Long-acting cabotegravir pharmacokinetics with and without oral lead-in for HIV PrEP.

Long-acting cabotegravir is approved for pre-exposure prophylaxis and combination HIV treatment, both initiated with optional short-term oral lead-in (OLI). We evaluated the impact of OLI on long-acting cabotegravir pharmacokinetics. Cabotegravir plasma concentrations were compared between HIV-positive participants initiating injections with (n = 278) or without (n = 110) OLI in phase III treatment study FLAIR and in HIV-negative participants using OLI (n = 263) in pivotal pre-exposure prophylaxis studies HPTN 083 and HPTN 084. Cabotegravir pharmacokinetic profiles were simulated in three populations (assigned-male-at-birth, 50%-assigned-female-at-birth, and assigned-female-at-birth) under three scenarios: first injection given (A) 1 or (B) 3 days after final OLI dose (OLI-injection gap) or (C) without OLI. The PK objective was 80% of participants achieving 4× in vitro protein-adjusted 90% maximal inhibitory concentration (PA-IC90) and 50% achieving 8× PA-IC90. Observed trough concentrations (Cτ) were similar with and without OLI (P > 0.3). With a 3-day OLI-injection gap, simulated pre-injection Cτ remained above PK objective. Approximately 1-2 weeks after the first injection, simulated PK profiles became nearly identical among all scenarios. Without OLI, it was predicted that 80% of participants achieve 4× PA-IC90 in 1.2, 1.8, and 2.8 days after the first injection in each population, respectively, and 50% achieve 8× PA-IC90 in 1.4, 2.1, and 3.8 days, respectively. Observed long-acting cabotegravir exposure was similar with or without OLI, supporting optional OLI use. Cabotegravir exposure was predicted to remain above PK objective for OLI-injection gaps of ≤3 days and rapidly achieve PK objective after first injection without OLI. Findings are consistent between assigned-male-at-birth and assigned-female-at-birth populations.This study is registered with ClinicalTrials.gov as NCT02720094.

HPTN 083-02: factors influencing adherence to injectable PrEP and retention in an injectable PrEP study.

INTRODUCTION: HPTN 083 demonstrated the superiority of long-acting cabotegravir (CAB-LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) as pre-exposure prophylaxis (PrEP) among cisgender men and transgender women who have sex with men (MSM/TGW). HPTN 083 provided the first opportunity to understand experiences with injectable PrEP in a clinical trial. METHODS: Participants from two US sites (Chicago, IL and Atlanta, GA) and one international site (Rio de Janeiro, Brazil) were purposively sampled for individual qualitative interviews (N = 40), between November 2019 and March 2020, to explore trial experiences, barriers to adherence and other factors that may have impacted study implementation or outcomes. The blinded phase ended early due to efficacy; this analysis includes interviews conducted prior to unblinding with three groups defined by adherence (i.e. injection visit attendance): adherent (n = 27), non-adherent (n = 12) and early discontinuers (n = 1). Data were organized using NVivo software and analysed using content analysis. RESULTS: Participants (mean age: 27) were primarily cisgender MSM (90%) and Black/African American (60%). Reasons for trial enrolment and PrEP use included a preference for using HIV prevention medication versus treatment in the event of HIV acquisition; the ability to enhance health via study-related education and services; access to a novel, convenient HIV prevention product at no cost; and contributing to MSM/TGW communities through research. Participants contrasted positive experiences with study staff with their routine clinical care, and emphasized increased scheduling flexibility, thorough communication, non-judgemental counselling and open, affirming environments (e.g. compassion, less stigma) as adherence facilitators. Injection experiences were positive overall; some described early injection-related anxiety, which abated with time and when given some measure of control (e.g. pre-injection countdown), and minimal injection site discomfort. Some concerns and misperceptions about injectable PrEP were reported. Barriers to adherence, across all adherence categories, included structural factors (e.g. financial constraints, travel) and competing demands (e.g. work schedules). CONCLUSIONS: Respondents viewed injectable PrEP trial participation as a positive experience and a means of enhancing wellbeing. Study site flexibility and affirming clinic environments, inclusive of non-judgemental counselling, were key facilitators of adherence. To support injection persistence, interventions that address structural barriers and promote flexible means of injection delivery may be most effective.

HIV-1 Incidence, Adherence, and Drug Resistance in Individuals Taking Daily Emtricitabine/Tenofovir Disoproxil Fumarate for HIV-1 Pre-Exposure Prophylaxis: Pooled Analysis From 72 Global Studies.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) with emtricitabine/tenofovir disoproxil fumarate (F/TDF) has high efficacy against HIV-1 acquisition. Seventy-two prospective studies of daily oral F/TDF PrEP were conducted to evaluate HIV-1 incidence, drug resistance, adherence, and bone and renal safety in diverse settings. METHODS: HIV-1 incidence was calculated from incident HIV-1 diagnoses after PrEP initiation and within 60 days of discontinuation. Tenofovir concentration in dried blood spots (DBS), drug resistance, and bone/renal safety indicators were evaluated in a subset of studies. RESULTS: Among 17,274 participants, there were 101 cases with new HIV-1 diagnosis (0.77 per 100 person-years; 95% CI 0.63-0.94). In 78 cases with resistance data, 18 (23%) had M184I or V, one (1.3%) had K65R, and three (3.8%) had both mutations. In 54 cases with tenofovir concentration data from DBS, 45 (83.3%), 2 (3.7%), 6 (11.1%), and 1 (1.9%) had average adherence of <2, 2-3, 4-6, and ≥7 doses/week, respectively, and the corresponding incidence was 3.9 (95% CI 2.9-5.3), 0.24 (0.060-0.95), 0.27 (0.12-0.60), and 0.054 (0.008-0.38) per 100 person-years. Adherence was low in younger participants, Hispanic/Latinx and Black participants, cisgender women, and transgender women. Bone and renal adverse event incidence rates were 0.69 and 11.8 per 100 person-years, respectively, consistent with previous reports. CONCLUSIONS: Leveraging the largest pooled analysis of global PrEP studies to date, we demonstrate that F/TDF is safe and highly effective, even with less than daily dosing, in diverse clinical settings, geographies, populations, and routes of HIV-1 exposure.

Daily Oral HIV Pre-exposure Prophylaxis Among Young Men Who Have Sex With Men in the United States: Cost-saving at Generic Drug Price.

BACKGROUND: Adherence and retention concerns raise questions about the effectiveness and cost-effectiveness of oral HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM). METHODS: Using an adolescent-focused simulation model, we compared annual HIV screening alone with tenofovir disoproxil fumarate/emtricitabine-based oral PrEP with every 3-month HIV screening in YMSM (aged 15-24) at increased risk of HIV. Data derived from published sources included: age-stratified HIV incidence/100 person-years (PY) on- or off-PrEP (0.6-10.1 or 0.4-6.4), PrEP retention at 6 years (28%), transmissions by HIV RNA level (0.0-78.4/100PY) and annual costs of antiretroviral therapy ($32 000-69 000), HIV care ($3100-34 600), and PrEP program/generic drug ($900/360). Outcomes included transmissions (percent of cohort infected), quality-adjusted life-years (QALYs), costs ($), and incremental cost-effectiveness ratios ($/QALY). We explored the sensitivity of findings to variation in HIV incidence and drug prices. RESULTS: Compared with annual screening alone, PrEP would increase QALYs (9.58 to 9.67), reduce new infections (37% to 30%), and decrease costs (by $5000) over 10 years. PrEP would remain cost-saving for HIV incidence off-PrEP ≥5.1/100PY or annual PrEP price ≤$1200. Over a lifetime horizon, PrEP would be cost-saving for HIV incidence off-PrEP ≥1.0/100PY, across all retention assumptions examined. PrEP would not be cost-effective at HIV incidence ≤0.1/100PY, regardless of drug price, due to programmatic costs. CONCLUSIONS: In US YMSM at increased risk of HIV, generic oral PrEP and every-3-month screening would be cost-saving compared with annual screening alone, even with high discontinuation and low adherence, over a range of HIV incidences.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

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.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Institute of Allergy and Infectious Diseases and ViiV Healthcare.

Breakthrough HIV-1 infection in setting of cabotegravir for HIV pre-exposure prophylaxis.

OBJECTIVE: We describe the first case of HIV-1 infection in the setting of long-acting injectable cabotegravir (CAB-LA) for HIV pre-exposure prophylaxis to occur in the real world. DESIGN: Case report. METHODS: Electronic medical records were reviewed to assess patient history and CAB-LA administration details. Plasma fourth-generation HIV-1/2 Ag/Ab combination immunoassay and HIV-1 RNA quantitative PCR were performed at each injection visit. RESULTS: We report a 28-year-old sex-diverse person assigned male at birth who acquired HIV-1 infection 91 days after transitioning from tenofovir alafenamideemtricitabine to CAB-LA despite on-time dosing and appropriate laboratory monitoring. CONCLUSION: This patient's history suggests HIV infection despite on-time and appropriate CAB-LA injections. To our knowledge, this is the first case of CAB-LA pre-exposure prophylaxis failure outside the setting of a clinical trial and highlights diagnostic and management challenges that may occur with such breakthrough infections.

Prevention, treatment and cure of HIV infection.

The development of antiretroviral therapy for the prevention and treatment of HIV infection has been marked by a series of remarkable successes. However, the efforts to develop a vaccine have largely failed, and efforts to discover a cure are only now beginning to gain traction. In this Review, we describe recent progress on all fronts - pre-exposure prophylaxis, vaccines, treatment and cure - and we discuss the unmet needs, both current and in the coming years. We describe the emerging arsenal of drugs, biologics and strategies that will hopefully address these needs. Although HIV research has largely been siloed in the past, this is changing, as the emerging research agenda is marked by multiple cross-discipline synergies and collaborations. As the limitations of antiretroviral drugs as a means to truly end the epidemic are becoming more apparent, there is a great need for continued efforts to develop an effective preventative vaccine and a scalable cure, both of which remain formidable challenges.

A linked physiologically based pharmacokinetic model for hydroxychloroquine and metabolite desethylhydroxychloroquine in SARS-CoV-2(-)/(+) populations.

Hydroxychloroquine (HCQ) is Food and Drug Administration (FDA)-approved for malaria, systemic and chronic discoid lupus erythematosus, and rheumatoid arthritis. Because HCQ has a proposed multimodal mechanism of action and a well-established safety profile, it is often investigated as a repurposed therapeutic for a range of indications. There is a large degree of uncertainty in HCQ pharmacokinetic (PK) parameters which complicates dose selection when investigating its use in new disease states. Complications with HCQ dose selection emerged as multiple clinical trials investigated HCQ as a potential therapeutic in the early stages of the COVID-19 pandemic. In addition to uncertainty in baseline HCQ PK parameters, it was not clear if disease-related consequences of SARS-CoV-2 infection/COVID-19 would be expected to impact the PK of HCQ and its primary metabolite desethylhydroxychloroquine (DHCQ). To address the question whether SARS-CoV-2 infection/COVID-19 impacted HCQ and DHCQ PK, dried blood spot samples were collected from SARS-CoV-2(-)/(+) participants administered HCQ. When a previously published physiologically based pharmacokinetic (PBPK) model was used to fit the data, the variability in exposure of HCQ and DHCQ was not adequately captured and DHCQ concentrations were overestimated. Improvements to the previous PBPK model were made by incorporating the known range of blood to plasma concentration ratios (B/P) for each compound, adjusting HCQ and DHCQ distribution settings, and optimizing DHCQ clearance. The final PBPK model adequately captured the HCQ and DHCQ concentrations observed in SARS-CoV-2(-)/(+)participants, and incorporating COVID-19-associated changes in cytochrome P450 activity did not further improve model performance for the SARS-CoV-2(+) population.

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.

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.

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

BACKGROUND: Dried 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. METHODS: Whole 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. RESULTS: DBS 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%). CONCLUSIONS: We 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.

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of $500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs $150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82% of setting-scenarios at the cost of $144 per year, in 52% at $264, and in 87% at $114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

A community-partnered approach for diversity in COVID-19 vaccine clinical trials.

Introduction: Communities of color have faced disproportionate morbidity and mortality from COVID-19, coupled with historical underrepresentation in US clinical trials, creating challenges for equitable participation in developing and testing a safe and effective COVID-19 vaccine. Methods: To increase diversity, including racial and ethnic representation, in local Los Angeles County NIH-sponsored Phase 3 SARS-CoV-2 vaccine clinical trials, we used deliberative community engagement approaches to form a Community Consultant Panel (CCP) that partnered with trial research teams. Thirteen members were recruited, including expertise from essential workers, community-based and faith-based organizations, or leaders from racial and ethnic minority communities. Results: Working closely with local investigators for the vaccine studies, the CCP provided critical insight on best practices for community trust building, clinical trial participation, and reliable information dissemination regarding COVID-19 vaccines. Modifying recruitment, outreach, and trial protocols led to majority-minority participants (55%-78%) in each of the three vaccine clinical trials. CCP's input led to cultural tailoring of recruitment materials, changes in recruitment messaging, and supportive services to improve trial accessibility and acceptability (transportation, protocols for cultural competency, and support linkages to care in case of an adverse event). Barriers to clinical trial participation unable to be resolved included childcare, requests for after-hours appointment availability, and mobile locations for trial visits. Conclusion: Using deliberative community engagement can provide critical and timely insight into the community-centered barriers to COVID-19 vaccine trial participation, including addressing social determinants of health, trust, clinical trial literacy, structural barriers, and identifying trusted messenger and reliable sources of information.

Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel.

Importance: Recent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice. Objective: Based on a critical evaluation of new data, to provide clinicians with recommendations on use of antiretroviral drugs for the treatment and prevention of HIV, laboratory monitoring, care of people aging with HIV, substance use disorder and HIV, and new challenges in people with HIV, including COVID-19 and monkeypox virus infection. Evidence Review: A panel of volunteer expert physician scientists were appointed to update the 2020 consensus recommendations. Relevant evidence in the literature (PubMed and Embase searches, which initially yielded 7891 unique citations, of which 834 were considered relevant) and studies presented at peer-reviewed scientific conferences between January 2020 and October 2022 were considered. Findings: Initiation of antiretroviral therapy (ART) is recommended as soon as possible after diagnosis of HIV. Barriers to care should be addressed, including ensuring access to ART and adherence support. Integrase strand transfer inhibitor-containing regimens remain the mainstay of initial therapy. For people who have achieved viral suppression with a daily oral regimen, long-acting injectable therapy with cabotegravir plus rilpivirine given as infrequently as every 2 months is now an option. Weight gain and metabolic complications have been linked to certain antiretroviral medications; novel strategies to ameliorate these complications are needed. Management of comorbidities throughout the life span is increasingly important, because people with HIV are living longer and confronting the health challenges of aging. In addition, management of substance use disorder in people with HIV requires an evidence-based, integrated approach. Options for preexposure prophylaxis include oral medications (tenofovir disoproxil fumarate or tenofovir alafenamide plus emtricitabine) and, for the first time, a long-acting injectable agent, cabotegravir. Recent global health emergencies, like the SARS-CoV-2 pandemic and monkeypox virus outbreak, continue to have a major effect on people with HIV and the delivery of services. To address these and other challenges, an equity-based approach is essential. Conclusions and Relevance: Advances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Long-Acting Injectable Therapy for People with HIV: Looking Ahead with Lessons from Psychiatry and Addiction Medicine.

Long-acting injectable antiretroviral medications are new to HIV treatment. People with HIV may benefit from a treatment option that better aligns with their preferences, but could also face new challenges and barriers. Authors from the fields of HIV, substance use treatment, and mental health collaborated on this commentary on the issues surrounding equitable implementation and uptake of LAI ART by drawing lessons from all three fields. We employ a socio-ecological framework beginning at the policy level and moving through the community, organizational, interpersonal, and patient levels. We look at extant literature on the topic as well as draw from the direct experience of our clinician-authors.

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.

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.

Pharmacokinetics of Emtricitabine/Tenofovir Disoproxil Fumarate Among Transgender Adolescents and Young Adults Without HIV Receiving Gender Affirming Hormones.

The transgender community has expressed concerns regarding drug-drug interactions between HIV-pre-exposure prophylaxis (PrEP) and gender-affirming hormones. In this study, we evaluated emtricitabine (F, FTC)/tenofovir (TFV) disoporoxil fumarate (TDF) pharmacokinetics (PK) among adolescent and young adult transgender persons receiving gender-affirming hormone therapy (GAHT). This was a prospective, observational study among transgender women (TW) and men (TM) without HIV, 15-24 years of age, receiving GAHT (estradiol with/without spironolactone, or testosterone). Participants received 1 month of directly observed daily F/TDF. Weekly convenience blood samples were collected for plasma TFV and FTC, and intracellular TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in peripheral blood mononuclear cells (PBMC) and dried blood spots (DBS). After 2-3 weeks of F/TDF dosing, intensive PK sampling was conducted. PK parameters were estimated using noncompartmental methods. Data were log-transformed and compared between TM and TW, and to historical data among cisgender adults. Plasma TFV exposures were similar between TM and TW [geometric mean ratio (GMR); confidence interval (95% CI): 1.06 (0.89-1.28)], whereas FTC plasma exposures were 21% higher in TM versus TW (95% CI: 1.07-1.38). TFV-DP in PBMC and DBS and FTC-TP in DBS did not differ between TM versus TW after controlling for creatinine clearance (CrCl), but FTC-TP in PBMC remained 46% (95% CI: 1.15-1.86) higher in TM versus TW. All PK exposures were within expected ranges based on historical studies. TM had higher FTC exposures compared with TW, but overall plasma and intracellular exposures for both drugs were within the range of historical studies, suggesting high PrEP efficacy will be retained in adolescent and young adult transgender persons. Registered at ClinicalTrials.gov (NCT03652623).