Search

Vaporized nicotine (VN) use is increasing among people with HIV (PWH). We examined demographics, patterns of use, depression, and panic symptoms associated with VN and combustible cigarette (CC) use among PWH.We analyzed VN use among PWH in care at 7 US sites. PWH completed a set of patient-reported outcomes, including substance use and mental health. We categorized VN use as never vs. ever with frequency of use (days/month) and CC use as never, former, or current. We used relative risk regression to associate VN and CC use, depression, and panic. Linear regression estimated each relationship with VN frequency. Models were adjusted for demographics.Among 7,431 PWH, 812 (11%) reported ever-using VN, and 264 (4%) reported daily use. Half (51%) of VN users concurrently used CC. VN users were more likely than those without use to be younger, white, and to report ever-using CC. PWH reporting former CC use reported ≥8.5 more days per month of VN use compared to never CC use (95%CI: 5.5-11.5 days/month) or current (95%CI: 6.6-10.5 days/month). Depression (RR: 1.20 [95%CI: 1.02-1.42]) and panic disorder (1.71 [95%CI: 1.43-2.05]) were more common among PWH ever-using VN. Depression was common among PWH using VN (27%) and CC (22%), as was panic disorder (21% for VN, 16% for CC).Our study elucidated demographic associations with VN use among PWH, revealed overlap of VN and CC use, and associations with depression/panic symptoms, suggesting roles of VN in self-medication and CC substitution, warranting further longitudinal/qualitative research.

Describe health of transgender women (TW) with HIV vs. cisgender men and women (CM, CW) in a U.S. HIV care cohort. Data were from Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), 2005–2022. TW were identified using clinical data/identity measures. PWH (n = 1285) were included in analyses (275 TW, 547 CM, 463 CW). Cross-sectional multivariable analyses compared HIV outcomes/co-morbidities between TW/CM and TW/CW, and adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were estimated. TW had poorer adherence (> 90% adherent; aOR 0.57; 95%CI 0.38, 0.87) and were more likely to miss ≥ 3 visits in the past year than CM (aOR 1.50, 95%CI 1.06, 2.10); indicated more anxiety compared to both CM and CW (p ≤ 0.001, p = 0.02); hepatitis C infection (p = 0.03) and past-year/lifetime substance treatment (p = 0.004/p = 0.001) compared to CM; and substance use relative to CW. TW with HIV differed in HIV clinical outcomes and co-morbidities from CM and CW.

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement.Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410.

People with HIV (PWH) have persistently elevated levels of inflammation and immune activation despite suppressive antiretroviral therapy (ART), with specific biomarkers showing associations with non-AIDS-defining morbidities and mortality. We investigated the potential role of the HIV-specific adaptive immune response, which also persists under ART, in driving levels of these clinically relevant biomarkers.Cohort-based study.HIV-specific IFN-γ-producing T-cell responses and antibody concentrations were measured in blood at study entry in the ACTG A5321 cohort, following a median of 7 years of suppressive ART. HIV persistence measures including cell-associated (CA)-DNA, CA-RNA, and plasma HIV RNA (single-copy assay) were also assessed at study entry. Plasma inflammatory biomarkers and T-cell activation and cycling were measured at a pre-ART time point and at study entry.Neither the magnitudes of HIV-specific T-cell responses nor HIV antibody levels were correlated with levels of the inflammatory or immune activation biomarkers, including hs-CRP, IL-6, neopterin, sCD14, sCD163, TNF-α, %CD38 + HLA-DR + CD8 + and CD4 + cells, and %Ki67 + CD8 + and CD4 + cells - including after adjustment for pre-ART biomarker level. Plasma HIV RNA levels were modestly correlated with CD8 + T-cell activation ( r = 0.25, P = 0.027), but other HIV persistence parameters were not associated with these biomarkers. In mediation analysis, relationships between HIV persistence parameters and inflammatory biomarkers were not influenced by either HIV-specific T-cell responses or antibody levels.Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.

To define the incidence of clinically detected coronavirus disease 2019 (COVID-19) in people with HIV (PWH) in the United States and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19.Observational study within the CFAR Network of Integrated Clinical Systems cohort in seven cities during 2020.We calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4+ cell count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores.Among 16 056 PWH in care, of whom 44.5% were black, 12.5% were Hispanic, with a median age of 52 years (IQR 40-59), 18% had a current CD4+ cell count less than 350 cells/μl, including 7% less than 200; 95.5% were on antiretroviral therapy (ART), and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and black PWH respectively, than non-Hispanic white PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or black identity, lowest historical CD4+ cell count less than 350 cells/μl (proxy for CD4+ nadir), current low CD4+ : CD8+ ratio, diabetes, and obesity.Our results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWH. PWH with immune exhaustion as evidenced by lowest historical CD4+ cell count or current low CD4+ : CD8+ ratio had greater risk of COVID-19.

BackgroundInsomnia is common among people with HIV (PWH) and may be associated with increased risk of myocardial infarction (MI). This study examines the association between insomnia and MI by MI type among PWH.SettingLongitudinal cohort study of PWH at 5 Centers for AIDS Research Network of Integrated Clinical Systems sites.MethodsClinical data and patient-reported measures and outcomes from PWH in care between 2005 and 2018 were used in this study. Insomnia, measured at baseline, was defined as having difficulty falling or staying asleep with bothersome symptoms. The Centers for AIDS Research Network of Integrated Clinical Systems centrally adjudicates MIs using expert reviewers, with distinction between type 1 MI (T1MI) and type 2 MI (T2MI). Associations between insomnia and first incident MI by MI type were measured using separate Cox proportional hazard models adjusted for age, sex, race/ethnicity, traditional cardiovascular disease risk factors (hypertension, dyslipidemia, poor kidney function, diabetes, and smoking), HIV markers (antiretroviral therapy, viral suppression, and CD4 cell count), and stimulant use (cocaine/crack and methamphetamine).ResultsAmong 12,448 PWH, 48% reported insomnia. Over a median of 4.4 years of follow-up, 158 T1MIs and 109 T2MIs were identified; approximately half of T2MIs were attributed to sepsis or stimulant use. After adjustment for potential confounders, we found no association between insomnia and T1MI (hazard ratio = 1.05, 95% confidence interval: 0.76 to 1.45) and a 65% increased risk of T2MI among PWH reporting insomnia compared with PWH without insomnia (hazard ratio = 1.65, 95% confidence interval: 1.11 to 2.45).ConclusionsPWH reporting insomnia are at an increased risk of T2MI, but not T1MI, compared with PWH without insomnia, highlighting the importance of distinguishing MI types among PWH.

Most clinical trials evaluating COVID-19 therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal SARS-CoV-2 RNA levels from baseline were commonly assessed using analysis of covariance (ANCOVA) or mixed models for repeated measures (MMRM) with single-imputation for results below assay lower limits of quantification (LLoQ). Analyzing changes in viral RNA levels with singly-imputed values can lead to biased estimates of treatment effects. In this paper, using an illustrative example from the ACTIV-2 trial, we highlight potential pitfalls of imputation when using ANCOVA or MMRM methods, and illustrate how these methods can be used when considering values

In first-line antiretroviral therapy (ART) for human immunodeficiency virus (HIV) treatment, some subgroups of patients may respond better to an efavirenz-based regimen than an integrase strand transfer inhibitor (InSTI)-based regimen, or vice versa, due to patient characteristics modifying treatment effects. Using data based on nearly 16,000 patients from the North American AIDS Cohort Collaboration on Research and Design from 2009–2016, statistical methods for precision medicine were employed to estimate an optimal treatment rule that minimizes the 5-year risk of the composite outcome of acquired immune deficiency syndrome (AIDS)-defining illnesses, serious non-AIDS events, and all-cause mortality. The treatment rules considered were functions that recommend either an efavirenz- or InSTI-based regimen conditional on baseline patient characteristics such as demographic information, laboratory results, and health history. The estimated 5-year risk under the estimated optimal treatment rule was 10.0% (95% confidence interval (CI): 8.6, 11.3), corresponding to an absolute risk reduction of 2.3% (95% CI: 0.9, 3.8) when compared with recommending an efavirenz-based regimen for all patients and 2.6% (95% CI: 1.0, 4.2) when compared with recommending an InSTI-based regimen for all. Tailoring ART to individual patient characteristics may reduce 5-year risk of the composite outcome compared with assigning all patients the same drug regimen.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4 + and CD8 + T cell activation, lower CD4 + T cell exhaustion, and more robust Gag-specific CD4 + T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4 + T cell% and CD4 + /CD8 + ratio, more functional NK cells, and a lower CD4 + T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Clinical research to achieve antiretroviral therapy-free remission requires quantitative assays of the HIV-1 reservoir. Intact proviral DNA (IPD) measurement has greater throughput than the quantitative viral outgrowth assay (QVOA). In 25 individuals with well-documented long-term viral suppression, IPD levels and infectious units per million CD4+ T cells by QVOA strongly correlated (r = 0.59, P = .002), and IPD correlated with total cell-associated HIV-1 DNA and cell-associated HIV-1 RNA (r = 0.62 and r = 0.59, P ≤ .002). IPD may provide an accessible marker of inducible replication-competent virus, total numbers of infected cells, and cellular expression of HIV-1 RNA.

Objective: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. Methods: Four cohortswith participantswhoinitiatedARTduring acute infection or during chronic infectionwere enrolled in a cross-sectional, noninterventional study.Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIVDNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. Results: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. Conclusion: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.

ImportanceIntegrase strand transfer inhibitor (INSTI)–containing antiretroviral therapy (ART) is currently the guideline-recommended first-line treatment for HIV. Delayed prescription of INSTI-containing ART may amplify differences and inequities in health outcomes.ObjectivesTo estimate racial and ethnic differences in the prescription of INSTI-containing ART among adults newly entering HIV care in the US and to examine variation in these differences over time in relation to changes in treatment guidelines.Design, Setting, and ParticipantsRetrospective observational study of 42 841 adults entering HIV care from October 12, 2007, when the first INSTI was approved by the US Food and Drug Administration, to April 30, 2019, at more than 200 clinical sites contributing to the North American AIDS Cohort Collaboration on Research and Design.ExposuresCombined race and ethnicity as reported in patient medical records.Main Outcomes and MeasuresProbability of initial prescription of ART within 1 month of care entry and probability of being prescribed INSTI-containing ART. Differences among non-Hispanic Black and Hispanic patients compared with non-Hispanic White patients were estimated by calendar year and time period in relation to changes in national guidelines on the timing of treatment initiation and recommended initial treatment regimens.ResultsOf 41 263 patients with information on race and ethnicity, 19 378 (47%) as non-Hispanic Black, 6798 (16%) identified as Hispanic, and 13 539 (33%) as non-Hispanic White; 36 394 patients (85%) were male, and the median age was 42 years (IQR, 30 to 51). From 2007-2015, when guidelines recommended treatment initiation based on CD4+ cell count, the probability of ART initiation within 1 month of care entry was 45% among White patients, 45% among Black patients (difference, 0% [95% CI, −1% to 1%]), and 51% among Hispanic patients (difference, 5% [95% CI, 4% to 7%]). From 2016-2019, when guidelines strongly recommended treating all patients regardless of CD4+ cell count, this probability increased to 66% among White patients, 68% among Black patients (difference, 2% [95% CI, −1% to 5%]), and 71% among Hispanic patients (difference, 5% [95% CI, 1% to 9%]). INSTIs were prescribed to 22% of White patients and only 17% of Black patients (difference, −5% [95% CI, −7% to −4%]) and 17% of Hispanic patients (difference, −5% [95% CI, −7% to −3%]) from 2009-2014, when INSTIs were approved as initial therapy but were not yet guideline recommended. Significant differences persisted for Black patients (difference, −6% [95% CI, −8% to −4%]) but not for Hispanic patients (difference, −1% [95% CI, −4% to 2%]) compared with White patients from 2014-2017, when INSTI-containing ART was a guideline-recommended option for initial therapy; differences by race and ethnicity were not statistically significant from 2017-2019, when INSTI-containing ART was the single recommended initial therapy for most people with HIV.Conclusions and RelevanceAmong adults entering HIV care within a large US research consortium from 2007-2019, the 1-month probability of ART prescription was not significantly different across most races and ethnicities, although Black and Hispanic patients were significantly less likely than White patients to receive INSTI-containing ART in earlier time periods but not after INSTIs became guideline-recommended initial therapy for most people with HIV. Additional research is needed to understand the underlying racial and ethnic differences and whether the differences in prescribing were associated with clinical outcomes.

ImportanceRecent advances in treatment and prevention of HIV warrant updated recommendations to guide optimal practice.ObjectiveBased 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 ReviewA 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.FindingsInitiation 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 RelevanceAdvances in treatment and prevention of HIV continue to improve outcomes, but challenges and opportunities remain.

Background Symptoms during acute COVID-19 can limit daily activities and delay return to work and school. Little is known about the association between SARS-CoV-2 burden in either the upper airway or plasma and the duration of COVID-19 symptoms. Methods ACTIV-2/A5401 is a platform trial for COVID-19 treatments in non-hospitalized symptomatic adults enrolled within 10 days of symptom onset. We included participants randomized to placebo from August 2020 to July 2021. Participants self-reported severity of 13 symptoms daily from day 0 (baseline) to 28 as Absent 0, Mild 1, Moderate 2, Severe 3; total symptom score was calculated as the sum of all scores. Anterior nasal (AN) and plasma SARS-CoV-2 RNA levels at day 0 were measured with a quantitative qPCR assay. The relationship between day 0 RNA and time to symptom improvement or resolution (first of 2 consecutive days of all symptoms improved or resolved from day 0, respectively) was evaluated using proportional hazards regression adjusted for time from symptom onset. Time to resolution of distinct symptoms was also assessed. Results Among 570 participants randomized to placebo, median age was 48 years, 51% were female, and median time since symptom onset at baseline was 6 days; 7% had prior COVID-19 vaccination. At day 0, AN RNA was detectable in 80% with a median of 4.1 log10 copies/ml (n=533, quartiles: 1.7, 6.0) and plasma RNA was detectable in 19% (91/476). Detectable plasma RNA at day 0, but not AN RNA, was associated with more severe symptoms at day 0 (2.4-point higher mean total symptom score, P=0.001). Both high AN (≥6 vs < 2 log10 copies/ml, adjusted hazard ratio [aHR] 0.63, P=0.001) and detectable plasma RNA (aHR 0.74, P=0.03) at day 0 predicted delayed symptom improvement. High AN RNA at day 0 also predicted a delay in symptom resolution (aHR 0.59, P=0.001). Both high AN RNA and detectable plasma RNA levels predicted delays in the resolution of cough and shortness of breath. Detectable plasma RNA also predicted delayed body pain resolution. Conclusion COVID-19 outpatients with high AN or detectable plasma SARS-CoV-2 RNA at day 0 are more likely to have prolonged symptoms, particularly respiratory symptoms. Additional studies are needed to determine whether the decline in viral load with early treatment impacts symptom duration. Disclosures Kara W. Chew, M.D., M.S., Merck Sharp & Dohme: Grant/Research Support|Pardes Bioscences: Advisor/Consultant Joseph J. Eron, MD, GSK: Advisor/Consultant|Merck: Advisor/Consultant Eric S. Daar, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Merck: Advisor/Consultant|ViiV: Advisor/Consultant|ViiV: Grant/Research Support David A. Wohl, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Lilly: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Judith S. Currier, M.D., MSc, Merck: Advisor/Consultant Davey M. Smith, M.D., M.A.S., Arena Pharmaceuticals: Advisor/Consultant|Bayer Pharmaceuticals: Advisor/Consultant|Brio Clinical.: Advisor/Consultant|Fluxergy: Advisor/Consultant|Kiadis: Advisor/Consultant|Linear Therapies: Advisor/Consultant|Matrix BioMed: Advisor/Consultant|Model Medicines: Advisor/Consultant|Signant Health: Advisor/Consultant|VxBiosciences: Advisor/Consultant Jonathan Z. Li, MD, MMSc, Abbvie: Advisor/Consultant|Merck: Grant/Research Support.

Background Predictors of SARS-CoV-2 RNA levels and changes over time during early COVID-19 are not well characterized. Methods ACTIV-2 is a phase II/III randomized, placebo-controlled, platform trial to evaluate investigational agents for treatment of COVID-19 in non-hospitalized adults. Participants enrolled within 10 days of symptom onset. Nasopharyngeal samples were collected for SARS-CoV-2 RNA testing on Days 0, 3, 7, 14 and 28; RNA was quantified with qPCR assay. SARS-CoV-2 seropositivity was defined as detectable IgG to any of nucleocapsid, receptor binding domain, S1 and S2 antigens by Bio-Plex multiplex assay. Censored linear regression and repeated measures Poisson models evaluated predictors of RNA including age, sex, race, ethnicity, risk of severe COVID-19, diabetes, BMI, obesity (BMI > 35 kg/m2) and serostatus. Results The study enrolled 537 participants from Aug 2020 to July 2021 at US sites. Median age was 48 years; 49% were female sex, >99% cis-gender, 83% white, 29% Hispanic/Latino, and 21% had BMI > 35 kg/m2. At Day 0, median symptom duration was 6 days, 50% were seropositive (2 were vaccinated) and 17% had RNA below the lower limit of quantification (LLoQ). Higher Day 0 RNA was associated with shorter symptom duration (Spearman correlation = -0.40, p< 0.001), as well as older age, white race, lower BMI and seronegativity, even when adjusting for symptom duration (all p< 0.03). Among the 203 on placebo with Day 0 RNA ≥ LLoQ, female sex had larger decreases in RNA at Day 3 vs male sex (difference in mean change: -0.8 log10 copies/mL (95% CI: -1.2, -0.4), p< 0.001) when adjusted for symptom duration and Day 0 RNA; this difference was also observed when evaluating the proportion with RNA < LLoQ at Day 3 (Risk Ratio (95% CI): 2.38 (1.11, 5.09)). Seropositivity at Day 0 was associated with higher probability of RNA < LLoQ at Days 3 and 7 (p< 0.001) in adjusted models. Seropositivity at Day 0 did not differ by sex. Conclusion In this well characterized clinical trial cohort, shorter symptom duration, older age, white race, lower BMI and seronegativity were associated with higher RNA in early infection. Female sex and seropositivity were associated with earlier viral clearance. Further research is needed to determine if viral decay differences mediated by these host factors influence clinical outcomes. Disclosures Joseph J. Eron, MD, Adagio Therapeutics: data safety monitoring committee|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Eric S. Daar, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|GSK/ViiV: Advisor/Consultant|GSK/ViiV: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support David A. Wohl, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Lilly: Grant/Research Support|Merck: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Rachel A. Bender Ignacio, MD, MPH, Abbvie: Advisor/Consultant|SeaGen: Advisor/Consultant Justin Ritz, M.S., Alnylam Pharmaceuticals: Stocks/Bonds Urvi Parikh, PhD, Merck: Advisor/Consultant Judith S. Currier, M.D., MSc, Merck and Company: Advisor/Consultant Davey M. Smith, M.D., M.A.S., BAYER: Advisor/Consultant|Kiadis: Advisor/Consultant|Linear Therapies: Advisor/Consultant|Linear Therapies: Stocks/Bonds|MODEL MEDICINES: Advisor/Consultant|MODEL MEDICINES: Stocks/Bonds|Vx Biosciences: Advisor/Consultant|Vx Biosciences: Stocks/Bonds Kara W. Chew, M.D., M.S., Merck Sharp & Dohme: Grant/Research Support.

Background Substantial changes in access and delivery of primary HIV care occurred during the COVID-19 pandemic. To assess how care access changed during the COVID-19 pandemic, we estimated ED use among PWH in care 2017-2021 in the southeastern US. Methods For each calendar year, among PWH in care in the UNC CFAR HIV Clinical Cohort (defined as having a clinic visit in the current or prior year), we estimated the percent of patients with ≥ 1 ED visit in a given year, overall and by age, gender, race/ethnicity, HIV viral load (VL), and CD4 count. We estimated risk ratios (RRs) comparing patient characteristics and years 2020-2021 vs. 2017-2019, using Poisson regression with generalized estimating equations to account for repeated measures. Results Among 2129 PWH in care 2017-2021 (N≈1700-1800 in each year), 57% identified as Black, 31% White, 8% Hispanic, 26% women, with median age of 47 years (IQR 35-55). During the study period, there were 3645 ED visits over 8813 person-years, a rate of 41.4 ED visits-per 100 person-years(95% CI 36.8-46.5) per 100 person-years. The 845 PWH with at least one ED visit during the study period contributed a median of 2 visits each (IQR 1-5). The unadjusted probability of having ≥1 ED visit in a given year was higher among women vs. men (RR=1.14, 95% CI 0.99-1.32), Black vs. White PWH (1.31, 1.13-1.52), with VL ≥ 40 copies/mL (1.40, 1.20-1.64), and with CD4 < 200 (1.66, 1.32-2.09) or 200-349 (1.50, 1.25-1.79) vs. ≥ 500 cells/μL; age was not associated with ED use. Compared with 2017-2019, the annual probability of having ≥ 1 ED visit was lower in 2020-2021, with RRs of 0.83 (95% CI 0.76-0.90) in unadjusted analyses and 0.80 (95% CI 0.71-0.90) after adjusting for demographics, VL, and CD4. There was also a significant unadjusted decrease for 2020-2021 vs. 2017-2019 among women, men, PWH who were Black, White, < 40 or 50-59 years old, and with CD4 >500 (Fig. B-F, all P< 0.05). Conclusion Among PWH in HIV care, ED use was higher among women, Black PWH, and PWH with poorly controlled HIV. ED use decreased 2020-2021 in most groups, indicating that PWH during the COVID-19 pandemic may be delaying seeking care for acute conditions, or accessing care in other ways. Work is ongoing to characterize reasons for ED visits across calendar years and examine the impact of reduced ED utilization among PWH. Disclosures Joseph J. Eron, MD, Adagio Therapeutics: data safety monitoring committee|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

Background The marked increase in injecting drug use (IDU) in the past decade presents concern for increased HIV transmission among people who inject drugs (PWID) and explosive outbreaks. Among statewide HIV molecular surveillance, we assessed demographic, clinical, and reported behavioral risk factors associated with HIV clusters involving PWID in North Carolina (NC). Methods Persons ≥ 13 years old with HIV-infection residing in NC with ≥ 1 partial pol sequence collected between April 2010 and December 2021 were included in the study. We used an automated cluster analysis pipeline to detect genetic clusters (nextHIV2), defined as ≥ 2 sequences with a pairwise genetic distance < 1.5%. Logistic regression was used to estimate the risk and adjusted odds ratios of the relationship between the demographic factors that were likely associated with HIV clustering. Graphics were generated using the R packages ggplot2 and igraph. Results Among 19,641 persons with a sequence, 1,611 were PWID. Of these, 347 (21.5%) PWID were members of 248 clusters involving a total of 2,083 persons (size ranged 2–104). Sixty-four clusters (25%) had ≥2 PWID, whereas 2 (1%) included at least 5 PWID. The most commonly injected drug among cluster members was methamphetamine (19%). Overall, in a univariate analysis, younger age, dual risks of male-to-male sex and IDU, having sex under the influence of drugs, recent IDU (past 12 months), acute HIV infection, higher viral loads and higher CD4 T-cell count at the time of HIV diagnosis were significantly associated with clustering PWID individuals (all P< 0.001). In multivariate analyses, only recent IDU and higher CD4 T-cell count at the time of HIV diagnosis were significantly associated with clustering (P< 0.01). In addition, the proportion of PWID in clusters increased from 11.2% in 2010–2013 to 28.5% in 2018–2021 (P< 0.001). Nodes are colored by their reported PWID in darkred and reported non-PWID in blue. Conclusion We detected an increase in HIV genetic clusters among PWID in NC in recent years. Our results support the use of routine local molecular HIV surveillance to identify high priority clusters and offer prevention interventions for specific risk groups to prioritize limited public health resources. Disclosures Joseph J. Eron, MD, GSK: Advisor/Consultant|Merck: Advisor/Consultant.

Background Long-acting injectable antiretroviral therapy (LAI) is an exciting alternative to daily oral ART. Less frequent dosing afforded by LAI may be especially pertinent for persons who inject drugs (PWID), who experience more HIV-related mortality largely driven by inadequate ART adherence. We used the Consolidated Framework on Implementation Research (CFIR) to characterize determinants of LAI implementation, focusing on use among PWID, in Hanoi, Vietnam. Methods We conducted in-depth interviews with HIV-infected PWID, ART providers, and policymakers using purposive sampling, recruiting respondents with diverse ART experience from public HIV/ART clinics and national regulatory agencies. Participants were briefed regarding LAI ART, including administration, effectiveness, side effects, and dosing frequency. Data were coded and analyzed using thematic analysis. Results We interviewed 19 PWID, 14 providers, and five policymakers (February-November, 2021). We identified recurrent themes in CFIR domains. Intervention: All informants were excited about LAI, citing convenience and discrete dosing as major facilitators. Surprisingly, provider concerns, including more frequent clinic visits and injection reactions, were rarely voiced by PWID who described monthly injections as similar to current visit frequency and cited “high pain tolerance.” Outer: Providers and policymakers were eager to offer patients ART choice but were divided as to if LAI distribution should proceed with sub-population prioritization. Inner: Providers described personnel and clinic logistic concerns but were confident these could be addressed. Individual: Providers were motivated and confident in their ability to deliver LAI. Process: Transitions to new ART and provision of COVID-19 vaccines were frequently invoked by providers and policymakers as interventions informing LAI implementation. FigureDeterminants of LAI ART implementation in Vietnam using the domains of the Consolidated Framework on Implementation Research Conclusion Using CFIR, we identified multiple determinants of LAI implementation in Vietnam. Stakeholders agreed that LAI was feasible and acceptable. Medication tolerance and efficacy concerns highlight the importance of patient and provider education. Areas where stakeholders diverge should be considered in designing LAI implementation strategies. Disclosures Joseph J. Eron, MD, Adagio Therapeutics: data safety monitoring committee|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

Background After initiation of antiviral therapy (ART), plasma HIV-1 RNA is usually undetectable after one month. In rare cases, viral suppression may not be achieved despite good adherence and with virus susceptible to ART. We used ultra-deep Primer ID next gen sequencing (NGS) to study the viral population and evolution of HIV-1 in two patients with persistent viremia on intensive ART. Methods We extracted viral RNA from plasma samples collected at multiple timepoints over the duration of the treatment from two patients (VEX1 and VEX2). We constructed Primer ID NGS libraries covering part of the pol gene and the env V1/V3 region and sequenced them on the Illumina MiSeq platform. We used the ‘tcs’ pipeline to construct template consensus sequences (TCS) for each region, and searched for drug resistance mutations (DRMs). The Geno2pheno pipeline was used to predict co-receptor tropisms. Results Patient VEX1 was followed for two years on ART. VEX2 restarted ART in the hospital and received directly observed therapy for nearly 6 months. Both had over 1 million viral copies/mL at the initiation of ART, and the CD4 cell counts were extremely low. Their viral loads slowly declined to approx. 10,000 copies/mL at the end of follow-up but complete viral suppression was not achieved for either patient despite appropriate ART. DRMs were not detected in either patient throughout the treatment with detection sensitivity as low as 0.1%. The sequencing results for VEX1 showed that there were both X4- and R5-tropic viruses at all timepoints and R5 viruses decayed much more slowly than X4 viruses, up to 35-fold more slowly in the initial 3 months of ART. Phylogenetic analysis revealed that the persistent R5 viruses were largely clonal while little clonality was found in the persistent X4 virus. In VEX2, all viruses were R5-tropic. There were three major distinct lineages in the viral population, and two of them completely disappeared after the initiation of ART while the other lineage persisted throughout therapy (Fig 1). The persistent lineage in VEX2 was highly clonal. Pooled maximum likelihood tree at env V1V3 region of 3 time points from patient VEX2. Sequences in red were from 2018 when we obtained the initial specimen from the patient. Sequences in blue were from Sept 2021 when the patient restarted ART. Sequences in green were from Oct 2021 when the patient were on ART for 3 weeks. The patient had 3 major viral lineages, L1, L2, and L3. From 2018 to Sept 2021, we could see the viral evolution of the three lineages (blue arrows). After 3 weeks of ART, L1 and L2 disappeared, while the L3 persisted. We could also see that L3 had several clonal populations which did not respond to ART nor evolve from 2018 to 2021. The additional sequences from Nov 2021 to Feb 2022 were identical to the sequences obtained on Oct 2021 (not shown on this figure). Conclusion Our study shows that persistent viremia on ART can come from clonal viral lineages that carry no DRMs. Clonally expanded and infected host cells might contribute to the phenomenon. Further study is needed to explore the origin of these clonal viral genomes. Disclosures Jonathan Parr, MD, Abbott Laboratories: Donation of laboratory testing and reagents|Gilead Sciences: Grant/Research Support|Virology Education: Honoraria|World Health Organization: Advisor/Consultant|World Health Organization: Grant/Research Support David A. Wohl, M.D., Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Lilly: Grant/Research Support|Merck: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Joseph J. Eron, MD, Adagio Therapeutics: data safety monitoring committee|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Glaxo Smith Kline: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support.

Integrase strand transfer inhibitor (InSTI)-based regimens have been recommended as first-line antiretroviral therapy (ART) for adults with HIV. But data on long-term effects of InSTI-based regimens on virologic outcomes remain limited. Here we examined whether InSTI improved long-term virologic outcomes compared with efavirenz (EFV).We included adults from the North American AIDS Cohort Collaboration on Research and Design who initiated their first ART regimen containing either InSTI or EFV between 2009 and 2016. We estimated differences in the proportion virologically suppressed up to 7 years of follow-up in observational intention-to-treat and per-protocol analyses.Of 15 318 participants, 5519 (36%) initiated an InSTI-based regimen and 9799 (64%) initiated the EFV-based regimen. In observational intention-to-treat analysis, 81.3% of patients in the InSTI group and 67.3% in the EFV group experienced virologic suppression at 3 months after ART initiation, corresponding to a difference of 14.0% (95% CI 12.4-15.6). At 1 year after ART initiation, the proportion virologically suppressed was 89.5% in the InSTI group and 90.2% in the EFV group, corresponding to a difference of -0.7% (95% CI -2.1 to 0.8). At 7 years, the proportion virologically suppressed was 94.5% in the InSTI group and 92.5% in the EFV group, corresponding to a difference of 2.0% (95% CI -7.3 to 11.3). The observational per-protocol results were similar to intention-to-treat analyses.Although InSTI-based initial ART regimens had more rapid virologic response than EFV-based regimens, the long-term virologic effect was similar. Our findings may inform guidelines regarding preferred initial regimens for HIV treatment.

Background Understanding advances in the care and treatment of adults with HIV as well as remaining gaps requires comparing differences in mortality between persons entering care for HIV and the general population. Objective To assess the extent to which mortality among persons entering HIV care in the United States is elevated over mortality among matched persons in the general U.S. population and trends in this difference over time. Design Observational cohort study. Setting Thirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design. Participants 82 766 adults entering HIV clinical care between 1999 and 2017 and a subset of the U.S. population matched on calendar time, age, sex, race/ethnicity, and county using U.S. mortality and population data compiled by the National Center for Health Statistics. Measurements Five-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function. Results Overall 5-year mortality among persons entering HIV care was 10.6%, and mortality among the matched U.S. population was 2.9%, for a difference of 7.7 (95% CI, 7.4 to 7.9) percentage points. This difference decreased over time, from 11.1 percentage points among those entering care between 1999 and 2004 to 2.7 percentage points among those entering care between 2011 and 2017. Limitation Matching on available covariates may have failed to account for differences in mortality that were due to sociodemographic factors rather than consequences of HIV infection and other modifiable factors. Conclusion Mortality among persons entering HIV care decreased dramatically between 1999 and 2017, although those entering care remained at modestly higher risk for death in the years after starting care than comparable persons in the general U.S. population. Primary funding source National Institutes of Health.

As of March 2021, coronavirus disease 2019 (COVID-19) had caused more than 123 million infections and almost 3 million deaths worldwide. Dramatic advances have been made in vaccine development and nonpharmaceutical interventions to stop the spread of infection. However, treatments to stop disease progression are limited. A wide variety of “repurposed” drugs evaluated for treatment of COVID-19 have had little or no benefit. More recently, intravenous monoclonal antibody (mAb) combinations have been authorized by the US Food and Drug Administration for emergency use for outpatients with mild to moderate COVID-19 including some active against emerging severe acute respiratory syndrome coronavirus 2 variants of concern. Easier to administer therapeutics including intramuscular and subcutaneous mAbs and oral antivirals are in clinical trials. Reliable, safe, effective COVID-19 treatment for early infection in the outpatient setting is of urgent and critical importance. Availability of such treatment should lead to reduced progression of COVID-19.

While randomized trials remain the best evidence for treatment effectiveness, lack of generalizability often remains an important concern. Additionally, when new treatments are compared against existing standards of care, the potentially small benefit of the new treatment may be difficult to detect in a trial without extremely large sample sizes and long follow-up times. Recent advances in ‘data fusion’ provide a framework to combine results across studies that are applicable to a given population of interest and allow treatment comparisons that may not be feasible with traditional study designs. We propose a data fusion-based estimator that can be used to combine information from two studies: 1) a study comparing a new treatment to the standard of care in the local population of interest, and 2) a study comparing the standard of care to placebo in a separate, distal population. We provide conditions under which the parameter of interest can be identified from the two studies described and explore properties of the estimator through simulation. Finally, we apply the estimator to estimate the effect of triple- versus monotherapy for the treatment of HIV using data from two randomized trials. The proposed estimator can account for underlying population structures that induce differences in case mix, adherence, and outcome prevalence between the local and distal populations, and the estimator can also account for potentially informative loss to follow-up. Approaches like those detailed here are increasingly important to speed the approval and adoption of effective new therapies by leveraging multiple sources of information.

OBJECTIVE To examine recent trends and differences in all-cause and cause-specific hospitalization rates by race, ethnicity, and gender among persons with HIV (PWH) in the United States and Canada. DESIGN HIV clinical cohort consortium. METHODS We followed PWH at least 18 years old in care 2005-2015 in six clinical cohorts. We used modified Clinical Classifications Software to categorize hospital discharge diagnoses. Incidence rate ratios (IRR) were estimated using Poisson regression with robust variances to compare racial and ethnic groups, stratified by gender, adjusted for cohort, calendar year, injection drug use history, and annually updated age, CD4+, and HIV viral load. RESULTS Among 27 085 patients (122 566 person-years), 80% were cisgender men, 1% transgender, 43% White, 33% Black, 17% Hispanic of any race, and 1% Indigenous. Unadjusted all-cause hospitalization rates were higher for Black [IRR 1.46, 95% confidence interval (CI) 1.32-1.61] and Indigenous (1.99, 1.44-2.74) versus White cisgender men, and for Indigenous versus White cisgender women (2.55, 1.68-3.89). Unadjusted AIDS-related hospitalization rates were also higher for Black, Hispanic, and Indigenous versus White cisgender men (all P

Objectives Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era. Methods Between 2012 and 2019, 3232 ART-naive PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time. Results Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens. Conclusions There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naive PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.