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IntroductionRandomized trials of new agents for HIV pre-exposure prophylaxis (PrEP) compare against emtricitabine and tenofovir disoproxil fumarate (F/TDF), without a placebo group. We used the well-characterized adherence-efficacy relationship for F/TDF to back-calculate the (non-PrEP) counterfactual background HIV incidence (bHIV) in a randomized trial of a novel PrEP agent and estimate comparative efficacy (to counterfactual bHIV).MethodsThe DISCOVER trial (ClinicalTrials.gov: NCT02842086) randomized 5387 men who have sex with men (MSM) and transgender women who have sex with men and demonstrated non-inferiority of emtricitabine and tenofovir alafenamide (F/TAF) to F/TDF (HIV incidence rate ratio [IRR] 0·47, 95% CI: 0·19 to 1.15). Tenofovir diphosphate (TFV-DP) levels in dried blood spots (DBS) were assessed for all diagnosed with HIV and in a random 10% of the cohort. We used a Bayesian model with a diffuse prior distribution, derived from established data relating tenofovir diphosphate levels to HIV prevention efficacy. This prior, combined with the F/TDF seroconversion rate and tenofovir diphosphate levels in DISCOVER, yielded Bayesian inferences on the counterfactual bHIV.ResultsThere were six versus 11 postbaseline HIV infections (0.14 vs. 0.25/100 person-years [PY]) on F/TAF and F/TDF respectively. Of the 11 on F/TDF, 10 had low, none had medium and one had high tenofovir diphosphate levels; among HIV-negative controls, 5% of the person-time years had low, 9% had medium and 86% had high TFV-DP levels. A non-informative prior distribution for counterfactual bHIV, combined with the prior for TFV-DP level-efficacy relationship, yielded a posterior counterfactual bHIV of 3·4 infections/100 PY (0.80 Bayesian credible interval [CrI] 1·9 to 5·9), which suggests a median HIV efficacy of 96% (0.95 CrI [88% to 99%]) for F/TAF and 93% (0.95 CrI [87% to 96%]) for F/TDF compared to bHIV.ConclusionsBased on the established connection of drug concentrations to PrEP prevention efficacy, a Bayesian framework can be used to estimate a synthetic non-PrEP control group in randomized, active-controlled PrEP trials that include a F/TDF-comparator group.

BackgroundBecause tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection.MethodsPlasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial.ResultsWhile plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine.ConclusionsWe found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.

Background While noninferiority of tenofovir alafenamide and emtricitabine (TAF/FTC) as preexposure prophylaxis (PrEP) for the prevention of human immunodeficiency virus (HIV) has been shown, interest remains in its efficacy relative to placebo. We estimate the efficacy of TAF/FTC PrEP versus placebo for the prevention of HIV infection. Methods We used data from the DISCOVER and iPrEx trials to compare TAF/FTC to placebo. DISCOVER was a noninferiority trial conducted from 2016 to 2017. iPrEx was a placebo-controlled trial conducted from 2007 to 2009. Inverse probability weights were used to standardize the iPrEx participants to the distribution of demographics and risk factors in the DISCOVER trial. To check the comparison, we evaluated whether risk of HIV infection in the shared tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) arms was similar. Results Notable differences in demographics and risk factors occurred between trials. After standardization, the difference in risk of HIV infection between the TDF/FTC arms was near zero. The risk of HIV with TAF/FTC was 5.8 percentage points lower (95% confidence interval [CI], −2.0% to −9.6%) or 12.5-fold lower (95% CI,.02 to.31) than placebo standardized to the DISCOVER population. Conclusions There was a reduction in HIV infection with TAF/FTC versus placebo across 96 weeks of follow-up. Clinical Trials Registration NCT02842086 and NCT00458393. [ABSTRACT FROM AUTHOR]

ImportanceSubstance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates.ObjectiveTo assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients.Design, setting, and participantsFrom July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months.InterventionsPatient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to $1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment.Main outcomes and measuresThe primary outcome was HIV viral suppression (≤200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up.ResultsOf 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34.1%) in the usual-treatment group experienced treatment success compared with 89 of 249 patients (35.7%) in the navigation-only group for a treatment difference of 1.6% (95% CI, -6.8% to 10.0%; P = .80) and compared with 98 of 254 patients (38.6%) in the navigation-plus-incentives group for a treatment difference of 4.5% (95% CI -4.0% to 12.8%; P = .68). The treatment difference between the navigation-only and the navigation-plus-incentives group was -2.8% (95% CI, -11.3% to 5.6%; P = .68).Conclusions and relevanceAmong hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months vs treatment as usual. These findings do not support these interventions in this setting.Trial registrationclinicaltrials.gov Identifier: NCT01612169.

Introduction: New HIV diagnoses have fallen in the past decade due to increased HIV testing, earlier diagnosis, earlier antiretroviral treatment, improved linkage to care and engagement in care, and the recent increased uptake of pre-exposure prophylaxis (PrEP). We propose a novel method to compute the rate of new HIV diagnoses at the Metropolitan Statistical Area (MSA) level in the US to support the evaluation of comprehensive treatment and prevention efforts over time. Methods: The number of new HIV diagnoses, number of individuals with a PrEP indication and aggregated person-time exposed to PrEP during the years 2012 to 2017 were used to compute a new HIV diagnosis rate for people at risk of HIV excluding those already on PrEP for the 105 MSAs in the US with published HIV surveillance data. In our calculation of person-time with a PrEP indication, time-at-risk excluded time on PrEP and time after an HIV diagnosis. We used a multivariate Poisson regression model to estimate HIV diagnosis rates by year and location. Results: From 2012 to 2017, the aggregate HIV diagnoses rate among high-risk individuals with an indication for PrEP in the 105 MSAs decreased from 4.14 per 100 person-years (PY) (95% CI 4.10 to 4.19) to 3.26 per 100 PY (95% CI 3.22 to 3.30). For the 25 US MSAs that overlapped with an ongoing large randomized clinical trial of PrEP in men who have sex with men (MSM), the HIV diagnosis rate from 2012 to 2017 decreased from 4.86 per 100 PY (95% CI 4.80 to 4.93) to 3.61 per 100 PY (95% CI 3.56 to 3.66), a decline that was more rapid than in non-study MSAs (IRR for trial site 1.19, 95% CI 1.18 to 1.20). Conclusions: We propose a model to estimate the background HIV diagnosis rate in people at risk for HIV and with a PrEP indication in US MSAs (excluding those on PrEP) using publically available surveillance data which can evaluate trends over time. Data generated using this methodology could be used by policy makers and local HIV prevention specialists to evaluate and monitor their prevention efforts for the population at risk in their communities. Keywords: modelling; PrEP; HIV prevention; public health; HIV epidemiology; HIV prevention trials, 1 | INTRODUCTION New HIV diagnoses have fallen over the past decade due to the following: (1) increased HIV testing, (2) earlier diagnosis of HIV infection, (3) earlier antiretroviral treatment [...]

Purpose: Transgender women are disproportionately affected by HIV and are underutilizing preexposure prophylaxis (PrEP). The lower uptake of PrEP by transgender women may be, in part, owing to the perception that taking PrEP may lower the efficacy of gender-affirming hormone therapy (GAHT) or to provider concerns that GAHT may lower the efficacy of PrEP. Methods: DISCOVER was a randomized, double-blind, noninferiority trial comparing emtricitabine (FTC, F) and tenofovir alafenamide (F/TAF) versus emtricitabine and tenofovir disoproxil fumarate (F/TDF) as PrEP among transgender women and cisgender men who have sex with men (MSM). This nested substudy of the DISCOVER trial compared the exposure of the active intracellular metabolites of FTC and tenofovir (TFV), FTC triphosphate (FTC-TP) and TFV diphosphate (TFV-DP), in peripheral blood mononuclear cells (PBMC) among transgender women receiving GAHT versus MSM within the F/TAF and F/TDF groups. Results: Our results demonstrate that TFV-DP and FTC-TP levels in PBMC were comparable between transgender women on GAHT and MSM receiving F/TAF, and between transgender women on GAHT and MSM receiving F/TDF. TFV-DP concentrations remained above the EC90 of 40 fmol/106 cells across all groups. No clinically significant drug–drug interactions of GAHT were observed with either F/TAF or F/TDF in this subanalysis. Conclusions: These findings are consistent with the clinical pharmacology of GAHT, FTC, TDF, and TAF reported in previous studies, and support the continued use of F/TAF and F/TDF for PrEP in transgender women. Clinicaltrials.gov registration number: NCT02842086. [ABSTRACT FROM AUTHOR]

Standard‐of‐care HIV pre‐exposure prophylaxis (PrEP) is highly efficacious, but uptake of and persistence on a daily oral pill is low in many settings. Evaluation of alternate PrEP products will require innovation to avoid the unpractically large sample sizes in noninferiority trials. We propose estimating HIV incidence in people not on PrEP as an external counterfactual to which on‐PrEP incidence in trial subjects can be compared. HIV recent infection testing algorithms (RITAs), such as the limiting antigen avidity assay plus viral load used on specimens from untreated HIV positive people identified during screening, is one possible approach. Its feasibility is partly dependent on the sample size needed to ensure adequate power, which is impacted by RITA performance, the number of recent infections identified, the expected efficacy of the intervention, and other factors. Screening sample sizes to support detection of an 80% reduction in incidence for 3 key populations are more modest, and comparable to the number of participants in recent phase III PrEP trials. Sample sizes would be significantly larger in populations with lower incidence, where the false recency rate is higher or if PrEP efficacy is expected to be lower. Our proposed counterfactual approach appears to be feasible, offers high statistical power, and is nearly contemporaneous with the on‐PrEP population. It will be important to monitor the performance of this approach during new product development for HIV prevention. If successful, it could be a model for preventive HIV vaccines and prevention of other infectious diseases. [ABSTRACT FROM AUTHOR]

The advent of antiretroviral therapy and biomedical prevention has transformed HIV from a fatal disease to a chronic condition where people with HIV (PWH) can live long, healthy lives. Yet, there remains a subset of PWH left behind from receiving timely HIV diagnosis and care. Striking inequalities in access to resources, socioeconomic disparities, and social forces have prevented certain PWH from achieving significant health and quality of life (QOL) improvements experienced by those who secure life-saving treatment. For decades, our multidisciplinary team developed a collaborative scientific portfolio focused on helping those left behind advance along the HIV continuum of care. In this manuscript, we highlight some of our U.S.-based social interventions that have addressed the disparities and sub-optimal QOL encountered by overlooked populations with the goal of achieving timely HIV diagnosis, care, and sustained viral suppression. We then outline our many lessons learned and vision for the next crucial steps ahead. [ABSTRACT FROM AUTHOR]