIV Prevention Trials.

Background: Stakeholder engagement is increasingly recognized as a key component of ethical research in leading ethics guidelines. Ethics commentators have also argued that engagement has several beneficial outcomes for the field. Aim: This paper reports on the beneficial outcomes of stakeholder engagement in HIV prevention trials as perceived by stakeholders in the field. Method: We conducted 28 interviews between 2019 and 2021 with interviewees from various stakeholder groups in 12 countries and used thematic analysis to analyze the transcripts. Findings: We found three major themes - namely emPowerment where engagement is perceived to empower stakeholders, Partnerships where engagement is perceived to build equitable relationships and Protections where engagement is perceived to strengthen protections for participants and community stakeholders and to improve science. Conclusions: These findings map closely onto beneficial outcomes envisaged by ethics guidelines, however, the relationship between outcomes seen as beneficial deserves further exploration.

Feasibility and acceptability of using biometric fingerprinting to track migrations and support retention in HIV prevention research in fishing population in East Africa

IntroductionFishing populations constitute a suitable key population amongst which to conduct HIV prevention trials due to very high HIV prevalence and incidence, however, these are highly mobile populations. We determined the feasibility and acceptability of using fingerprinting and geographical positioning systems to describe mobility patterns and retention among fisherfolks on the shoreline of Lake Victoria in South-western Uganda.MethodsBetween August 2015 and January 2017, two serial cross-sectional surveys were conducted during which fingerprinting of all residents aged 18–30 years on the shoreline of Lake Victoria was done. A mapper moving ahead of the survey team, produced village maps and took coordinates of every household. These were accessed by the survey team that assigned household and individual unique identifiers (ID) and collected demographic data. Using the assigned IDs, individuals were enrolled and their fingerprints scanned. The fingerprinting was repeated 6 months later in order to determine the participant’s current household. If it was different from that at baseline, a new household ID was assigned which was used to map migrations both within and between villages.ResultsAt both rounds, over 99% accepted to be fingerprinted. No fingerprinting faults were recorded at baseline and the level was under 1% at round two. Over 80% of the participants were seen at round two and of these, 16.3%, had moved to a new location whilst the majority, 85%, stayed within the same village. Movements between villages were mainly observed for those resident in large villages. Those who did not consider a fishing village to be their permanent home were less likely to be migrants than permanent residents (adjusted odds ratio = 0.37, 95%CI:0.15–0.94).ConclusionUse of fingerprinting in fishing populations is feasible and acceptable. It is possible to track this mobile population for clinical trials or health services using this technology since most movements could be traced within and between villages.

2896. Oral PrEP Uptake among HVTN 704/HPTN 085 Participants: Implications for the Future of Biomedical HIV Prevention Trials

Abstract Background The HVTN 704/HPTN 085 clinical trial (AMP study) assessed the efficacy of VRC01 broadly neutralizing antibody infusions for HIV prevention. It offered access to oral pre-exposure prophylaxis (PrEP) at no-cost to all participants as standard of HIV prevention care. Understanding PrEP initiation among trial participants and describing its impact on study endpoints can guide future HIV prevention trial design. Methods We characterized sociodemographic and geographic features of PrEP initiation (by self-report) using descriptive statistics. We used Cox models to identify factors associated with PrEP initiation and the association between PrEP initiation (as a time-dependent exposure) and HIV incidence. Results Of 2221 participants off PrEP at enrollment, 31.8% initiated PrEP during the trial. Median time to PrEP initiation was 60 days (range 1-673 days). Brazil had the highest proportion of PrEP initiation among their enrolled participants (83.2%) and Peru had the lowest (5.3%). In US sites, 54.2% initiated PrEP. Southern US sites had the highest proportion of PrEP initiation (68.8%) and the Midwest had the lowest (28.4%). In multivariate analysis, prior PrEP use [HR (95% CI) = 2.2 (1.3-4.0)] was associated with PrEP initiation. Participants from Switzerland [0.5 (0.3-1.0)] and Peru [0.08 (0.06-0.1)] had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood [2.6 (2.0-3.3)]. Age, race, gender, and sexual orientation were not associated with PrEP initiation. HIV incidence rate was 3.6/100 person-years (PY) before PrEP initiation, compared to 1.2/100 PY after PrEP initiation. PrEP initiators had 58% less risk of acquiring HIV after adjusting for behavioral risk score and treatment arm. In the US, higher local PrEP-to-need ratio was also associated with lower PrEP initiation [0.9 per 5 units (0.8-1.0)]. Conclusion Providing PrEP access to AMP participants reduced HIV acquisition among PrEP initiators. Study endpoints were still met due to heterogenous regional PrEP uptake and lower PrEP effectiveness than expected. These data suggest that offering oral PrEP to HIV prevention trial participants as standard of care is a feasible option to consider for future efficacy HIV prevention trial design. Disclosures Valeria D. Cantos, MD, Gilead Sciences: Grant/Research Support Srilatha Edupuganti, MD MPH FIDSA, Sanofi: Grant/Research Support Colleen F. Kelley, MD, MPH, Gilead Sciences: Grant/Research Support|Humanigen: Grant/Research Support|Moderna, Inc.: Grant/Research Support|Novavax, Inc: Grant/Research Support|Viiv Healthcare: Grant/Research Support

Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial

Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

Age Differences in the Associations Between Incarceration and Subsequent Substance Use, Sexual Risk-Taking, and Incident STI Among Black Sexual Minority Men and Black Transgender Women in the HIV Prevention Trials 061 Cohort.

Incarceration can lead to different risk behaviors often due to increased distress and disruption of social networks. It is not well known, however, how these associations may differ by age. In this study, we measure age differences in longitudinal associations between incarceration and substance use, sex risk, and sexually transmitted infection (STI) among Black sexual minority men and Black transgender women (BSMM/BTW). We recruited BSMM/BTW from 2009 to 2011 that were part of the HIV Prevention Trials Network 061 study. We compared those less than 30 years old (n = 375) to those 30 years old or greater (n = 794) examining substance use, sex risk, and STI infection stratified by age. Logistic regression with inverse probability weighting was used for the statistical analysis. Approximately 59% of the sample reported incarceration history. In adjusted analysis, incarceration was more strongly associated with alcohol use and stimulant use among older individuals as was sexual risk behaviors including buying and selling sex. Concurrent partnerships were associated with the younger age groups. STI incidence was associated with younger individuals while associations with HIV infection were similar for the two age groups. Understanding differences in substance use and STI risk among age cohorts is imperative to the design and implementation of re-entry programs. Younger BSMM/BTW participating in re-entry support programs may benefit in particular from HIV/STI prevention and care efforts, while post-release substance abuse treatment and harm reduction programs should target older individuals with continued substance abuse.

Increasing Spiritual Beliefs are Associated With Lower HIV Incidence Among Black Men Who Have Sex With Men: Results From HPTN 061 Longitudinal Study.

There is a limited understanding about the impact of spiritual beliefs and activities on HIV seroconversion among black men who have sex with men (BMSM), which we investigate in this study. United States. The HIV Prevention Trials Network Study 061 collected demographic and biomedical assessments among BMSM across 6 United States cities for longitudinal analysis. Spiritual beliefs and spiritual activities are constructed composite scales. Bivariate analyses among 894 who provided data at 12-month follow-up compared men who seroconverted to HIV between baseline and 6 months with those who remained uninfected with HIV at 12 months. Cox proportional hazard regression among 944 men tested spiritual beliefs and activities on the longitudinal risk of HIV seroconversion adjusting for age and any sexually transmitted infection (STI). Among this sample, HIV incidence between baseline and 6 months was 1.69%, (95% confidence intervals [CI]: 1.04 to 2.77). Men who seroconverted to HIV were significantly younger than those who remained uninfected at the 12-month follow-up: (mean age 27, SD = 11 vs 37, SD = 12) and a higher proportion reported any STI (46.67% vs 11.39%, P < 0.01). A one-unit increase in spiritual beliefs was associated with lower hazard rate of seroconverting to HIV at follow-up [adjusted hazard ratio (aHR) = 0.37, 95% CI: = (0.16 to 0.87)]. Religious service attendance and spiritual activities were unrelated to seroconverting. Spirituality is important in the lives of BMSM. Biomedical and behavioral HIV prevention interventions should consider assessing spiritual beliefs in HIV care among BMSM.

Estimating counterfactual placebo HIV incidence in HIV prevention trials without placebo arms based on markers of HIV exposure.

Developing alternative approaches to evaluating absolute efficacy of new HIV prevention interventions is a priority, as active-controlled designs, whereby individuals without HIV are randomized to the experimental intervention or an active control known to be effective, are increasing. With this design, however, the efficacy of the experimental intervention to prevent HIV acquisition relative to placebo cannot be evaluated directly. One proposed approach to estimate absolute prevention efficacy is to use an HIV exposure marker, such as incident rectal gonorrhea, to infer counterfactual placebo HIV incidence. We formalize a statistical framework for this approach, specify working regression and likelihood-based estimation approaches, lay out three assumptions under which valid inference can be achieved, evaluate finite-sample performance, and illustrate the approach using a recent active-controlled HIV prevention trial. We find that in finite samples and under correctly specified assumptions accurate and precise estimates of counterfactual placebo incidence and prevention efficacy are produced. Based on data from the DISCOVER trial in men and transgender women who have sex with men, and assuming correctly specified assumptions, the estimated prevention efficacy for tenofovir alafenamide plus emtricitabine is 98.1% (95% confidence interval: 96.4%-99.4%) using the working model approach and 98.1% (95% confidence interval: 96.4%-99.7%) using the likelihood-based approach. Careful assessment of the underlying assumptions, study of their violation, evaluation of the approach in trials with placebo arms, and advancement of improved exposure markers are needed before the HIV exposure marker approach can be relied upon in practice.

Efficacy, safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis in transgender women: a secondary analysis of the HPTN 083 trial

The HIV Prevention Trials Network (HPTN) 083 trial showed that long-acting injectable cabotegravir was more effective than tenofovir disoproxil fumarate plus emtricitabine in preventing HIV in cisgender men and transgender women who have sex with men. We aimed to characterise the cohort of transgender women included in HPTN 083. HPTN 083 is an ongoing, phase 2b/3, randomised, multicentre, double-blind, double-dummy clinical trial done at 43 sites in seven countries (Argentina, Brazil, Peru, the USA, South Africa, Thailand, and Viet Nam). HIV-negative participants were randomly assigned (1:1) to receive injectable cabotegravir or tenofovir disoproxil fumarate plus emtricitabine. The study design and primary outcomes of the blinded phase of HPTN 083 have already been reported. An enrolment minimum of 10% transgender women was set for the trial. Here we characterise the cohort of transgender women enrolled from Dec 6, 2016, to May 14, 2020, when the study was unblinded. We report sociodemographic characteristics, use of gender affirming hormone therapy, and behavioural assessments of the transgender women participants. Laboratory testing and safety evaluations are also reported. The trial is registered at ClinicalTrials.gov, NCT02720094. HPTN 083 enrolled 570 transgender women (304 tenofovir disoproxil fumarate plus emtricitabine; 266 injectable cabotegravir). Transgender women were primarily from Asia (225 [39%]) and Latin America (205 [36%]); 330 (58%) reported using gender affirming hormone therapy. Intimate partner violence was common (270 [47%] reported emotional abuse and 172 [30%] reported physical abuse) and 323 (57%) reported a history of childhood sexual abuse. 159 (28%) transgender women disagreed that they were at risk for HIV, and 142 (25%) screened positive for depressive symptoms. During study follow-up, incidence of syphilis was 16·25% (95% CI 13·28-19·69), rectal gonorrhoea was 11·66% (9·14-14·66), and chlamydia was 20·61% (17·20-24·49). Frequency of adverse events was similar between the treatment groups. Nine seroconversions occurred among transgender women during the blinded phase of the study (seven in the tenofovir disoproxil fumarate plus emtricitabine group and two in the injectable cabotegravir group); overall incidence was 1·19 per 100 person-years (95% CI 0·54-2·25): 1·80 per 100 person-years (0·73-3·72) in the tenofovir disoproxil fumarate plus emtricitabine group and 0·54 per 100 person-years (0·07-1·95) in the injectable cabotegravir group (hazard ratio 0·34 [95% CI 0·08-1·56]). Cabotegravir concentrations did not differ by gender affirming hormone therapy use. HIV prevention strategies for transgender women cannot be addressed separately from social and structural vulnerabilities. Transgender women were well represented in HPTN 083 and should continue to be prioritised in HIV prevention studies. Our results suggest that injectable cabotegravir is a safe and effective pre-exposure prophylaxis option for transgender women. National Institute of Allergy and Infectious Diseases and ViiV Healthcare.

Associations between police harassment and distrust in and reduced access to healthcare among Black sexual minority men: A longitudinal analysis of HPTN 061.

Evaluate associations between racialized and homophobia-based police harassment (RHBPH) and healthcare distrust and utilization among Black Sexual Minority Men (BSMM). We utilized data from a longitudinal cohort study from HIV Prevention Trials Network (HPTN) 061 with baseline, six and 12 month follow-up assessments. Using multivariable analysis, we evaluated associations between RHBPH and healthcare distrust and utilization reported at the 6 and 12 month visits. Of 1553 BSMM present at baseline, 1160 were available at six-month follow-up. In multivariable analysis, increasing frequency of RHBPH was associated with increasing levels of distrust in healthcare providers (aOR 1.31, 95% CI: 1.00, 1.74) and missing 50% or more of healthcare visits at six-month follow-up (aOR 1.93, 95% CI: 1.09, 3.43). Recent experiences of RHBPH are associated with reduced trust in and access to healthcare among BSMM, with more frequent RHBPH associated with greater vulnerability.

Managing household income and antiretroviral therapy adherence among people living with HIV in a low-income setting: a qualitative data from the HPTN 071 (PopART) trial in South Africa

BackgroundSouth Africa is reported to have the highest burden of HIV with an estimated 8.2 million people living with HIV (PLHIV) in 2021- despite adopting the World Health Organisation (WHO) universal HIV test and treat (UTT) recommendations in 2016. As of 2021, only an estimated 67% (5.5 million) of all PLHIV were accessing antiretroviral therapy (ART), as per recorded clinic appointments attendance. Studies in sub-Saharan Africa show that people living in low-income households experience multiple livelihood-related barriers to either accessing or adhering to HIV treatment including lack of resources to attend to facilities and food insecurity. We describe the interactions between managing household income and ART adherence for PLHIV in low-income urban and semi-urban settings in the Western Cape, South Africa.MethodsWe draw on qualitative data collected as part of the HPTN 071 (PopART) HIV prevention trial (2016 – 2018) to provide a detailed description of the interactions between household income and self-reported ART adherence (including accessing ART and the ability to consistently take ART as prescribed) for PLHIV in the Western Cape, South Africa. We included data from 21 PLHIV (10 men and 11 women aged between 18 and 70 years old) from 13 households. As part of the qualitative component, we submitted an amendment to the ethics to recruit and interview community members across age ranges. We purposefully sampled for diversity in terms of age, gender, and household composition.ResultsWe found that the management of household income interacted with people’s experiences of accessing and adhering to ART in diverse ways. Participants reported that ART adherence was not a linear process as it was influenced by income stability, changing household composition, and other financial considerations. Participants reported that they did not have a fixed way of managing income and that subsequently caused inconsistency in their ART adherence. Participants reported that they experienced disruptions in ART access and adherence due to competing household priorities. These included difficulties balancing between accessing care and/or going to work, as well as struggling to cover HIV care-related costs above other basic needs.ConclusionOur analysis explored links between managing household income and ART adherence practices. We showed that these are complex and change over the course of treatment duration. We argued that mitigating negative impacts of income fluctuation and managing complex trade-offs in households be included in ART adherence support programmes.

Earlier sexual debut as a risk factor for substance use among men who have sex with men (MSM) in Kazakhstan.

Limited research have examined predictors of illicit use of drugs and binge drinking among gay, bisexual, and other men who have sex with men (MSM) in Kazakhstan and Central Asia. This study examines earlier sexual debut as a risk factor for lifetime and recent substance use behaviors among MSM in Kazakhstan. We conducted a secondary analysis of self-reported data from a NIDA-funded HIV prevention trial including 902 adult cisgender MSM in Kazakhstan who completed structured screening interviews. Logistic regression models were used to estimate associations between earlier sexual debut (ages 16 and older as the reference group) and lifetime and recent substance use, with covariance adjustment for sociodemographic characteristics. The majority of MSM in our sample reported lifetime binge drinking behavior (73%) and illicit use of drugs (65%). Participants with an earlier sexual debut before 13 years old had significantly higher odds of lifetime binge drinking and any illicit use of drugs (aOR= 2.3, 95%CI: 1.2-4.5; aOR=3.0, 95%CI: 1.6-5.8). MSM who reported an earlier sexual debut between 13-15 years old had significantly higher odds of lifetime binge drinking and illicit use of any drugs (aOR=1.6, 95%CI: 1.1-2.3; aOR=1.6, 95%CI: 1.1-2.3); as well as recent binge drinking behavior (aOR=1.6, 95%CI: 1.2-2.3). Future research should examine pathways between earlier sexual experiences and substance use behaviors among sexually diverse populations. Earlier sexual experiences during childhood and adolescence may be relevant contextual information for interventions aimed at substance use risk prevention, treatment, and recovery among MSM populations.

Causes and risk factors of death among people who inject drugs in Indonesia, Ukraine and Vietnam: findings from HPTN 074 randomized trial

IntroductionThe HIV Prevention Trials Network (HPTN) 074 study demonstrated a positive effect of an integrated systems navigation and psychosocial counseling intervention on HIV treatment initiation, viral suppression, medication assisted treatment (MAT) enrollment, and risk of death among people who inject drugs (PWID). In this sub-study, we analyzed the incidence, causes, and predictors of death among HIV-infected and uninfected participants.MethodsThe HPTN 074 randomized clinical trial was conducted in Indonesia, Ukraine, and Vietnam. HIV-infected PWID with unsuppressed viral load (indexes) were recruited together with at least one of their HIV-negative injection partners. Indexes were randomized in a 1:3 ratio to the intervention or standard of care.ResultsThe trial enrolled 502 index and 806 partner participants. Overall, 13% (66/502) of indexes and 3% (19/806) of partners died during follow-up (crude mortality rates 10.4 [95% CI 8.1–13.3] and 2.1 [1.3–3.3], respectively). These mortality rates were for indexes nearly 30 times and for partners 6 times higher than expected in a population of the same country, age, and gender (standardized mortality ratios 30.7 [23.7–39.0] and 5.8 [3.5–9.1], respectively). HIV-related causes, including a recent CD4 < 200 cells/μL, accounted for 50% of deaths among indexes. Among partners, medical conditions were the most common cause of death (47%). In the multivariable Cox model, the mortality among indexes was associated with sex (male versus female aHR = 4.2 [1.5–17.9]), CD4 count (≥ 200 versus < 200 cells/μL aHR = 0.3 [0.2–0.5]), depression (moderate-to-severe versus no/mild aHR = 2.6 [1.2–5.0]) and study arm (intervention versus control aHR = 0.4 [0.2–0.9]). Among partners, the study arm of the index remained the only significant predictor (intervention versus control aHR = 0.2 [0.0–0.9]) while controlling for the effect of MAT (never versus ever receiving MAT aHR = 2.4 [0.9–7.4]).ConclusionsThe results confirm that both HIV-infected and uninfected PWID remain at a starkly elevated risk of death compared to general population. Mortality related to HIV and other causes can be significantly reduced by scaling-up ART and MAT. Access to these life-saving treatments can be effectively improved by flexible integrated interventions, such as the one developed and tested in HPTN 074.

Relationships Between Stress-Responsive Biomarkers, ART Adherence, and Viral Suppression Among Adolescent Girls and Young Women Living With HIV in South Africa: An HPTN 068 Analysis.

Adolescent girls and young women (AGYW) living with HIV who have higher stress levels may be at risk of stress-related biological alterations, which could influence HIV progression and adherence to antiretroviral therapy (ART). We aimed to estimate associations among stress-responsive biomarkers, ART adherence, and viral suppression in AGYW living with HIV in South Africa. We also hypothesized that psychosocial stressors [eg, depression, food insecurity, low socioeconomic status (SES), and HSV-2] would be associated with higher biomarker levels. We used 2018/2019 data from the HIV Prevention Trials Network 068 cohort to assess associations between stress-responsive biomarkers and viral suppression (<1000 copies/mL) and ART adherence measured using dried blood spot cards. Stress-responsive biomarkers included C-reactive protein, herpes simplex virus type 1, and cytomegalovirus infection and reactivation. Associations were estimated using unadjusted log-binomial or ordinal logistic regression models. In 166 AGYW living with HIV, there was no association between stress-responsive biomarkers and viral suppression or ART adherence. However, increased C-reactive protein levels were associated with higher HSV-2 infection [odds ratio (OR) 1.98; 95% confidence interval (CI) 1.11, 3.52], being a government grant recipient (OR 3.21; 95% CI: 1.30, 7.92), lower food insecurity (OR 0.34; 95% CI: 0.13, 0.90), and increased body mass index (OR 1.07; 95% CI: 1.01, 1.14). High prevalence of psychosocial stressors and persistent herpesviruses in AGYW living with HIV has the potential to lead to poorer health outcomes. More research is needed to untangle relationships between economic stability, chronic disease, and chronic stress.

Electronic health records to capture primary outcome measures: two case studies in HIV prevention research

BackgroundThere is increasing interest in the use of electronic health records (EHRs) to improve the efficiency and cost-effectiveness of clinical trials, including the capture of outcome measures.Main textWe describe our experience of using EHRs to capture the primary outcome measure — HIV infection or the diagnosis of HIV infection — in two randomised HIV prevention trials conducted in the UK. PROUD was a clinic-based trial evaluating pre-exposure prophylaxis (PrEP), and SELPHI was an internet-based trial evaluating HIV self-testing kits. The EHR was the national database of HIV diagnoses in the UK, curated by the UK Health Security Agency (UKHSA). In PROUD, linkage to the UKHSA database was performed at the end of the trial and identified five primary outcomes in addition to the 30 outcomes diagnosed by the participating clinics. Linkage also produced an additional 345 person-years follow-up, an increase of 27% over clinic-based follow-up. In SELPHI, new HIV diagnoses were primarily identified via UKHSA linkage, complemented by participant self-report through internet surveys. Rates of survey completion were low, and only 14 of the 33 new diagnoses recorded in the UKHSA database were also self-reported. Thus UKHSA linkage was essential for capturing HIV diagnoses and the successful conduct of the trial.ConclusionsOur experience of using the UKHSA database of HIV diagnoses as a source of primary outcomes in two randomised trials in the field of HIV prevention was highly favourable and encourages the use of a similar approach in future trials in this disease area.

Spatial variations in STIs among women enrolled in HIV prevention clinical trials in Durban, KwaZulu-Natal, South Africa

ABSTRACT South Africa is faced with a high HIV and STI prevalence and incidence, respectively, with pockets of high burden areas driving these diseases. Localised monitoring of the HIV epidemic and STI endemic would enable more effective targeted prevention strategies. We assessed spatial variations in curable STI incidence among a cohort of women enrolled in HIV prevention clinical trials between 2002 and 2012. STI incidence rates from 7557 South African women enrolled in five HIV prevention trials were geo-mapped using participant household GPS coordinates. Age and period standardised incidence rates were calculated for 43 recruitment areas and Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and spatial patterns of STI infections in recruitment communities. Overall age and period standardised STI incidence rate were estimated as 15 per 100 PY and ranged from 6 to 24 per 100 PY. We identified five significant STI high risk areas with higher-than-expected incidence of STIs located centrally (three-locations) and southern neighbouring areas of Durban (two-locations). Younger age (<25), not married/cohabitating, parity <3 and poor education were all significant correlates of high STI communities. Findings demonstrate sustained STI incidence rates across the greater Durban area. The role of STI incidence in HIV acquisition in high HIV endemic areas need to be revisited as current highly effective PrEP interventions do not protect from STI acquisition. In these settings there is an urgent need for integrative HIV and STI prevention and treatment services.

Development and validation of a liquid chromatographic-tandem mass spectrometric assay for the quantification of cabotegravir and rilpivirine from dried blood spots

BackgroundDried blood spots (DBS) have been utilized as a blood plasma alternative for therapeutic drug monitoring and pharmacologic analysis. There are analytical and physiochemical considerations in bridging drug concentrations from plasma to DBS. Recently, the long-acting antiretroviral cabotegravir (CAB) has been approved for HIV prevention, and a co-packaged regimen of long-acting CAB and rilpivirine (RPV) has been approved for HIV treatment. Measurement of these drugs in blood collected as DBS may offer increased capacity and flexibility in translational applications. MethodsWhole blood was spiked with CAB and RPV and spotted on DBS cards. Following extraction and addition of isotopically labeled internal standards, samples were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. The method was validated according to regulatory recommendations, and the assay was evaluated in remnant samples from an HIV prevention trial in which paired DBS and plasma samples were collected. ResultsDBS CAB and RPV concentrations were linear from 25 to 20,000 ng/mL and 2–2500 ng/mL, respectively. Precision, accuracy, and matrix effect results were acceptable. DBS RPV demonstrated stability under all tested conditions; DBS CAB showed mean biases of − 23.5% when stored at room temperature for 36 days, and − 18.0% at 40 °C and 100% humidity for two days. DBS measurements for CAB and RPV were an average 54.0% and 14.1% lower, respectively, as compared to paired plasma samples. Derived conversion factors of 1.79 and 1.16 were applied to DBS CAB and RPV measurements, respectively, to estimate plasma concentrations. Estimated plasma CAB and RPV concentrations showed mean biases of 2.2% and 0.6%, respectively. In a CAB clinical trial, application of the conversion factor resulted in agreement between estimated plasma CAB concentrations from DBS and plasma CAB concentrations (y = 1.08x - 79.2, r = 0.932; mean bias of −3.2%; 95% CI: −48.2% to 41.9%). ConclusionsWe developed and validated a novel LC-MS/MS assay for the quantification of CAB and RPV from DBS, and identified conversion factors to estimate plasma concentrations from spotted blood.

Mediation of the Effect of Incarceration on Selling Sex Among Black Sexual Minority Men and Black Transgender Women in the HPTN 061 Study.

Incarceration among Black sexual minority men and Black transgender women (BSMM/BTW) is disproportionately high in the United States. Limited research has documented the disruptive effect of incarceration on sexual networks and sexual partnership exchange among BSMM/BTW. We estimate the influence of incarceration on selling sex and mediating pathways among 1169 BSMM/BTW enrolled in the HIV Prevention Trials Network (HPTN) 061 cohort to assess this relationship. Mediators investigated were social support, violence, illicit drug use, and distress due to experienced racism and homophobia. During the 6months following baseline, 14% of the cohort was incarcerated, including 24% of BTW. After adjustment, recent incarceration was associated with 1.57 (95% CI 1.02, 2.42) times the risk of subsequently selling sex. The hypothesized mediators together explained 25% of the relationship, with an indirect effect risk ratio of 1.09 (95% CI 0.97, 1.24). Our results document an association and call for more research investigating mechanisms.