Pharmacologic evaluation of delayed long-acting cabotegravir administration among cisgender women in HPTN 084.

HPTN 084 demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with daily oral tenofovir disoproxil fumarate-emtricitabine (F/TDF) for HIV prevention in women. CAB-LA (600 mg) or placebo injections were administered 4 weeks after an initial dose (loading dose) and every 2 months (Q2M) thereafter; this is the approved regimen. Participants experienced both loading dose and Q2M delays during the trial. CAB concentrations were evaluated before a delay, at the visit associated with the delay, and the visit after a delayed injection was administered. During the blinded phase of the trial, 194 participants randomized to CAB-LA experienced at least one injection delay. Plasma CAB concentrations were maintained above the 4× protein adjusted 90% inhibitory concentration (4× PA-IC90; protocol-specific threshold) for all loading dose and 98% of Q2M delays when injections were administered up to 6 weeks late. The feasibility of shifting to an every 3-month (Q3M) regimen in females was interrogated via simulation studies using a population pharmacokinetic model. Q3M injections in both CAB-naïve (with a loading dose) and previously CAB-exposed females were predicted to yield higher steady-state exposures than in males on the approved Q2M regimen. Although there is observed forgiveness following an isolated delayed CAB-LA injection and simulations suggest acceptable CAB-LA exposures in women with a 600 mg CAB-LA Q3M regimen, empirical efficacy of this regimen has not been established, and transitioning to this dosing schema is not recommended. Future pharmacokinetic bridging studies are aimed at evaluating higher dose CAB-LA formulations administered less frequently. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT03164564.

Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women.

BACKGROUND: Safe and effective long-acting injectable agents for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection are needed to increase the options for preventing HIV infection. METHODS: We conducted a randomized, double-blind, double-dummy, noninferiority trial to compare long-acting injectable cabotegravir (CAB-LA, an integrase strand-transfer inhibitor [INSTI]) at a dose of 600 mg, given intramuscularly every 8 weeks, with daily oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for the prevention of HIV infection in at-risk cisgender men who have sex with men (MSM) and in at-risk transgender women who have sex with men. Participants were randomly assigned (1:1) to receive one of the two regimens and were followed for 153 weeks. HIV testing and safety evaluations were performed. The primary end point was incident HIV infection. RESULTS: The intention-to-treat population included 4566 participants who underwent randomization; 570 (12.5%) identified as transgender women, and the median age was 26 years (interquartile range, 22 to 32). The trial was stopped early for efficacy on review of the results of the first preplanned interim end-point analysis. Among 1698 participants from the United States, 845 (49.8%) identified as Black. Incident HIV infection occurred in 52 participants: 13 in the cabotegravir group (incidence, 0.41 per 100 person-years) and 39 in the TDF-FTC group (incidence, 1.22 per 100 person-years) (hazard ratio, 0.34; 95% confidence interval, 0.18 to 0.62). The effect was consistent across prespecified subgroups. Injection-site reactions were reported in 81.4% of the participants in the cabotegravir group and in 31.3% of those in the TDF-FTC group. In the participants in whom HIV infection was diagnosed after exposure to CAB-LA, INSTI resistance and delays in the detection of HIV infection were noted. No safety concerns were identified. CONCLUSIONS: CAB-LA was superior to daily oral TDF-FTC in preventing HIV infection among MSM and transgender women. Strategies are needed to prevent INSTI resistance in cases of CAB-LA PrEP failure. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 083 ClinicalTrials.gov number, NCT02720094.).

Extended Analysis of HIV Infection in Cisgender Men and Transgender Women Who Have Sex with Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083.

HPTN 083 demonstrated that injectable cabotegravir (CAB) was superior to oral tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) for HIV prevention in cisgender men and transgender women who have sex with men. We previously analyzed 58 infections in the blinded phase of HPTN 083 (16 in the CAB arm and 42 in the TDF-FTC arm). This report describes 52 additional infections that occurred up to 1 year after study unblinding (18 in the CAB arm and 34 in the TDF-FTC arm). Retrospective testing included HIV testing, viral load testing, quantification of study drug concentrations, and drug resistance testing. The new CAB arm infections included 7 with CAB administration within 6 months of the first HIV-positive visit (2 with on-time injections, 3 with ≥1 delayed injection, and 2 who restarted CAB) and 11 with no recent CAB administration. Three cases had integrase strand transfer inhibitor (INSTI) resistance (2 with on-time injections and 1 who restarted CAB). Among 34 CAB infections analyzed to date, diagnosis delays and INSTI resistance were significantly more common in infections with CAB administration within 6 months of the first HIV-positive visit. This report further characterizes HIV infections in persons receiving CAB preexposure prophylaxis and helps define the impact of CAB on the detection of infection and the emergence of INSTI resistance.

Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

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

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.

HIV RNA Screening Reduces Integrase Strand Transfer Inhibitor Resistance Risk in Persons Receiving Long-Acting Cabotegravir for HIV Prevention.

BACKGROUND: The HPTN 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was superior to tenofovir-disoproxil fumarate/emtricitabine for human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). Integrase strand transfer inhibitor (INSTI) resistance-associated mutations (RAMs) were detected in some participants with HIV infection. We used a low viral load INSTI genotyping assay to evaluate the timing of emergence of INSTI RAMs and assessed whether HIV screening with a sensitive RNA assay would have detected HIV infection before INSTI resistance emerged. METHODS: Single-genome sequencing to detect INSTI RAMs was performed for samples with viral loads <500 copies/mL from 5 participants with previously identified INSTI RAMs and 2 with no prior genotyping results. RESULTS: Major INSTI RAMs were detected in all 7 cases. HIV RNA testing identified infection before major INSTI RAMs emerged in 4 cases and before additional major INSTI RAMs accumulated in 1 case. Most INSTI RAMs were detected early when the viral load was low and CAB concentration was high. CONCLUSIONS: When using CAB-LA PrEP, earlier detection of HIV infection with a sensitive RNA assay may allow for earlier treatment initiation with the potential to reduce INSTI resistance risk. Further studies are needed to evaluate the value and feasibility of HIV RNA testing with CAB-LA PrEP.

Multiple Infection and Human Immunodeficiency Virus Superinfection Among Persons who Inject Drugs in Indonesia and Ukraine.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 074 study evaluated an integrated human immunodeficiency virus (HIV) treatment and prevention strategy among persons who inject drugs (PWID) in Indonesia, Ukraine, and Vietnam. We previously detected multiple HIV infection in 3 of 7 (43%) of seroconverters with 3-8 HIV strains per person. In this report, we analyzed multiple HIV infection and HIV superinfection (SI) in the HPTN 074 cohort. METHODS: We analyzed samples from 70 participants in Indonesia and Ukraine who had viral load >400 copies/mL at enrollment and the final study visit (median follow-up, 2.5 years). HIV was characterized with Sanger sequencing, next-generation sequencing, and phylogenetic analysis. Additional methods were used to characterize a rare case of triple-variant SI. RESULTS: At enrollment, multiple infection was detected in only 3 of 58 (5.2%) participants with env sequence data. SI was detected in only 1 of 70 participants over 172.3 person-years of follow-up (SI incidence, 0.58/100 person-years [95% confidence interval, .015-3.2]). The SI case involved acquisition of 3 HIV strains with rapid selection of a strain with a single pol region cluster. CONCLUSIONS: These data from a large cohort of PWID suggest that intrahost viral selection and other factors may lead to underestimation of the frequency of multiple HIV infection and SI events.

Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084.

BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.

Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

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.

Association between drug use and ART use among people living with HIV who inject drugs in Vietnam, Ukraine and Indonesia: results from HPTN 074.

Background and objective: Drug use type and frequency may affect Anti-Retroviral Therapy (ART) uptake for HIV-infected people who inject drugs (PWID). This paper assesses the association between self-reported baseline drug use and ART among HIV-infected PWID in Indonesia, Ukraine and Vietnam. Methods: Data on self-reported baseline drug use and ART among HIV-infected PWID at the 26- and 52-week follow-ups were extracted from the HIV Prevention Trials Network (HPTN) 074, a randomized, controlled vanguard study to facilitate HIV treatment for PWID in Indonesia, Ukraine, and Vietnam. Multivariable logistic regression models were fit by study site and the whole HPTN 074 sample, using a 0.5 type I error rate. Results: The response rate were 83.3% and 77.0% at 26th and 52th weeks. At 26-week, baseline use of over one non-opiate/non-stimulant drug was associated with lower odds of ART use among Indonesian participants (OR = 0.21, 95%CI: 0.05-0.82); and baseline injecting drugs for over 20 days in the previous month was associated with lower odds of ART use among all HPTN 074 sample (OR = 0.59, 95% CI: 0.36-0.97). Conclusion: The association of a specific drug use pattern with later ART uptake implies the importance of medication-assisted treatment to enhance ART uptake and adherence among participants.

Characterization of Human Immunodeficiency Virus (HIV) Infection in Cisgender Men and Transgender Women Who Have Sex With Men Receiving Injectable Cabotegravir for HIV Prevention: HPTN 083.

BACKGROUND: The HIV Prevention Trials Network (HPTN) 083 trial demonstrated that long-acting cabotegravir (CAB-LA) was more effective than tenofovir disoproxil fumarate-emtricitabine (TDF/FTC) in preventing human immunodeficiency virus (HIV) in cisgender men and transgender women who have sex with men. We characterized HIV infections that occurred in the blinded phase of HPTN 083. METHODS: Retrospective testing included HIV testing, viral load testing, quantification of study drugs, and HIV drug resistance testing. RESULTS: Fifty-eight infections were evaluated, including 51 incident infections (12 in CAB arm and 39 in TDF/FTC arm). In many cases (5 in CAB arm and 37 in TDF/FTC arm), infection was associated with low or unquantifiable study drug concentrations. In 4 cases, infection occurred with on-time CAB-LA injections and expected plasma CAB concentrations. CAB exposure was associated with prolonged viral suppression and delayed antibody expression. In some cases, delayed HIV diagnosis resulted in CAB provision to participants with undetected infection, delayed antiretroviral therapy, and emergence of drug resistance; most of these infections would have been detected earlier with viral load testing. CONCLUSIONS: Early detection of HIV infection and prompt antiretroviral therapy initiation could improve clinical outcomes in persons who become infected despite CAB-LA prophylaxis. Further studies are needed to elucidate the correlates of HIV protection in persons receiving CAB-LA.

Exploring individual-level barriers to HIV medication adherence among men who have sex with men in the HIV Prevention Trials Network (HPTN 065) study.

African-American men who have sex with men (MSM) with HIV are more likely to have unsuppressed viral load than other racial/ethnic groups. HPTN 065 Study, completed in 2015, consisted of five interconnected study components conducted at clinics in Bronx, New York and Washington, D.C. Participants completed surveys with questions related to socio-demographic factors and individual-level HIV medication adherence barriers, such as forgetting doses or fear of taking medications in front of others. Descriptive analyses and ordinal logistic regression with robust standard errors were conducted. Fifty-seven per cent of participants (N = 359) were African-American (57.1%) and roughly 40% had no more than a high school education. Mean age was 48 years. Overall, MSM with viral load suppression identified fewer individual-level barriers to adherence (p < .01) and individuals with depressive symptoms identified a greater number of barriers to adherence (p < .01). Compared to African-Americans, white MSM had a lower likelihood of identifying barriers to adherence (p < .05). Findings suggest that individual-level barriers to HIV medication adherence are common among MSM, irrespective of time since diagnosis and viral suppression. Race-specific interventions which address intersectional stigma are needed to improve health outcomes among African-American MSM, who bear much of the burden of poor HIV outcomes in the United States.

Examining stigma, social support, and gender differences in unsuppressed HIV viral load among participants in HPTN 065.

Successful navigation of the HIV care continuum is necessary to maintain viral suppression. We explored gender-stratified correlates of being virally unsuppressed in the Prevention for Positives (P4P) component of HPTN 065. The outcome of interest was unsuppressed viral load (> 40 copies/mL) among individuals already living with HIV. Correlates included medication adherence factors, social support and stigma. Logistic regression models were stratified by gender (N = 673). Men-specific correlates of being virally unsuppressed included opposite-sex partners, older age and HIV disclosure stigma. Women-specific correlates included time since diagnosis, and personal-level barriers to medication adherence. When more individuals knew about their HIV status, women had over twice the likelihood of being virally unsuppressed; no such association was seen among men. Additionally, higher levels of social support were not associated with viral suppression among women. Interventions should consider gender-specific approaches to engaging social support in de-stigmatization of HIV and promotion of medication adherence and subsequent viral suppression.

A scalable, integrated intervention to engage people who inject drugs in HIV care and medication-assisted treatment (HPTN 074): a randomised, controlled phase 3 feasibility and efficacy study.

BACKGROUND: People who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use. METHODS: This randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants. FINDINGS: Between Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded. INTERPRETATION: This vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered. FUNDING: US National Institutes of Health.

Use of Antiretroviral Drug Testing to Assess the Accuracy of Self-reported Data from HIV-Infected People Who Inject Drugs.

We used antiretroviral (ARV) drug testing to evaluate the accuracy of self-reported data for HIV status and antiretroviral treatment (ART) among people who inject drugs enrolled in an HIV prevention trial. ARV drugs were detected in enrollment samples from 72/482 = 14.9% HIV-infected participants (39/52 = 75.0% who reported being on ART; 33/430 = 7.7% who reported not being on ART). Overall, 213/482 = 44.2% participants indicated that they were not aware of their HIV-positive status prior to study entry; of those, 30 had ARV drugs detected at enrollment, including 15 who also had ARV drugs detected at the screening visit. These participants were likely aware of their HIV-positive status at study entry but did not report this to study staff. This study shows that self-reported data on HIV testing history and ART may not be accurate and that ARV drug testing can help identify persons who are aware of their HIV-positive status and are on ART.

Expanding Hospital Human Immunodeficiency Virus Testing in the Bronx, New York and Washington, District of Columbia: Results From the HPTN 065 Study.

Background: Human immunodeficiency virus (HIV) testing is critical for both HIV treatment and prevention. Expanding testing in hospital settings can identify undiagnosed HIV infections. Methods: To evaluate the feasibility of universally offering HIV testing during emergency department (ED) visits and inpatient admissions, 9 hospitals in the Bronx, New York and 7 in Washington, District of Columbia (DC) undertook efforts to offer HIV testing routinely. Outcomes included the percentage of encounters with an HIV test, the change from year 1 to year 3, and the percentages of tests that were HIV-positive and new diagnoses. Results: From 1 February 2011 to 31 January 2014, HIV tests were conducted during 6.5% of 1621016 ED visits and 13.0% of 361745 inpatient admissions in Bronx hospitals and 13.8% of 729172 ED visits and 22.0% of 150655 inpatient admissions in DC. From year 1 to year 3, testing was stable in the Bronx (ED visits: 6.6% to 6.9%; inpatient admissions: 13.0% to 13.6%), but increased in DC (ED visits: 11.9% to 15.8%; inpatient admissions: 19.0% to 23.9%). In the Bronx, 0.4% (408) of ED HIV tests were positive and 0.3% (277) were new diagnoses; 1.8% (828) of inpatient tests were positive and 0.5% (244) were new diagnoses. In DC, 0.6% (618) of ED tests were positive and 0.4% (404) were new diagnoses; 4.9% (1349) of inpatient tests were positive and 0.7% (189) were new diagnoses. Conclusions: Hospitals consistently identified previously undiagnosed HIV infections, but universal offer of HIV testing proved elusive.

Social Network Factors as Correlates and Predictors of High Depressive Symptoms Among Black Men Who Have Sex with Men in HPTN 061.

Depression is linked to a range of poor HIV-related health outcomes. Minorities and men who have sex with men (MSM), suffer from high rates of depression. The current study examined the relationship between depressive symptoms and social network characteristics among community-recruited Black MSM in HPTN 061 from 6 US cities. A social network inventory was administer at baseline and depression was assessed with the CES-D at baseline, 6, and 12-months. At baseline, which included 1167 HIV negative and 348 HIV positive participants, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms. In longitudinal mixed models, size of emotional, financial, and medical support networks were significantly associated with fewer depressive symptoms as was the number of network members seen weekly. In the multivariate analyses, size of medical appointment network remained statistically significant (aOR 0.89, CI 0.81-0.98). These findings highlight the importance of network support of medical care on depression and suggest the value of support mobilization.

Delivering integrated strategies from a mobile unit to address the intertwining epidemics of HIV and addiction in people who inject drugs: the HPTN 094 randomized controlled trial protocol (the INTEGRA Study).

BACKGROUND: Persons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations. METHODS: HPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization. DISCUSSION: This trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

HIV DNA Levels in Persons Who Acquired HIV in the Setting of Long-Acting Cabotegravir for HIV Prevention: Analysis of Cases from HPTN 083 and 084.

We evaluated HIV DNA levels in individuals who received long-acting cabotegravir (CAB-LA) or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) pre-exposure prophylaxis in the HPTN 083 and 084 trials and had HIV DNA testing performed to help determine HIV status. HIV DNA testing was performed using peripheral blood mononuclear cell (PBMC) samples collected after a reactive HIV test was obtained at a study site. DNA was quantified using droplet digital PCR (lower limit of detection [LLOD]: 4.09 copies/million PBMCs). Final HIV status and the timing of the first HIV-positive visit were determined by an independent adjudication committee based on HIV test results from real-time site testing and retrospective testing at a centralized laboratory. HIV DNA testing was performed for 133 participants [21 HIV-positive (7 CAB-LA arm, 14 TDF/FTC arm) and 112 HIV-negative; 1-6 tests/person]. For persons with HIV, the time between the first HIV-positive visit and collection of the first sample for DNA testing was a median of 81 days for those receiving CAB-LA (range 41-246) and 11 days for those receiving TDF/FTC (range 3-127). Four (57.1%) of the seven CAB-LA cases with infection had a low initial DNA result [three detected

Estimating the impact of HIV PrEP regimens containing long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate/emtricitabine among men who have sex with men in the United States: a mathematical modelling study for HPTN 083.

Background: The HPTN 083 trial demonstrated superiority of HIV pre-exposure prophylaxis (PrEP) containing long-acting injectable cabotegravir (CAB) to daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) among men who have sex with men (MSM). We compared the potential population-level impact of TDF/FTC and CAB among MSM in Atlanta, Georgia. Methods: An MSM HIV transmission model was calibrated to Atlanta-specific data on HIV prevalence and PrEP usage (percentage of uninfected MSM on PrEP), assuming only PrEP-indicated MSM used PrEP. CAB effectiveness (efficacy × adherence) of 91% was estimated using data from HPTN 083 and previous TDF/FTC trials. We estimated HIV infections averted over 5/10 years if TDF/FTC use were maintained, or if all TDF/FTC users switched to CAB in January 2022 (vs. no PrEP or continued TDF/FTC use). CAB scenarios with 10%/20% more users were also considered. Progress towards Ending the HIV Epidemic (EHE) goals (75%/90% fewer HIV infections in 2025/2030 vs. 2017) was estimated. Findings: We predicted TDF/FTC at current usage (∼28%) would avert 36.3% of new HIV infections (95% credible interval 25.6-48.7%) among all Atlanta MSM over 2022-2026 vs. no PrEP. Switching to CAB with similar usage may prevent 44.6% (33.2-56.6%) infections vs. no PrEP and 11.9% (5.2-20.2%) infections vs. continued TDF/FTC. Increasing CAB usage 20% could increase the incremental impact over TDF/FTC to 30.0% over 2022-2026, getting ∼60% towards reaching EHE goals (47%/54% fewer infections in 2025/2030). Reaching the 2030 EHE goal would require 93% CAB usage. Interpretation: If CAB effectiveness were like HPTN 083, CAB could prevent more infections than TDF/FTC at similar usage. Increased CAB usage could contribute substantially towards reaching EHE goals, but the usage required to meet EHE goals is unrealistic. Funding: NIH, MRC.