Brett Hanscom

Background: Long-acting antiretroviral therapy may improve adherence and decrease stigma, yet affordable combination formulations for global usage are lacking. The TLC-ART program engineered an injectable 3-drug combination in a novel nanoparticle (DcNP) product “TLC-ART 101,” composed of lopinavir (LPV), ritonavir (RTV), and tenofovir (TVF) and 2 lipid excipients. We report safety and pharmacokinetics from this first-in-human study. Methods: Three dose cohorts of people without human immunodeficiency virus (HIV) received a single subcutaneous dose of 1.5, 3.0, or 4.0 mL in an adaptive trial of up to 64 days. LPV, RTV, and TFV were measured over time in plasma, peripheral blood mononuclear cells (PBMCs), and lymph nodes. Results: All 12 participants completed the study. One participant experienced anaphylaxis, and 4 had nonserious hypersensitivity events (rash, lip swelling, generalized pruritus). All participants had grade 1–2 injection-site reactions. At the highest dose, median LPV half-life (T1/2) was 17 days, and LPV was detectable through 2 months in most participants. RTV T1/2 was 12 hours. Plasma TFV T1/2 was 3.5 days; TFV diphosphate was detected intracellularly through 14 days. Total exposure (area under the curve) was higher in PBMCs versus plasma for all 3 drugs. Conclusions: The first human application of this novel HIV DcNP resulted in detection of LPV through 2 months and TFV up to 4 days in plasma, and no meaningful prolongation of RTV. Systemic hypersensitivity was common, and although IgE elevation was not observed, additional mechanistic understanding is required prior to further development of this DcNP pipeline. Clinical Trials Registration: NCT05850728.

Objectives: To describe HPTN 094 study’s peer navigation (PN) intervention, implemented in 5 urban US cities among people who inject drugs (PWID) at risk for or living with HIV, including guiding theories, core components, navigator training, available services, implementation challenges, and implications for future PN intervention research dissemination. Methods: This 2-arm, randomized, open-label study assessed outcomes for PWID receiving integrated care services delivered in a mobile health unit that provided medication for opioid use disorder (MOUD), HIV prevention/treatment, and other health care in addition to PN to community services compared with PN to community services alone. Participants were PWID with opioid use disorder (OUD) not receiving MOUD and were either at risk for HIV or living with HIV. The PN model was grounded in 5 complementary theories addressing individual, interpersonal, social, systemic, and structural determinants of care. Variables used to measure PN intervention utility were number of sessions attended, session length, session topics, and in-person versus remote navigation sessions. Results: Across study sites, participants without HIV (PWOH; n = 409) completed 3390 PN sessions and participants with HIV (PWH; n = 38) completed 365 PN sessions; the median number of sessions per participant was 6 in both groups. Most sessions were conducted in person and commonly addressed MOUD, HIV prevention or HIV care, and other medical or social service needs. These findings support the feasibility of delivering a flexible, theory-informed PN model for urban PWID and help characterize how peer navigation was used to address substance use, HIV, and broader service needs within HPTN 094. Conclusions: The PN model is acceptable with urban PWID and potentially for people with other public health concerns in underserved communities. The findings have implications for future research examining the effectiveness and dissemination of the PN intervention.

Background: Pre-exposure prophylaxis (PrEP) is highly effective for human immunodeficiency virus (HIV) prevention. However, breakthrough infections can occur, even with optimal adherence. We evaluated the performance of prospective HIV ribonucleic acid (RNA) screening in cisgender men and transgender women who have sex with men using long-acting injectable cabotegravir (CAB-LA) PrEP in HIV Prevention Trials Network (HPTN) 083. Methods: In the Open Label Extension of HPTN 083, sites performed HIV rapid antigen/antibody (Ag/Ab) and RNA testing at each visit. Results from site testing and retrospective HIV testing were used to determine final HIV status and identify the first HIV-positive visit. Results: HIV RNA screening was associated with fewer diagnostic delays (7% vs 47% of cases, P = .02) and earlier treatment initiation (median 15 vs 62 days, P = .02). Drug resistance was less frequent with RNA screening (15% vs 31% of cases, P = .22). Five cases were first detected with RNA testing only. Sensitivity and specificity of RNA testing were 93% (95% CI: 76, 99) and 99.92% (95% CI: 99.88, 99.95), respectively. However, positive predictive value (PPV) was low overall (55%; 95% CI: 40, 69) and was lower if CAB-LA was administered <6 months earlier (29%; 95% CI: 13, 49). Some false-positive RNA test results led to delay or discontinuation of CAB-LA injections. Conclusions: HIV RNA screening improved clinical outcomes in the setting of CAB-LA PrEP, but the PPV for RNA screening was low which could compromise patient care.

Background: The HIV Prevention Trials Network (HPTN) 083 Trial demonstrated the superiority of long-acting, injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis among cisgender men (MSM) and transgender women (TGW) who have sex with men. Plasma CAB concentrations associated with HIV protection in humans are unknown. Methods: We conducted a nested case-control study to investigate the association between plasma CAB concentrations and HIV risk. Plasma CAB concentrations were estimated for participants with confirmed HIV and for HIV-negative controls, who were matched on region, gender, and race. The window of HIV acquisition for cases was defined as the time between the last HIV-negative visit and the first HIV-positive visit; this window was used to evaluate CAB exposure for cases and their matched controls. Participants were categorized by the minimum estimated CAB concentration (CABmin) during this window relative to the protein-adjusted 90% CAB inhibitory concentration (1× PA-IC90) and 4× PA-IC90. HIV risk was modeled using conditional logistic regression. Results: Plasma CABmin was ≥4× PA-IC90 in 26% of HIV-positive cases, compared with 76% of matched controls. Plasma CABmin ≥4× PA-IC90 was associated with a 93% reduction in risk of HIV acquisition compared with CABmin <1× PA-IC90 (95% CI: 76%, 98%, P < .001). CABmin between 1× and 4× PA-IC90 had an estimated risk reduction of 79% compared with CABmin <1× PA-IC90 (95% CI: −19%, 96%, P = .07). Conclusions: Consistent plasma CAB concentrations ≥4× PA-IC90 were estimated to provide 93% protection against HIV in MSM and TGW.

In a randomized clinical trial, pre-exposure prophylaxis (PrEP) with long-acting cabotegravir (CAB-LA) had a better bone safety profile than tenofovir disoproxil fumarate–emtricitabine (TDF-FTC) over 105 weeks. For individuals with low bone mineral density or other fracture risk factors, CAB-LA PrEP should be considered over TDF-based PrEP. Clinical Trials Registration. clinicaltrials.gov (NCT02720094).

Background: Sexually transmitted infections (STIs) have been shown to facilitate human immunodeficiency virus (HIV) transmission and acquisition. HPTN 083, a global clinical trial, demonstrated superiority of long-acting cabotegravir (CAB-LA) versus daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV prevention among transgender women and cisgender men who have sex with men. This analysis assessed whether CAB-LA maintained protective efficacy when bacterial STIs (syphilis, rectal/urethral gonorrhea, and chlamydia) were present. Methods: STI events per 100 person-years were calculated, including by subgroups (age, race/ethnicity, gender, education, treatment arm, drug use, alcohol use, region/country, condom usage, partner number, marital status, baseline STI). Association between baseline factors and STI incidence was modeled using Poisson regression. Cox proportional hazards modeling with STI status as a time-varying covariate was used to evaluate potential interactions between STI status and the relative efficacy of CAB-LA versus TDF/FTC. Findings: Among 3859 participants, overall STI incidence rate was 50.7 infections/100 person-years. STIs were diagnosed in 1562 (40.5%) participants; 79% of STIs occurred in 25% of the participants. STI incidence was not different by preexposure prophylaxis arm. In the final multivariable model, age, region, race, education level, marital status, and baseline STI were associated with incident STI (P < .05). HIV incidence was lower with CAB-LA versus TDF/FTC with or without STIs (hazard ratios 0.37 and 0.31, respectively), with no significant interaction between STIs and the HR for HIV incidence (P = .75). Conclusions: In a large preexposure prophylaxis trial with high STI incidence, CAB-LA maintained robust protective efficacy relative to TDF/FTC in the setting of bacterial STIs.

Introduction: The 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. Methods: The 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. Results: The 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]). Conclusions: The 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.

Background/Aims: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy.Methods: Here we describe some unique aspects of the trial’s design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring.Results: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control.Conclusions: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small—as will often be the case—nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

Introduction: People who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention.Methods: We present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two‐arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV‐positive index and their HIV‐negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours.Results: The majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self‐reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test – Alcohol Consumption Questions (AUDIT‐C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions.Conclusions: While regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the ‘constancy’ assumption. If the constancy assumption fails, decisions based on the chosen non-inferiority margin may be incorrect, and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. When there are strong, observable predictors of constancy, such as dosing and adherence to the active-control product, we can specify conditions where the constancy assumption will likely fail. We propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population characteristics. We describe a pre-specified method, using baseline characteristics or post-baseline predictors in the active-control arm, to adapt the non-inferiority margin at the end of the study if constancy is violated. Adaptive margins can help adjust for constancy violations that will inevitably occur in real clinical trials, while maintaining pre-specified levels of Type I error and power.