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Introduction The first complete long-acting antiretroviral therapy (ART) regimen, cabotegravir + rilpivirine long-acting (CAB + RPV LA) injectable, was approved in the US for HIV-1 treatment in individuals on a stable antiretroviral regimen with a viral load < 50 copies/mL, no treatment failure history, and no resistance to either cabotegravir or rilpivirine. We describe injection schedule adherence and virologic effectiveness of CAB + RPV LA in routine clinical care in the US. Methods From the OPERA ® cohort, all adults with HIV who received their first CAB + RPV LA injection and ≥ 1 continuation injections between 21 January 2021 and 15 March 2022 were included. The injection target date was updated monthly and set to the same date of the month as the previous injection. Continuation injections administered within 7 days before or after the target date were considered on time, as per the label. Virologic undetectability (viral load < 50 copies/mL), suppression (viral load < 200 copies/mL), and confirmed virologic failure (2 consecutive viral loads ≥ 200 copies/mL or 1 viral load ≥ 200 copies/mL followed by discontinuation) were described among individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load. Results Among 321 individuals on CAB + RPV LA, 90% of the continuation injections were administered on time (within ± 7 days of the target date). Of the 237 individuals with a viral load < 50 copies/mL at initiation and ≥ 1 follow-up viral load, nearly all were undetectable (95%) or suppressed (99%) at their last viral load measurement, 96% maintained virologic suppression with all measured viral loads < 200 copies/mL, and four confirmed virologic failures were observed. Injection delays were infrequent, and did not affect virologic outcomes over the short term. Conclusion In this large US cohort, most monthly CAB + RPV LA injections were administered on time and high levels of virologic control were achieved. These results suggest that CAB + RPB LA injectable can be administered effectively during routine clinical care.

Abstract Background Increases in lipids have been observed in people with HIV (PWH) switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF). We assessed changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) following a switch from TDF to TAF. Methods Adults with ≥1 lipid measure before and after switch from TDF to TAF were identified in the OPERA cohort. Multivariable linear regression using generalized estimating equations was used to estimate predicted changes in lipids over time on TAF, modeled flexibly with linear splines. Results A total of 6451 PWH switched from TDF to TAF, of whom 4328 maintained all other agents. LDL-C increased significantly by 1.40 mg/dL/mo over the first 3 months on TAF, by 0.33 mg/dL/mo between 3 and 9 months and then plateauing beyond 9 months. TG increased significantly by 3.52 mg/dL/mo over the first 3 months of TAF, by 0.91 mg/mL/mo between 3 and 9 months and by 0.72 mg/mL/mo between 9 and 16 months, but decreased thereafter. Similar patterns were observed in analyses restricted to PWH who switched from TDF to TAF but maintained all other agents. Conclusions TDF-to-TAF switch was associated with LDL-C and TG increases over the first 9 to 16 months on TAF. The dynamic patterns observed cannot be attributed to changes in other agents.

Background Two-drug regimens (2DRs) have been introduced in recent years to potentially reduce antiretroviral therapy (ART) toxicities and drug-drug interactions while demonstrating comparable efficacy to three-drug regimens (3DRs) for people with HIV (PWH). The objective of this study was to compare the real-world effectiveness and durability of a single-tablet 2DR of dolutegravir/lamivudine (DTG/3TC) with that of commonly prescribed 3DRs in ART-experienced, virologically suppressed PWH during the first 24 months of DTG/3TC availability in the United States. Methods Virologically suppressed (viral load [VL] < 200 copies/mL) adult PWH initiating DTG/3TC 2DR, bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), or a DTG-based 3DR between 01MAY2019 and 31OCT2020 were identified in the OPERA ® cohort and followed through 30APR2021. Univariate Poisson regression (incidence rates) and marginal structural Cox proportional hazards models with inverse probability of treatment weights (hazard ratios) were used to quantify relationships between regimen type and confirmed virologic failure (2 consecutive VLs ≥ 200 copies/mL) or regimen discontinuation. Reasons for discontinuation were examined. Results A total of 8,037 ART-experienced, virologically suppressed PWH met the inclusion criteria and switched to DTG/3TC ( n  = 1,450), BIC/FTC/TAF ( n  = 5,691), or a DTG-based 3DR ( n  = 896). Incidence rates of confirmed virologic failure were low for all groups, at 0.66 (DTG/3TC), 0.84 (BIC/FTC/TAF), and 1.78 (DTG 3DR) per 100 person-years (py). Compared to DTG/3TC, only the DTG 3DRs were associated with a statistically significant increased hazard of confirmed virologic failure (hazard ratio: 5.21, 95% confidence interval: 1.85, 14.67). Discontinuation rates per 100 py were highest in the DTG 3DR group (24.90), followed by the DTG/3TC group (17.69) and the BIC/FTC/TAF group (8.30). Regardless of regimen, discontinuations were infrequently attributed to effectiveness (VL ≥ 200 copies/mL; 4%) or tolerability (adverse diagnoses, side effects, or lab abnormalities; 6%). Conclusions Among virologically suppressed PWH initiating a new regimen, few individuals experienced virologic failure in real-world clinical care. While rates of regimen discontinuation were high, most discontinuations could not be attributed to a lack of virologic control or poor tolerability. These findings suggest that DTG/3TC is an effective option for ART-experienced, virologically suppressed PWH.

Introduction Cabotegravir + rilpivirine long‐acting (CAB+RPV LA) injectable was approved in the United States in 2021 for HIV‐1 treatment in virologically suppressed (viral load [VL] <50 copies/mI individuals. In clinical trials, CAB+RPV LA was non‐inferior to oral antiretroviral therapy (ART) regimens in virologically suppressed individuals. We compared real‐world effectiveness between CAB+RPV LA and oral ART regimens and assessed predictors of confirmed virologic failure (CVF) on CAB+RPV LA. Methods From the OPERA® cohort, ART‐experienced, virologically suppressed adults with HIV switching to CAB+RPV LA or a new oral ART regimen between 21 January 2021 and 31 December 2022 were followed through 30 June 2023. CVF was defined as 2 VL ≥200 copies/ml or 1 VL ≥200 copies/ml + discontinuation. Logistic regression was used to assess CVF risk by regimen and CVF predictors among CAB+RPV LA users. Results During the study period, 1362 virologically suppressed adults switched to CAB+RPV LA, and 2783 switched to a new oral ART regimen (92% second‐generation integrase inhibitor [INSTI]‐based). Compared to oral ART users, CAB+RPV LA users were younger, on their prior regimen less time and more likely to switch from an INSTI; median CD4 counts at initiation were similar. At study end, 81% of CAB+RPV LA users and 80% of oral ART users were on their respective regimens. CVF risk with CAB+RPV LA did not statistically differ compared to oral ART (adjusted odds ratio: 0.64; 95% confidence interval [CI]: 0.34, 1.14). Among CAB+RPV LA users, only baseline CD4 predicted CVF; every 100 CD4 cells/µl increase was associated with 20% lower CVF risk (OR [95% CI]: 0.80 [0.64, 0.97]). Conclusions In the United States, routine clinical care, CVF risk did not differ between a switch to CAB+RPV LA or new oral ART, with most individuals remaining on their regimens at study end. Lower CD4 count at initiation was the only predictor of CVF on CAB+RPV LA.

Background We evaluated the impact of the CHORUS™ app on adherence to the cabotegravir and rilpivirine long-acting injectable (CAB + RPV LAI) monthly injections schedule. Methods Healthcare centers (HCCs) were randomized to access CHORUS™ CAB + RPV LAI features (intervention) or not (control) from 01OCT2021-31JAN2022. Target window adherence (maintenance injections ≤7 days before/after target day) was assessed with multivariate logistic regression (generalized estimating equations). Results CAB + RPV LAI was administered to 188 and 79 individuals at intervention and control HCCs, respectively. Intervention was not associated with improved target window adherence (adjusted odds ratio: 0.61 [95% CI: 0.30-1.25]). However, app use was associated with increased odds of adherence compared to no app use among all intervention HCCs (2.98 [1.26-7.06]) and at smaller HCCs (3.58 [1.31-9.80]). Conclusions While access to CHORUS™ CAB + RPV LAI features did not improve target window adherence, app use did, especially at smaller HCCs which may not have established LAI management procedures. Trial registration https://clinicaltrials.gov/show/NCT04863261. Plain Language Summary Evaluation of a mobile app and web portal to help with the timely injections of cabotegravir + rilpivirine long-acting injections Cabotegravir + rilpivirine long-acting injectable (CAB+RPV LAI) is the first long-acting regimen for HIV treatment, which was approved in the US in 2021. CAB+RPV LAI should be administered ≤7 days before/after the target date. We conducted a trial to evaluate the impact of the CHORUS™ app and web portal on the timing of monthly CAB+RPV injections. The intervention clinics had access to features designed to help with CAB+RPV LAI management, including flagging delayed/missed injections and appointment scheduling status. Control clinics did not have access to these features and managed CAB+RPV LAI administration on their own. Access to the app and web portal features for intervention clinics had no impact on timing of injections compared to control clinics. However, intervention clinics who actively used the app were close to three times more likely to give injections on-time than intervention clinics who did not use the app. The effect of app use was seen specifically among smaller clinics caring for <1000 people with HIV: smaller clinics that actively used the app were 3.58 times more likely to give injections on-time than those who did not use the app. In conclusion, while access to CHORUS™ CAB+RPV LAI features in the app and the web portal did not improve the likelihood of on time injections, actively using the app did make a difference, especially at smaller clinics which may not have established injection management procedures.

Background Sustained, routine care is vital to the health of people with HIV (PWH) and decreasing transmission of HIV. We evaluated whether the identification of PWH at-risk of falling out of care and prompts for outreach were effective in retaining PWH in care in the United States. Methods In this cluster randomized controlled trial, 20 AIDS Healthcare Foundation Healthcare Centers (HCCs) were randomized to the intervention ( n  = 10) or control ( n  = 10) arm; all maintained existing retention efforts. The intervention included daily automated flags in CHORUS™, a mobile app and web-based reporting solution utilizing electronic health record data, that identified PWH at-risk of falling out of care to clinic staff. Among flagged PWH, the association between the intervention and visits after a flag was assessed using logistic regression models fit with generalized estimating equations (independent correlation structure) to account for clustering. To adjust for differences between HCCs, models included geographic region, number of PWH at HCC, and proportions of PWH who self-identified as Hispanic or had the Ryan White Program as a payer. Results Of 15,875 PWH in care, 56% were flagged; 76% (intervention) and 75% (control) resulted in a visit, of which 76% were within 2 months of the flag. In adjusted analyses, flags had higher odds of being followed by a visit (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 0.97, 1.21) or a visit within 2 months (OR: 1.07, 95% CI: 0.97, 1.17) at intervention than control HCCs. Among at-risk PWH with viral loads at baseline and study end, the proportion with < 50 copies/mL increased in both study arms, but more so at intervention (65% to 74%) than control (62% to 67%) HCCs. Conclusion Despite challenges of the COVID-19 pandemic, adding an intervention to existing retention efforts, and the reality that behavior change takes time, PWH flagged as at-risk of falling out of care were marginally more likely to return for care at intervention than control HCCs and a greater proportion achieved undetectability. Sustained use of the retention module in CHORUS™ has the potential to streamline retention efforts, retain more PWH in care, and ultimately decrease transmission of HIV. Trial Registration The study was first registered at Clinical Trials.gov (NCT04147832, https://clinicaltrials.gov/show/NCT04147832 ) on 01/11/2019.

Introduction Although weight gain has been reported with the use of integrase strand transfer inhibitors (InSTI), concurrent use of tenofovir alafenamide (TAF) has been implicated in recent studies. This study examined weight changes in people living with HIV (PLWH) who switched from tenofovir disoproxil fumarate (TDF) to TAF, to clarify the relative contribution to weight gain of core agents versus TDF to TAF switch. Methods Antiretroviral‐experienced, virologically suppressed PLWH in the U.S. OPERA cohort were included if they switched from TDF to TAF (5NOV2015‐28FEB2019) and either maintained all other antiretrovirals or switched from a non‐InSTI to an InSTI. Linear mixed models were used to assess weight changes before/after the switch to TAF (restricted cubic splines on time) and rates of change over time (linear splines on time, based on the shape of the weight change curves). Changes in weight on TDF or TAF were assessed among those who maintained other antiretrovirals (overall, by core class), and those who maintained an InSTI or switched to an InSTI (by core agent). All models were adjusted for age, sex, race, (age‐sex, race‐sex interactions), BMI, CD4 cell count, endocrine disorders and concurrent medications that could affect weight. Results A total of 6908 PLWH were included, with 5479 maintaining all other antiretrovirals (boosted protease inhibitor: 746, non‐nucleoside reverse transcriptase inhibitor: 1452, InSTI: 3281) and 1429 switching from a non‐InSTI to an InSTI (elvitegravir/cobicistat: 1120, dolutegravir: 174, bictegravir: 129). In adjusted models, modest weight gain was observed over time on TDF for most (0.24 to 0.71 kg/year); raltegravir was the exception with weight loss. Switching to TAF was associated with early, pronounced weight gain for all (1.80 to 4.47 kg/year). This effect with TAF switch was observed both in PLWH maintaining other antiretrovirals and those switching to an InSTI, regardless of which InSTI agent was used. Weight gain tended to slow down or plateau approximately nine months after switch to TAF. Conclusions In this large, diverse U.S. cohort of PLWH, switching from TDF to TAF was associated with pronounced weight gain immediately after switch, regardless of the core class or core agent, suggesting an independent effect of TAF on weight gain.

Introduction The CUSTOMIZE hybrid III implementation‐effectiveness study evaluated implementation of once‐monthly long‐acting (LA) cabotegravir + rilpivirine in diverse US healthcare settings. Here, we report patient participant perspectives after 12 months in CUSTOMIZE. Methods CUSTOMIZE was a phase IIIb, 12‐month study conducted from July 2019 to October 2020 at eight diverse US HIV clinics that enrolled virologically suppressed people living with HIV‐1 (PLHIV) on a stable oral regimen to receive monthly cabotegravir + rilpivirine LA injections after a 1‐month oral lead‐in. Participants were administered quantitative surveys before injections at months 1 (baseline), 4 and 12. A randomly selected subset of participants was interviewed at baseline and month 12. Data collection at month 12 was completed by October 2020 (during the COVID‐19 pandemic). Results At baseline, 109 and 34 participants completed surveys and interviews, respectively; 87% were male; 35% were Black or African American. All participants who remained in the study at month 12 (n = 102) maintained HIV‐1 RNA <50 copies/ml; two participants withdrew due to injection‐related reasons. Mean total scores measuring acceptability and appropriateness of cabotegravir + rilpivirine LA were high at baseline (4.5–4.6 out of 5) and month 12 (4.7–4.9). At month 12, 74% of participants reported nothing interfered with receiving LA injections; injection pain or soreness was the most common concern (15%). Time spent in the clinic and coming to the clinic for monthly injections was very or extremely acceptable after 12 months for most participants (93% and 87%, respectively), with 64% reporting having spent ≤30 minutes in the clinic for injection visits. At month 12, 92% of participants preferred LA injections to daily oral tablets (3%); 97% plan to continue LA treatment going forward. In month 12 interviews, 24 (77%) of 31 participants reported the COVID‐19 pandemic did not impact their ability to receive treatment. Conclusions Once‐monthly cabotegravir + rilpivirine LA was highly acceptable among PLHIV who were virologically suppressed on a stable antiretroviral regimen and interested in trying LA therapy, with few participants reporting challenges receiving LA injections. Implementation data from CUSTOMIZE suggest that monthly LA injections provide a convenient and appealing treatment option for PLHIV.

IntroductionDolutegravir (DTG), Elvitegravir (EVG), Raltegravir (RAL) and Darunavir (DRV) are commonly prescribed core agents for antiretroviral therapy (ART), and a need exists to compare their clinical effectiveness, as defined by virologic failure risks in real-world settings.MethodsThis observational analysis of a US clinical cohort consisted of ART-naïve people living with HIV (PLWH) in the OPERA database initiating DTG-, EVG-, RAL- or DRV-based regimens between August 2013 and July 2016, with follow-up to July 2017. PLWH were observed from first core agent initiation until core agent discontinuation, clinical activity cessation, death, or study end. Key outcomes included viral suppression (HIV RNA < 50 copies/mL) and confirmed virologic failure (two consecutive viral loads > 200 copies/mL or a viral load > 200 copies/mL followed by discontinuation). Association between core agent and time to virologic failure was assessed with multivariate Cox proportional hazards models.ResultsOverall, 4049 ART-naïve PLWH initiated EVG (47.4%), DTG (34.7%), DRV (14.6%), or RAL (3.2%). DTG and EVG initiators had generally similar baseline demographics and clinical characteristics, including race, risk of infection, baseline viral load, and baseline CD4 levels. RAL and DRV initiators were older and generally sicker than DTG initiators. During follow-up, more DTG initiators achieved virologic suppression (78.7%) compared with EVG (73.6%; p < 0.05), RAL (51.9%; p < 0.0001) and DRV (48.6%; p < 0.0001) initiators. Compared to DTG, both RAL and DRV were associated with higher rates of virologic failure, with adjusted hazard ratios (95% confidence interval) of 4.70 (3.03, 7.30) and 2.38 (1.72, 3.29), respectively. No difference was observed between EVG and DTG with an adjusted hazard ratio of 1.24 (0.94, 1.64).ConclusionIn this large cohort representative of PLWH in care in the US, ART-naïve PLWH prescribed DTG had better virologic outcomes than RAL and DRV, but had virologic failure risks comparable to EVG, although RAL and DRV were preferentially prescribed to sicker individuals.FundingViiV Healthcare.

Background and Objective Many people living with HIV (PLWH) on stable tenofovir disoproxil fumarate (TDF)-containing regimens have switched to tenofovir alafenamide (TAF), despite the potential lipid-lowering effect of TDF. We aimed to assess the impact of switching from TDF to TAF on lipids in real-world clinical practice. Methods PLWH prescribed TDF for ≥ 4 weeks who switched to TAF were identified in the OPERA cohort. Patterns of dyslipidemia were compared before and after switch based on NCEP ATPIII guidelines. Elevated 10-year risk of atherosclerotic cardiovascular disease (ASCVD ≥ 7.5%) and statin use were assessed. Results Among 6423 PLWH switched from TDF to TAF, the proportion with dyslipidemia/severe dyslipidemia observed after switch from TDF to TAF increased statistically significantly ( p < 0.0001) with total cholesterol (5–10%), low-density lipoprotein cholesterol (16–23%), and triglycerides (21–27%), but decreased statistically significantly with high-density lipoprotein cholesterol (35–30%, p < 0.0001). These patterns of dyslipidemia persisted in sensitivity analyses restricted to PLWH who maintained all other antiretrovirals ( N = 4328) or stratified by pharmaco-enhancer use before and after switch. An elevated ASCVD risk was detected in 29% before and 31% after switch. As many as 59% of PLWH with an elevated ASCVD risk were not prescribed a statin after switch from TDF to TAF. Conclusions In this large, diverse population of PLWH in the USA, the switch from TDF to TAF was associated with development of less favorable lipid profiles, regardless of pharmaco-enhancers or third-agent use. Statins remained underutilized after a switch from TDF to TAF.