Faculty Bibliography

INTRODUCTION/BACKGROUND: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: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/CONCLUSIONS: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.

BACKGROUND:Multi-class resistance, intolerance, and drug-drug interactions can result in unique antiretroviral (ART) combinations for heavily treatment-experienced (HTE) people living with HIV (PLWH). We aimed to compare clinical outcomes between HTE and non-HTE PLWH. METHODS:Eligible ART-experienced PLWH in care in the OPERA® Cohort were identified in a cross-sectional manner on December 31, 2016 and observed from the date of initiation of the ART regimen taken on December 31, 2016 until loss to follow up, death, study end (December 31, 2018), or becoming HTE (non-HTE group only). In the absence of resistance data, HTE was defined based on the ART regimens used (i.e., exposed to ≥ 3 core agent classes or regimen suggestive of HTE). Time to virologic undetectability, failure, and immunologic preservation were assessed using Kaplan-Meier methods; cumulative probabilities were compared between the two groups. Regimen changes, incident morbidities, and death were described. RESULTS:A total of 24,183 PLWH (2277 HTE PLWH, 21,906 non-HTE) were followed for a median of 28 months (IQR 21, 38). Viremic HTE PLWH (viral load [VL] ≥ 50 copies/mL) were less likely to achieve undetectability (VL < 50 copies/mL; 24-month cumulative probability: 80% [95% Confidence Interval 77-82]) than their non-HTE counterparts (85% [84-86]). No difference was observed in the probability of maintaining VLs < 200 copies/mL over the first 48 months after achieving suppression (< 50 copies/mL). HTE PLWH were less likely than non-HTE PLWH to maintain CD4 cell counts ≥ 200 cells/µL (24-month cumulative probability: 95% HTE [91-93]; 97% non-HTE [97-97]), and more likely to change regimens (45% HTE; 41% non-HTE). Incident non-AIDS defining event (ADE) morbidities were common in both populations, though more likely among HTE PLWH (45%) than non-HTE PLWH (35%). Incident ADE morbidities and deaths were uncommon among HTE (ADEs 5%; deaths 2%) and non-HTE (ADEs 2%; deaths 1%) PLWH. CONCLUSIONS:HTE PLWH were at greater risk of unfavorable treatment outcomes than non-HTE PLWH, suggesting additional therapeutic options are needed for this vulnerable population.

Background. HIV-associated wasting (i.e., progressive, involuntary weight loss with both fat and lean tissue loss; HIVAW) is an under-appreciated AIDS-defining illness; the 2012-2018 period prevalence was reported as 18% in a recent claims study in the United States. We aimed to assess the association between incident HIVAW/ low weight and all-cause mortality in the era of modern combination antiretroviral therapy (ART). Methods. In the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort, PWH without (a) any prior HIVAW/low weight, (b) malignancy within 3 years, and (c) opportunistic infection within 1 year who were active in care between 2016 and 2020 were followed through death, loss to follow-up, or study end (31OCT2021). HIVAW/low weight included a wasting or low BMI/underweight diagnosis (ICD codes, title search) or BMI < 20 kg/m2. Hazard ratios (HR) and 95% confidence intervals (CI) for the association between time-dependent incident HIVAW/low weight (exposure) and all-cause mortality (outcome) were estimated with extended Cox regression models. The adjusted model included age at baseline, race, ethnicity, and time-dependent covariates (log10 viral load, Veterans Aging Cohort Study [VACS] Mortality Index score). Viral load and VACS score were included as surrogate markers for ART use and comorbidities, respectively. Linear and quadratic terms of continuous variables were included. Results. Of 67,119 PWH without prior HIVAW/low weight in OPERA, 62,314 (93%) PWH had non-missing covariate data and were included in the models; baseline characteristics did not differ between the full and model study populations (Table 1). Over a median follow-up of 45 months (interquartile range: 27, 65), there were 4,755 (8%) cases of incident HIVAW/low weight and 1,354 (2%) deaths. In the adjusted model, PWH who experienced incident HIVAW/low weight had a significantly increased risk of death over follow-up than those who did not experience HIVAW/low weight (HR: 1.96; 95% CI: 1.68, 2.27) (Table 2). Conclusion. In this analysis of 62,314 PWH in care, incident HIVAW/low weight was associated with twice the risk for all-cause mortality in the modern ART era. Particular attention needs to be paid to HIVAW/low weight among PWH to restore health and potentially reduce the risk of death

Background. The first long-acting (LA) antiretroviral therapy (ART) regimen, cabotegravir+rilpivirine (CAB+RPV) injection, was approved by the FDA in January 2021 for ART-experienced, people with HIV (PWH) with undetectable viral load (VL< 50 copies/mL). We assessed clinical effectiveness of CAB+RPV LA in the first year of use in the United States (US). Methods. Using electronic health record data from the OPERA cohort, all ART-experienced adults who received >=1 CAB+RPV LA prescriptions for the first time between 21Jan2021 and 28Feb2022 were followed until 13Mar2022. Discontinuation was defined as an ART switch or > 2 consecutive missed doses. VL were monitored from first injection until end of follow-up or discontinuation. Confirmed virologic failure was defined as 2 consecutive VLs > 200 copies/mL or 1 VL > 200 copies/mL + discontinuation. Results were stratified by VL at first prescription (i.e., suppressed: < 200 copies/mL; viremic: >= 200 copies/mL). Results. Of 994 PWH prescribed CAB+RPV, all were ART-experienced and 85% had undetectable VL (< 50 copies/mL), 90% were suppressed (< 200 copies/mL), and the remainder had VL >=200/mL (6%) or missing baseline VL (4%). Of those prescribed, 344 (38%) received CAB+RPV LA injections over a median 53 (IQR: 35, 79) days; 14% were women, 36% were Black, 29% were Hispanic, 25% had a BMI of >=30, and the median age was 40 (IQR: 32, 53) years (Table 1). At the end of observation, 62% had not yet received CAB+RPV injections as they were in the process of approval, were on oral lead-in, or had been denied. At study end, 310 (90%) of the 344 remained on CAB +RPV LA with median follow-up of 3.4 (2.2, 6.1) months. Among those with VLs after first injection, the last VL was < 200 copies/mL in 99% and < 50 copies/mL in 94% (Table 2); all follow-up VLs were < 200 copies/mL in 97%, and < 50 copies/mL in 88%. Thirty viremic PWH received CAB+RPV LA injections (Table) with a median VL at first prescription of 4.2 (IQR: 3.2, 4.9) log copies/mL. Five or fewer PWH experienced confirmed virologic failure in each of the suppressed and viremic groups. Conclusion. In this real-world cohort of PWH who received CAB+RPV LA injections in the US, observations from the first year suggest that this regimen is effective among virologically suppressed individuals. (Table Presented)

Background. In-vitro neutralizing antibody (Ab) titers correlated with ~250 IU/ mL Spike Ig Ab level for the Delta COVID-19 variant, establishing the 2021 French and Swiss cutoff for booster guidance. In a New York City healthcare clinic where those guidelines were adopted, we aimed to quantify vaccination responses in HIV + and HIV- individuals to assess the utility of quantifying antibodies to guide booster timing. Methods. Adults who were fully vaccinated against SARS-CoV-2 virus (i.e., 2 Pfizer, 2 Moderna or 1 J&J vaccine) were included if >1 Roche SARS-CoV-2 Semi-Quant Spike Ig Ab test was performed >21 days after vaccination and before any booster (through 03DEC2021). Vaccine response was assessed at the first Ab test and considered adequate (>250 IU/mL) or inadequate (low: >=51 to <=250 IU/ mL; no response: < 51 IU/mL). The rate of Ab decline was estimated with linear regression, using all sequential Ab tests over the first 6 months between vaccination and boosting. Analyses were stratified by vaccine type, HIV status and CD4 count in HIV+ ( >200 cells/muL cutoff). Results. Out of 1979 patients, 869 completed their primary vaccinations, of whom 825 (95%) had >=1 eligible Ab test (HIV+: 512; HIV-: 313; Table). Overall, 83% had an adequate immune response to vaccination (Pfizer: 82%, Moderna: 94%, J&J: 51%), with similar findings regardless of HIV status and CD4 count (Figure 1). In those with >=2 Ab tests within six months between vaccination and boosting, Ab levels declined at a rate of 91 IU/mL per month (95% CI: -138, -44). While some variation was observed, rates of Ab decay were generally consistent across vaccine, HIV status and CD4 count strata (Figure 2). Only 1/7 breakthrough COVID-19 infections occurred post booster (6 days later Conclusion. In the pre-omicron era, primary COVID immunization with a mRNA vaccine generally yielded adequate Ab responses, although inadequate responses were observed in 19% of Pfizer, 6% of Moderna, and 49% of J&J vaccine recipients. Ab levels decreased at an average rate of 91 IU/mL per month after primary immunization. Variability in vaccine responses and Ab declines show the utility of measuring spike Ig Ab levels rather than using empiric time frames for booster guidance. Omicron-specific quantitative IgG neutralization levels must be established to inform preventative care

Background. Paired with other active antiretrovirals (ARVs), fostemsavir (FTR) may offer heavily treatment-experienced (HTE) people with HIV (PWH) options for continuing effective treatment. Durability and effectiveness of FTR-containing regimens in routine clinical care in the United States were assessed. Methods. Electronic health record data from the OPERA cohort were used to identify adults initiating FTR-containing regimens between 2JUL2020 (FDA approval) and 1SEP2021. Eligible PWH were followed from first FTR prescription (baseline) until FTR discontinuation, death, loss to follow up, or study end (28FEB2022). Durability was assessed as frequency of FTR discontinuation. Virologic outcomes assessed at 6 and 12 months (+/-3 months) included suppression (viral load [VL] < 50 copies/mL), virologic failure (2 consecutive VL >=200 copies/mL or 1 VL >=200 copies/ mL + FTR discontinuation within 120 days after suppression), and viral blips (1 VL >=50 copies/mL preceded and followed by VLs < 50 copies/mL). Analyses were stratified by baseline viral load (bVL < 50 copies/mL; bVL >=50 copies/mL). Results. Overall, 86 PWH initiated FTR (bVL < 50: 30; bVL >=50: 55), with median follow up of 10.8 months (IQR: 6.8, 15.3). Compared to PWH with bVL >=50, those with bVL < 50 were older and more likely to be white and have lived longer with HIV (Table 1). Over follow up, 20% discontinued FTR (Table 2). Most (82%) FTR discontinuations were switches to alternative regimens; the remaining were ARV interruptions (no ARVs for > 45 days). Among PWH with bVL < 50, most maintained suppression (6 months: 74%; 12 months: 82%; Figure). Among PWH with bVL >=50 and with follow up VL during the period assessed, 33% were suppressed at 6 months, 36% were suppressed at 12 months, and 48% achieved suppression at any time over the entire follow up (Figure). In either group, <=5 PWH experienced virologic failure or blip, though the proportion of PWH with multiple follow up VLs was low. Conclusion. Despite a heterogenous population and diverse regimens, most HTE PWH remained on FTR at study end. Most PWH with bVL < 50 remained suppressed and half of PWH with bVL >=50 achieved suppression over the entire study period. Virologic failure and blips were infrequent, although follow up was limited in this early evaluation of real-world FTR use

Background. CAB+RPV LA is a complete regimen for treatment of virologically suppressed people with HIV (PWH). As an injectable therapeutic administered by a healthcare provider (HCP), CAB+RPV LA may alleviate challenges with adherence to daily oral therapy and reduce fear of HIV status disclosure with oral treatment. Real world perspectives from HCPs and PWH are needed to enable successful delivery of this treatment in US healthcare settings. Methods. BEYOND is a 2 year prospective, observational, real-world study of utilization, outcomes, and experience of PWH initiating CAB+RPV LA across 30 US sites. HCPs at participating sites (treaters, injectors, drug acquisition/reimbursement staff) completed surveys at site activation (Sep 2021-Feb 2022; with follow-up surveys planned at 6, 12, 24 months) evaluating experiences to date with implementation of CAB+RPV LA at their sites. Results. HCPs from 24 sites responded to the initial survey (Table 1). 75% ofHCPs estimated that >=25% of their PWH are eligible for CAB+RPV LA, and 71% of sites are proactively discussing the regimen with >=25% of PWH. The majority (79%) of treaters reported they were extremely/very positive about administering CAB+RPV LA. Over 90% of injectors reported a positive overall opinion about administering CAB+RPV LA, and 86% reported the injections were easy to administer.Most (87%) HCPs reported injection visits taking <=45 minutes, including waiting time. Over 95% of sites have patient reminder systems; 86% will manually identify missed injections and all reported manual follow up by site staff. All sites utilizing the injection education video on the external HCP website (n=15/15) found it helpful and 94% (n=16/17) utilizing reimbursement specialists found them to be helpful. In their experience to date, most clinics reported only needing to increase coordination with the pharmacy team and add injection training to implement CAB+RPV LA. The most frequently reported benefits of implementing CAB+RPV LAbyHCPs included assurance of patient adherence and patient engagement in their HIV treatment (Table 2). Conclusion. Early real-world data from US HCPs in this study indicates interest in and anticipated uptake of CAB+RPV LA at their sites, positive overall opinion, and multiple benefits of administering the CAB+RPV LA regimen to PWH

An observational cohort study was conducted with data from the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort to investigate weight gain among virologically suppressed people with HIV (PWH) switching to regimens containing tenofovir alafenamide/emtricitabine/ (TAF/FTC). Virologically suppressed, ART-experienced PWH switching to TAF/FTC with either darunavir/cobicistat (DRV/c), elvitegravir (EVG)/c, dolutegravir (DTG) or bictegravir (BIC) were selected. Cox proportional hazards models were used to assess the risk of excessive weight gain (i.e. ≥5% gain within 28 weeks or ≥10% within 54 weeks), by regimen. A linear mixed effects model with random intercept and restricted cubic splines on time was used to assess continuous changes in weight. Confounding was controlled for with both inverse probability of treatment weighting and traditional covariate adjustment. Among 5,536 PWH, 18% gained ≥5% of their weight within 28 weeks, and 9% gained ≥10% within 54 weeks. There were no differences in the risk of excessive weight gain by regimen, although there was a non-statistically significant 20% increase in the risk of gaining ≥10% within 54 weeks with all regimens compared to DRV/c. Throughout follow-up, the mean predicted weight remained fairly constant, with no notable differentiation between regimens. Expected weight gains ranged from +0.2 kg to +0.3 kg at 6 months and from +0.5 kg to +0.6 kg at 24 months. In conclusion, in this study of virologically suppressed, ART-experienced PWH switching to regimens containing TAF/FTC and either DRV/c, EVG/c, DTG or BIC, up to 18% experienced excessive levels of weight gain. However, no statistically significant difference was observed across regimens.

BACKGROUND:With obesity on the rise among people living with HIV (PLWH), there is growing concern that weight gain may result as an undesired effect of antiretroviral therapy (ART). This analysis sought to assess the association between ART regimens and changes in BMI among ART-experienced, virologically suppressed PLWH. METHODS:ART-experienced, virologically suppressed PLWH ≥18 years of age in the OPERA cohort were included for analysis if prescribed a new regimen containing one of the following core agents: dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), raltegravir (RAL), rilpivirine (RPV), or boosted darunavir (bDRV), for the first time between August 1, 2013 and December 31, 2017. Multivariable linear regression was used to assess the association between regimen and mean changes in BMI at 6, 12, and 24 months after switch. RESULTS:(RPV) at 24 months following switch, but gains were observed with every regimen. In adjusted analyses, compared to DTG, only bDRV was associated with a smaller increase in BMI at all time points, while EVG/c and RAL were associated with smaller increases in BMI at 6 months only. Overall, results were consistent in analyses stratified by baseline BMI category. CONCLUSION/CONCLUSIONS:BMI increases were relatively small but followed an upward trend over time in this cohort of treatment-experienced, suppressed PLWH. Gains were attenuated with a longer period of follow-up. BMI gains did not differ by regimens, except for bDRV regimens which were consistently associated with smaller BMI increases than DTG.

Preventing HIV transmission is a crucial step in ending the HIV epidemic. Safe and effective pre-exposure prophylaxis (PrEP) has been available in the United States since 2012. We set out to determine if persons at greatest risk for HIV acquisition were receiving HIV PrEP. HIV-negative individuals from the Observational Pharmaco-Epidemiology Research & Analysis (OPERA) cohort who were prescribed daily PrEP were contrasted with newly diagnosed HIV persons without PrEP use between July 16, 2012 and October 31, 2020 to determine if the PrEP prescriptions reached the populations who were seroconverting. Poisson regression was used to estimate incidence rates of seroconversion to HIV among PrEP initiators, as well as new diagnoses of sexually transmitted infections among both the PrEP group and the newly HIV+ group. Out of the 14,598 PrEP users and 3558 persons newly diagnosed with HIV in OPERA, demographics varied widely. Older individuals, those of non-Black race, men, nonintravenous (IV) drug users, and those with commercial insurance were proportionally overrepresented among those prescribed PrEP compared to persons newly diagnosed with HIV during the same time period. Over 82% of new HIV+ individuals received care in the southern United States compared to only 45% of PrEP users. Seroconversion to HIV among PrEP users was generally uncommon, although more frequent among those who identified as Black individuals, especially in the 13-25 years old age range. In conclusion, providers need innovative programs to better identify, educate, and link those at greatest risk of HIV acquisition, especially young people, women, Black individuals, and IV drug users, to PrEP.