Showing papers by "Joseph J. Eron published in 2022"

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

Abstract: 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.

Viral and Symptom Rebound in Untreated COVID-19 Infection

Abstract: Background: There are reports of viral RNA and symptom rebound in people with COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories of COVID-19 has not been well described, we evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19. Methods: The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants recorded the severity of 13 targeted symptoms daily from day 0 to 28. Viral rebound was defined as [≥]0.5 log10 viral RNA copies/mL increase and symptom rebound was defined as a 4-point total symptom score increase from baseline. Baseline was defined as study day 4 (primary analysis) or 8 days from symptom onset (secondary analysis). Findings: In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to [≥]5.0 log10 RNA copies/mL and symptom rebound after initial improvement was observed in 1-2% of participants. Interpretation: Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare. Funding: This study was supported by the National Institute of Allergy and Infectious Diseases; ACTIV-2/A5401 ClinicalTrials.gov number NCT04518410.

Antiviral and clinical activity of bamlanivimab in a randomized trial of non-hospitalized adults with COVID-19

Abstract: Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94; 700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82-1.05 for 7000 mg [p(overall) = 0.88] and 0.81-1.21 for 700 mg [p(overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [p = 0.97], 7000 mg; 24 vs 20.5 days [p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2.

Factors Associated With Severity of COVID-19 Disease in a Multicenter Cohort of People With HIV in the United States, March–December 2020

Abstract: Supplemental Digital Content is Available in the Text. Background: Understanding the spectrum of COVID-19 in people with HIV (PWH) is critical to provide clinical guidance and risk reduction strategies. Setting: Centers for AIDS Research Network of Integrated Clinic System, a US multisite clinical cohort of PWH in care. Methods: We identified COVID-19 cases and severity (hospitalization, intensive care, and death) in a large, diverse HIV cohort during March 1, 2020–December 31, 2020. We determined predictors and relative risks of hospitalization among PWH with COVID-19, adjusted for disease risk scores. Results: Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March and December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized, and 12 died. PWH with current CD4 count <350 cells/mm3 [aRR 2.68; 95% confidence interval (CI): 1.93 to 3.71; P < 0.001] or lowest recorded CD4 count <200 cells/mm3 (aRR 1.67; 95% CI: 1.18 to 2.36; P < 0.005) had greater risks of hospitalization. HIV viral load and antiretroviral therapy status were not associated with hospitalization, although most of the PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared with other racial/ethnic groups (aRR 1.51; 95% CI: 1.04 to 2.19; P = 0.03). Chronic kidney disease, chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher hospitalization risk. PWH who were older, not on antiretroviral therapy, and with current CD4 count <350 cells/mm3, diabetes, and chronic kidney disease were overrepresented among PWH who required intubation or died. Conclusions: PWH with CD4 count <350 cells/mm3, and a history of CD4 count <200 cells/mm3, have a clear excess risk of severe COVID-19, accounting for comorbidities associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination and early treatment and monitored closely for worsening illness.

Mortality for adults entering HIV care under universal early treatment compared to the general US population.

Abstract: BACKGROUND Mortality among adults with HIV remains elevated over mortality in the US general population even in the years after entry into HIV care. We explore whether the elevation in 5-year mortality would have persisted if all adults with HIV had initiated antiretroviral therapy within 3 months of entering care. METHODS Among 82,766 adults entering HIV care at North American AIDS Cohort Collaboration clinical sites in the United States, we computed mortality over 5 years since entry into HIV care under observed treatment patterns. We then used inverse probability weights to estimate mortality under universal early treatment. To compare mortality with similar individuals in the general population, we used National Center for Health Statistics data to construct a cohort representing the subset of the US population matched to study participants on key characteristics. RESULTS For the entire study period (1999 - 2017), 5-year mortality among adults with HIV was 7.9 percentage points (95% confidence interval (CI): 7.6, 8.2) higher than the expected mortality based on the US general population. Under universal early treatment, the elevation in mortality for people with HIV would have been 7.2% (95% CI: 5.8, 8.6). In the most recent calendar period examined (2011-2017), the elevation in mortality for people with HIV was 2.6 percentage points (95% CI: 2.0, 3.3) under observed treatment patterns and 2.1 percentage points (95% CI: 0.0, 4.2) under universal early treatment. CONCLUSIONS Expanding early treatment may modestly reduce, but not eliminate, the elevation in mortality for people with HIV.

Comparative Pharmacokinetics of Tixagevimab/Cilgavimab (AZD7442) Administered Intravenously Versus Intramuscularly in Symptomatic SARS‐CoV‐2 Infection

Abstract: AZD7442 (Evusheld) is a combination of two human anti‐severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) monoclonal antibodies (mAbs), tixagevimab (AZD8895) and cilgavimab (AZD1061). Route of administration is an important consideration to improve treatment access. We assessed pharmacokinetics (PKs) of AZD7442 absorption following 600 mg administered intramuscularly (i.m.) in the thigh compared with 300 mg intravenously (i.v.) in ambulatory adults with symptomatic COVID‐19. PK analysis included 84 of 110 participants randomized to receive i.m. AZD7442 and 16 of 61 randomized to receive i.v. AZD7442. Serum was collected prior to AZD7442 administration and at 24 hours and 3, 7, and 14 days later. PK parameters were calculated using noncompartmental methods. Following 600 mg i.m., the geometric mean maximum concentration (Cmax) was 38.19 μg/mL (range: 17.30–60.80) and 37.33 μg/mL (range: 14.90–58.90) for tixagevimab and cilgavimab, respectively. Median observed time to maximum concentration (Tmax) was 7.1 and 7.0 days for tixagevimab and cilgavimab, respectively. Serum concentrations after i.m. dosing were similar to the i.v. dose (27–29 μg/mL each component) at 3 days. The area under the concentration‐time curve (AUC)0–7d geometric mean ratio was 0.9 for i.m. vs. i.v. Participants with higher weight or body mass index were more likely to have lower concentrations with either route. Women appeared to have higher interparticipant variability in concentrations compared with men. The concentrations of tixagevimab and cilgavimab after administration i.m. to the thigh were similar to those achieved with i.v. after 3 days from dosing. Exposure in the i.m. group was 90% of i.v. over 7 days. Administration to the thigh can be considered to provide consistent mAb exposure and improve access.

Monoclonal antibody treatment drives rapid culture conversion in SARS-CoV-2 infection

Abstract: •Longitudinal sampling of participants treated with monoclonal antibody bamlinivimab•Treatment with bamlanivimab results in rapid clearance of culturable SARS-CoV-2•Culturable virus detected upon viral rebound is linked to emergent mutations Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p < 0.0001). Recrudescence of culturable virus is detected in three participants with emerging mAb resistance and viral RNA rebound. While further studies are necessary to fully define the relationship between shed culturable virus and transmission, these results raise the possibility that mAbs may offer immediate (household) and public-health benefits by reducing onward transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (mAbs) are among the treatments recommended for high-risk ambulatory persons with coronavirus 2019 (COVID-19). Here, we study viral culture dynamics post-treatment in a subset of participants receiving the mAb bamlanivimab in the ACTIV-2 trial (ClinicalTrials.gov: NCT04518410). Viral load by qPCR and viral culture are performed from anterior nasal swabs collected on study days 0 (day of treatment), 1, 2, 3, and 7. Treatment with mAbs results in rapid clearance of culturable virus. One day after treatment, 0 of 28 (0%) participants receiving mAbs and 16 of 39 (41%) receiving placebo still have culturable virus (p < 0.0001). Recrudescence of culturable virus is detected in three participants with emerging mAb resistance and viral RNA rebound. While further studies are necessary to fully define the relationship between shed culturable virus and transmission, these results raise the possibility that mAbs may offer immediate (household) and public-health benefits by reducing onward transmission. As the coronavirus 2019 (COVID-19) pandemic progress, interventions have been developed to prevent transmission and progression to severe disease in infected persons. Monoclonal antibodies (mAbs) were among the first therapies to receive emergency-use authorization (EUA) for the treatment of COVID-19 and remain among the first-line therapy options for the outpatient management of high-risk individuals with mild to moderate COVID-19 (https://www.covid19treatmentguidelines.nih.gov). While the initial circulating strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were susceptible to all mAbs deployed clinically, recently emerging strains, in particular the Omicron variant, are substantially less susceptible to some mAbs.1Planas D. Saunders N. Maes P. Guivel-Benhassine F. Planchais C. Buchrieser J. Bolland W.-H. Porrot F. Staropoli I. Lemoine F. et al.Considerable escape of SARS-CoV-2 Omicron to antibody neutralization.Nature. 2022; 602: 671-675https://doi.org/10.1038/s41586-021-04389-zCrossref PubMed Scopus (255) Google Scholar,2Planas D. Veyer D. Baidaliuk A. Staropoli I. Guivel-Benhassine F. Rajah M.M. Planchais C. Porrot F. Robillard N. Puech J. et al.Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.Nature. 2021; 596: 276-280https://doi.org/10.1038/s41586-021-03777-9Crossref PubMed Scopus (833) Google Scholar Each variant has a unique mAb-susceptibility profile, and guidelines for clinical management have serially changed to account for the resistance pattern of the dominant circulating variant at any given time (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html). Currently, Bebtelovimab is the mAb of choice given its demonstrated activity against BA.1 and BA.2.3Dougan M. Azizad M. Chen P. Feldman B. Frieman M. Igbinadolor A. Kumar P. Morris J. Potts J. Baracco L. et al.Bebtelovimab, alone or together with bamlanivimab and etesevimab, as a broadly neutralizing monoclonal antibody treatment for mild to moderate, ambulatory COVID-19.medRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.03.10.22272100Crossref Scopus (0) Google Scholar,4Westendorf K. Zentelis S. Wang L. Foster D. Vaillancourt P. Wiggin M. Lovett E. van der Lee R. Hendle J. Pustilnik A. et al.LY-CoV1404 (bebtelovimab) potently neutralizes SARS-CoV-2 variants.Cell Rep. 2022; 39: 110812https://doi.org/10.1016/j.celrep.2022.110812Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar Interestingly, data suggest that emerging variants are not inevitably more broadly resistant to mAbs but may regain sensitivity to mAbs not active against earlier variants5Takashita E. Kinoshita N. Yamayoshi S. Sakai-Tagawa Y. Fujisaki S. Ito M. Iwatsuki-Horimoto K. Halfmann P. Watanabe S. Maeda K. et al.Efficacy of antiviral agents against the SARS-CoV-2 omicron subvariant BA.2.N. Engl. J. Med. 2022; 386: 1475-1477https://doi.org/10.1056/NEJMc2201933Crossref PubMed Scopus (45) Google Scholar (https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab-etesevimab/Pages/resumption-in-distribution-bamlanivimabetesevimab.aspx). All mAbs used to date for COVID-19 target the interaction between the SARS-CoV-2 spike protein and the ACE2 receptor on host cells, effectively blocking viral uptake. mAbs differ primarily in their binding site on the spike protein and potentially the affinity with which they bind; all mAbs currently in clinical use are of the immunoglobulin G1 (IgG1) subclass. Given that all mAbs have the same target and mechanism of action and are of the same subclass, clinical phenotypes observed upon treatment with one effective mAb are highly likely to be common to all effective mAbs. mAbs have been shown to accelerate the decay of SARS-CoV-2 levels in the upper respiratory tract,6Dougan M. Nirula A. Azizad M. Mocherla B. Gottlieb R.L. Chen P. Hebert C. Perry R. Boscia J. Heller B. et al.Bamlanivimab plus etesevimab in mild or moderate covid-19.N. Engl. J. Med. 2021; 385: 1382-1392https://doi.org/10.1056/NEJMoa2102685Crossref PubMed Scopus (177) Google Scholar,7Weinreich D.M. Sivapalasingam S. Norton T. Ali S. Gao H. Bhore R. Musser B.J. Soo Y. Rofail D. Im J. et al.REGN-COV2, a neutralizing antibody cocktail, in outpatients with covid-19.N. Engl. J. Med. 2021; 384: 238-251https://doi.org/10.1056/NEJMoa2035002Crossref PubMed Scopus (739) Google Scholar but their effects on duration of shedding culturable virus is unknown. While viral RNA is commonly used to assess viral burden, shedding of culturable virus could be a more sensitive indicator of antiviral activity. Further, in the absence of a proven correlate of infectiousness, culturable virus has been considered the best available proxy for the ability to transmit infection.8Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. Niemeyer D. Jones T.C. Vollmar P. Rothe C. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469https://doi.org/10.1038/s41586-020-2196-xCrossref PubMed Scopus (3729) Google Scholar We hypothesized that reduction in shedding of culturable virus might occur more rapidly than reduction in anterior nasal SARS-CoV-2 RNA levels following mAb treatment. A full understanding of the potential benefits and limitations of mAbs and other treatments would help determine their optimal use for preventing and treating SARS-CoV-2 infection. Bamlanivimab is a neutralizing mAb that received EUA as a treatment for individuals 12 years of age and older with mild to moderate COVID-19 in November 2020.9Chen P. Nirula A. Heller B. Gottlieb R.L. Boscia J. Morris J. Huhn G. Cardona J. Mocherla B. Stosor V. et al.SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with covid-19.N. Engl. J. Med. 2021; 384: 229-237https://doi.org/10.1056/NEJMoa2029849Crossref PubMed Scopus (649) Google Scholar We performed viral culture analysis of participants enrolled in the ACTIV-2 randomized placebo-controlled trial of bamlanivimab monotherapy for non-hospitalized adults with mild to moderate COVID-1910Chew K.W. Moser C. Daar E.S. Wohl D.A. Li J.Z. Coombs R. Ritz J. Giganti M. Javan A.C. Li Y. et al.Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.12.17.21268009Crossref Scopus (0) Google Scholar (ClinicalTrials.gov: NCT04518410). In that study, bamlanivimab treatment reduced respiratory tract (nasopharyngeal) viral RNA levels by 3 days post-treatment. In this work, we sought to understand how mAb treatment impacts the dynamics of shedding culturable SARS-CoV-2. To compare shedding of culturable virus and change in anterior nasal (AN) sample SARS-CoV-2 RNA over time after treatment with mAbs, we cultured virus from AN swabs collected from participants enrolled in the ACTIV-2 study10Chew K.W. Moser C. Daar E.S. Wohl D.A. Li J.Z. Coombs R. Ritz J. Giganti M. Javan A.C. Li Y. et al.Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.12.17.21268009Crossref Scopus (0) Google Scholar who had a baseline (pre-treatment, day 0) viral load of ≥6 log10 SARS-CoV-2 RNA copies/mL and available swab samples from study days 0, 1, 2, 3, and 7. Participants with evidence of bamlanivimab resistance mutations at baseline or during follow up based on our previous viral sequencing work11Choudhary M.C. Chew K.W. Deo R. Flynn J.P. Regan J. Crain C.R. Moser C. Hughes M. Ritz J. Ribeiro R.M. et al.Emergence of SARS-CoV-2 resistance with monoclonal antibody therapy.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.09.03.21263105Crossref Scopus (0) Google Scholar were excluded for the primary analysis. Of the 317 participants in the ACTIV-2 study, 69 met inclusion criteria for the primary analysis in this study: 310 had available day 0 AN swabs, 94 had baseline viral load ≥6 log10 SARS-CoV-2 RNA copies/mL, and 73 had swabs available at days 0, 1, 2, 3, and 7. Four participants were excluded from the primary analysis due to emergent resistance identified in our previous work.11Choudhary M.C. Chew K.W. Deo R. Flynn J.P. Regan J. Crain C.R. Moser C. Hughes M. Ritz J. Ribeiro R.M. et al.Emergence of SARS-CoV-2 resistance with monoclonal antibody therapy.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.09.03.21263105Crossref Scopus (0) Google Scholar Of the 69 participants meeting inclusion criteria, 39 were in the placebo arm and 30 were in the bamlanivimab arm (20 received the 7,000 mg dose and 10 received the 700 mg dose). Baseline participant characteristics, including age, race, comorbidities, days of symptoms before enrollment, and serostatus, were similar between groups (Table S1). Spike sequencing demonstrated that the majority of strains fell into SARS-CoV-2 clade 20A, with the remainder in clades 20B, 20C, 20E, and 20G (Figures S1A and S1B). No strains were variants of concern. Baseline AN RNA level was similar between groups (Figure 1A). Baseline viral culturability, as determined by cytopathic effect (CPE), was also similar between groups, with 39/39 (100%) participants in the placebo arm and 28/30 (93%) participants in the mAb arm with culture-positive baseline sample (Figure 1A). The two participants with baseline negative cultures were excluded from further analysis. For samples showing CPE (39 placebo and 28 mAb samples), we calculated the semiquantitative viral culture titer (tissue culture infectious dose 50 [TCID50]); the relationship between SARS-CoV-2 RNA and semiquantitative viral TCID50 was similar between groups at the time of enrollment (Figure 1B). Participants received either placebo or bamlanivimab on day 0. AN sample SARS-CoV-2 RNA was assessed prior to treatment (day 0) and at study days 1, 2, 3, and 7 post-treatment. Shedding of culturable virus was assessed prior to treatment (day 0) and at study days 1–7 post-treatment for all samples with viral loads >2 log10. While study day 1 AN swab viral RNA levels were similar between arms (Figures 1C and S2A), a significant difference in culture positivity was observed on day 1. In the placebo arm, the culture-positivity rate was 16/39 (41%) versus 0/28 (0%) in the bamlanivimab arm (p < 0.0001; Figures 1D and S2B). In the placebo arm on day 1, the lowest viral load associated with a positive culture was 5.5 log10 RNA copies/mL, and 16/25 (64%) of placebo-arm samples with a viral load ≥5.5 log10 RNA copies/mL were also found to be culture positive. In contrast, all 18 samples from the bamlanivimab arm with viral loads ≥5.5 log10 RNA copies/mL were culture negative. By day 2 post-treatment, 7 of 39 (18%) participants in the placebo arm were still culture positive; all participants in the bamlanivimab arm remained culture negative. On day 3, eight of 37 tested placebo participants remained culture positive, and on study day 7, one placebo participant remained culture positive. All bamlanivimab-treated participants remained culture negative from day 1 onward. To assess whether treatment with other mAbs would drive similarly rapid culture conversion, we queried a database developed as part of the POSITIVES study.12Boucau J. Marino C. Regan J. Uddin R. Choudhary M.C. Flynn J.P. Chen G. Stuckwisch A.M. Mathews J. Liew M.Y. et al.Duration of viable virus shedding in SARS-CoV-2 omicron variant infection.medRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.03.01.22271582Crossref Scopus (0) Google Scholar, 13Regan J. Flynn J.P. Choudhary M.C. Uddin R. Lemieux J. Boucau J. Bhattacharyya R.P. Barczak A.K. Li J.Z. Siedner M.J. Detection of the omicron variant virus with the Abbott BinaxNow SARS-CoV-2 rapid antigen assay.Open Forum Infect. Dis. 2022; 9: ofac022https://doi.org/10.1093/ofid/ofac022Crossref PubMed Scopus (6) Google Scholar, 14Seaman M.S. Siedner M.J. Boucau J. Lavine C.L. Ghantous F. Liew M.Y. Mathews J. Singh A. Marino C. Regan J. et al.Vaccine breakthrough infection with the SARS-CoV-2 delta or omicron (BA.1) variant leads to distinct profiles of neutralizing antibody responses.medRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.03.02.22271731Crossref PubMed Scopus (0) Google Scholar, 15Siedner M.J. Boucau J. Gilbert R.F. Uddin R. Luu J. Haneuse S. Vyas T. Reynolds Z. Iyer S. Chamberlin G.C. Duration of viral shedding and culture positivity with post-vaccination SARS-CoV-2 delta variant infections.JCI Insight. 2022; 7: e155483https://doi.org/10.1172/jci.insight.155483Crossref PubMed Scopus (11) Google Scholar The POSITIVES study is a longitudinal cohort of patients newly diagnosed with COVID-19; following enrollment, nasal swabs are collected thrice weekly for 2 weeks. Each sample is simultaneously analyzed by whole-genome sequencing, spike sequencing, viral load determination, and viral culture. As of April 20, 2022, 109 immunocompetent patients had been enrolled in the cohort; analysis of the dataset revealed that six individuals had received mAb therapy after a positive baseline culture (4 Delta variant treated with casirivimab/imdevimab, 1 Delta variant treated with bamlanivimab/etesevimab, and 1 Omicron variant infection treated with sotrovimab). Analyzing viral load (VL) and TCID50 for those patients revealed that all six had durable viral culture conversion at the sample taken subsequent to mAb treatment (Figure S3). Sampling was performed less frequently than for ACTIV-2 participants, but these results support the idea that mAb treatment drives viral culture conversion. Viral resistance to bamlanivimab monotherapy has been described both in vitro and clinically, with resistance attributed to defined mutations in the SARS-CoV-2 spike protein.2Planas D. Veyer D. Baidaliuk A. Staropoli I. Guivel-Benhassine F. Rajah M.M. Planchais C. Porrot F. Robillard N. Puech J. et al.Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.Nature. 2021; 596: 276-280https://doi.org/10.1038/s41586-021-03777-9Crossref PubMed Scopus (833) Google Scholar,11Choudhary M.C. Chew K.W. Deo R. Flynn J.P. Regan J. Crain C.R. Moser C. Hughes M. Ritz J. Ribeiro R.M. et al.Emergence of SARS-CoV-2 resistance with monoclonal antibody therapy.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.09.03.21263105Crossref Scopus (0) Google Scholar,16Wang P. Nair M.S. Liu L. Iketani S. Luo Y. Guo Y. Wang M. Yu J. Zhang B. Kwong P.D. et al.Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.Nature. 2021; 593: 130-135https://doi.org/10.1038/s41586-021-03398-2Crossref PubMed Scopus (935) Google Scholar We previously identified participants from ACTIV-2 with emergent bamlanivimab resistance mutations,11Choudhary M.C. Chew K.W. Deo R. Flynn J.P. Regan J. Crain C.R. Moser C. Hughes M. Ritz J. Ribeiro R.M. et al.Emergence of SARS-CoV-2 resistance with monoclonal antibody therapy.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.09.03.21263105Crossref Scopus (0) Google Scholar and these individuals were excluded from our primary analysis. We hypothesized that early viral culture clearance observed following bamlanivimab treatment was due to mAb binding and neutralization of virions and that mAb-resistance emergence would lead to renewed shedding of culturable virus. To test this hypothesis, we evaluated four participants with treatment-emergent bamlanivimab resistance mutations identified in our previous work;11Choudhary M.C. Chew K.W. Deo R. Flynn J.P. Regan J. Crain C.R. Moser C. Hughes M. Ritz J. Ribeiro R.M. et al.Emergence of SARS-CoV-2 resistance with monoclonal antibody therapy.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.09.03.21263105Crossref Scopus (0) Google Scholar virus from three participants had emergent E484K mutation and one had emergent E484Q mutation. All four participants had positive viral cultures at day 0; similar to other participants in the bamlanivimab treatment arm of this substudy, all four individuals converted their cultures to negative on day 1 (Figure 2A). However, the emergence of the E484K mutation following bamlanivimab treatment in the three participants was associated with rebound in VLs and return of positive viral cultures with rising TCID50 levels (Figures 2B–2D). The participant with emergent E484Q mutation in their infecting virus had only modest increases in VL and no re-emergence of positive viral cultures (Figure 2E). Our results demonstrate that mAb treatment drives a rapid reduction in AN shedding of culturable virus that precedes a detectable reduction in viral RNA level. To date, most experimental estimates of SARS-CoV-2 transmission have been based on population-level studies. Very few studies have prospectively evaluated transmission, and to our knowledge, no correlates of infectiousness have been definitively identified. Shedding viable virus is highly likely to be a necessary condition for infectiousness, and previous studies have suggested a duration of shedding culturable virus that correlates with an epidemiologically informed understanding of the period of infectiousness.8Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. Niemeyer D. Jones T.C. Vollmar P. Rothe C. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469https://doi.org/10.1038/s41586-020-2196-xCrossref PubMed Scopus (3729) Google Scholar In the absence of proven correlates of infectiousness, shedding culturable virus is a reasonable proxy for the potential to transmit infection. While targeted prospective studies will be needed to precisely define the relationship between SARS-CoV-2 culture positivity in any given assay and disease transmission, our results suggest that treatment with mAbs may markedly reduce the period that an individual with COVID-19 infection remains infectious. While bamlanivimab is not currently in clinical use, the identical molecular targets and mechanisms of action of all SARS-CoV-2-targeting mAbs that have been used clinically make it likely that our finding of rapid culture clearance will translate similarly to other mAb treatments. Indeed, our limited data for other variants and mAbs support this proposition (Figure S3). Whether this reduction in shedding of culturable virus is unique to mAbs or would be similarly observed with other treatments, such as antiviral drugs with different mechanisms of action, is incompletely known. A recent study demonstrating reduction in culturable SARS-CoV-2 by study day 3 in participants treated with molnupiravir relative to placebo suggests that this benefit may not be specific to mAb treatment but may hold across a range of COVID-19 therapies.17Fischer W. Eron J.J. Holman W. Cohen M.S. Fang L. Szewczyk L.J. Sheahan T.P. Baric R. Mollan K.R. Wolfe C.R. et al.Molnupiravir, an oral antiviral treatment for COVID-19.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.06.17.21258639Crossref Scopus (0) Google Scholar Targeted studies of the impact of various treatments on culture conversion will be needed to definitively determine those most likely to impact shedding of culturable virus. Our results additionally have implications for the potential of treated individuals to evolve and transmit SARS-CoV-2 strains with acquired resistance mutations. Re-emergence of culturable virus in a subset of ACTIV-2 participants with treatment-emergent mAb resistance suggests that the development of resistance mutations may lead to a return of infectiousness and the risk of transmission of mAb-resistant strains. The recrudescent shedding of culturable virus in a subset of mAb-treated individuals also suggests that time to initial culture conversion and sustained culture conversion provide complementary information. While rapid culture conversion may reflect a reduced initial period of infectiousness, sustained culture conversion would reflect durable loss of infectiousness. Lessons can potentially be taken from optimized management of HIV, in which combination therapy has been shown to be the most effective means of preventing viral evolution and the consequent emergence of resistant virus. Focused studies explicitly testing combinations of agents would potentially be helpful in defining optimal treatment regimens for COVID-19. While bamlanivimab is not currently used clinically, our resistance-related findings remain relevant given the recent reliance on the single mAb regimen sotrovimab and the report of emerging resistance against this regimen.18Rockett R.J. Basile K. Maddocks S. Fong W. Agius J.E. Mackinnon J.J. Arnott A. Chandra S. Gall M. Draper J. et al.Resistance conferring mutations in sars-cov-2 delta following sotrovimab infusion.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.12.18.21267628Crossref Scopus (0) Google Scholar Bebtelovimab is the most recent mAb to be granted EUA status (https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-new-monoclonal-antibody-treatment-covid-19-retains); whether resistance will emerge as it is more widely used to treat infections with newly emerging variants remains to be determined. Moving COVID-19 from a pandemic disease to an endemic disease will require making optimal use of the full arsenal of available interventions for prevention and treatment. While COVID-19 therapies have, to date, been evaluated based on benefit to the treated individual, our results suggest that mAbs may have an additional role to play in reducing the period of infectiousness and consequently reducing the risk of secondary transmission. CDC recommendations for the duration of isolation following COVID-19 infection have recently changed (https://www.cdc.gov/media/releases/2021/s1227-isolation-quarantine-guidance.html); the optimal duration of isolation remains unclear. If mAbs reduce the period that an individual remains infectious, such interventions could ultimately be used to reduce the recommended time of isolation, conferring significant individual and societal benefits. Understanding the virologic consequences of therapeutic interventions for SARS-CoV-2 infection is critical for informing the optimal deployment of COVID-19 therapies as we seek to shift toward an endemic phase of the disease and for informing public-health recommendations after treatment. Our cohort is comprised of individuals with symptomatic infection who were unvaccinated based on study timing. In this substudy, we focused on the subset of individuals most likely to have positive baseline cultures, namely those with baseline viral RNA level of ≥6 log10 SARS-CoV-2 RNA copies/mL. Based on the association we have previously observed between SARS-CoV-2 AN RNA level and likelihood of shedding culturable virus,15Siedner M.J. Boucau J. Gilbert R.F. Uddin R. Luu J. Haneuse S. Vyas T. Reynolds Z. Iyer S. Chamberlin G.C. Duration of viral shedding and culture positivity with post-vaccination SARS-CoV-2 delta variant infections.JCI Insight. 2022; 7: e155483https://doi.org/10.1172/jci.insight.155483Crossref PubMed Scopus (11) Google Scholar,19North C.M. Barczak A. Goldstein R.H. Healy B.C. Finkelstein D.M. Ding D.D. Kim A. Boucau J. Shaw B. Gilbert R.F. et al.Determining the incidence of asymptomatic SARS-CoV-2 among early recipients of COVID-19 vaccines (DISCOVER-COVID-19): a prospective cohort study of healthcare workers before, during and after vaccination.Clin. Infect. Dis. 2022; 74: 1275-1278https://doi.org/10.1093/cid/ciab643Crossref PubMed Scopus (6) Google Scholar,20Yonker L.M. Boucau J. Regan J. Choudhary M.C. Burns M.D. Young N. Farkas E.J. Davis J.P. Moschovis P.P. Bernard Kinane T. et al.Virologic features of severe acute respiratory syndrome coronavirus 2 infection in children.J. Infect. Dis. 2021; 224: 1821-1829https://doi.org/10.1093/infdis/jiab509Crossref PubMed Scopus (18) Google Scholar individuals with lower baseline viral RNA would be more likely to be culture negative at presentation. The precise relationship between baseline AN-swab-culture positivity, RNA level, and viral transmissibility remains to be precisely defined; whether with further optimization, virus could be reliably cultured from samples with lower viral RNA levels remains to be determined. However, the potential benefits of rapid culture conversion and reduced transmission might be greatest for individuals with high viral RNA levels and those presenting early in the course of illness, who are most likely to be culture positive.8Wölfel R. Corman V.M. Guggemos W. Seilmaier M. Zange S. Müller M.A. Niemeyer D. Jones T.C. Vollmar P. Rothe C. et al.Virological assessment of hospitalized patients with COVID-2019.Nature. 2020; 581: 465-469https://doi.org/10.1038/s41586-020-2196-xCrossref PubMed Scopus (3729) Google Scholar Because of available specimens, each individual was only sampled once for each time point. While this is typical for clinical cohort sampling, our measurements are likely noisier than they would be if duplicate sampling were possible. The nature of our samples makes positive controls internal to each specimen impossible. However, the randomized, placebo-controlled study design offers a solid comparison, as any sampling variability would be expected to be evenly distributed between groups. While we anticipate that results with bamlanivimab will translate to other mAbs, bamlanivimab, like all mAbs previously or currently in use as COVID-19 therapies, is an IgG1 subclass antibody. Not all antibody subclasses have the same distribution within the body, and it is possible that any future mAbs of different subclasses may not have similar effects. The members of the POSITIVES study team who are not otherwise listed as authors on the manuscript are Grace C. Chamberlin, Geoffrey Chen, Rebecca F. Gilbert, Surabhi L. Iyer, Jacob E. Lemieux, May Y. Liew, Taryn Lipiner, Caitlin Marino, Josh Mathews, Zahra Reynolds, Mark J. Siedner, Arshdeep Singh, Ashley M. Stuckwisch, Rockib Uddin, Tammy D. Vyas, and Jatin M. Vyas. Tabled 1REAGENT or RESOURCESOURCEIDENTIFIERBacterial and virus strainsIsolate USA-WA1/2020, GenBank: MN985325BEI ResourcesCat# NR-52281Biological samplesRemnant nasal swab samples in viral transport media – ACTIV2 trialChew et al., 2021 (ref.10Chew K.W. Moser C. Daar E.S. Wohl D.A. Li J.Z. Coombs R. Ritz J. Giganti M. Javan A.C. Li Y. et al.Bamlanivimab reduces nasopharyngeal SARS-CoV-2 RNA levels but not symptom duration in non-hospitalized adults with COVID-19.medRxiv. 2021; (Preprint at)https://doi.org/10.1101/2021.12.17.21268009Crossref Scopus (0) Google Scholar)N/ANasal swab samples in viral transport media – POSITIVES studyBoucau et al., 2022 (ref.12Boucau J. Marino C. Regan J. Uddin R. Choudhary M.C. Flynn J.P. Chen G. Stuckwisch A.M. Mathews J. Liew M.Y. et al.Duration of viable virus shedding in SARS-CoV-2 omicron variant infection.medRxiv. 2022; (Preprint at)https://doi.org/10.1101/2022.03.01.22271582Crossref Scopus (0) Google Scholar) or This studyN/AChemicals, peptides, and recombinant proteinsDulbecco’s Modified Eagle MediumFisher ScientificCat# MT10013CVHEPESFisher ScientificCat# MT25060CIPenicillin/StreptomycinFisher ScientificCat# MT30001CIGlutamineThermo ScientificCat# 35050061Fetal Bovine serumSigmaCat# F4135Trypsin-EDTAFisher ScientificCat# 25-200-072PolybreneSanta Cruz BiotechnologyCat# sc-134220Deposited dataGene Expression OmnibusAccession NumberPRJNA816433Experimental models: Cell linesVero-E6ATCCCat# CRL-1586Software and algo

Racial and ethnic disparities in coronavirus disease 2019 disease incidence independent of comorbidities, among people with HIV in the United States

Abstract: Objectives: 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. Design: Observational study within the CFAR Network of Integrated Clinical Systems cohort in seven cities during 2020. Methods: 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. Results: 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. Conclusion: 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.

The prevalence of mental health disorders in people with HIV and the effects on the HIV care continuum

Abstract: Objective: To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHDs). Design: Observational study of participants in the North American AIDS Cohort Collaboration on Research and Design. Methods: PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008 to 2018 based on International Classification of Diseases code mapping. Mental health (MH) multimorbidity was defined as having two or more MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥1 visit/year) and viral suppression (HIV RNA ≤200 copies/ml) by presence vs. absence of each MHD between 2016 and 2018. Results: Among 122 896 PWH, 67 643 (55.1%) were diagnosed with one or more MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008 and 2018, whereas bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016 to 2018 (N = 64 684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR = 0.98 [0.98–0.99]) as did PWH with MH multimorbidity (aPR = 0.99 [0.99–1.00]) compared with PWH without MHD. Conclusion: The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.

Natural Killer Cell Receptors and Ligands Are Associated With Markers of HIV-1 Persistence in Chronically Infected ART Suppressed Patients

Abstract: The latent HIV-1 reservoir represents a major barrier to achieving a long-term antiretroviral therapy (ART)-free remission or cure for HIV-1. Natural Killer (NK) cells are innate immune cells that play a critical role in controlling viral infections and have been shown to be involved in preventing HIV-1 infection and, in those who are infected, delaying time to progression to AIDS. However, their role in limiting HIV-1 persistence on long term ART is still uncharacterized. To identify associations between markers of HIV-1 persistence and the NK cell receptor-ligand repertoire, we used twin mass cytometry panels to characterize the peripheral blood NK receptor-ligand repertoire in individuals with long-term antiretroviral suppression enrolled in the AIDS Clinical Trial Group A5321 study. At the time of testing, participants had been on ART for a median of 7 years, with virological suppression <50 copies/mL since at most 48 weeks on ART. We found that the NK cell receptor and ligand repertoires did not change across three longitudinal samples over one year—a median of 25 weeks and 50 weeks after the initial sampling. To determine the features of the receptor-ligand repertoire that associate with markers of HIV-1 persistence, we performed a LASSO normalized regression. This analysis revealed that the NK cell ligands CD58, HLA-B, and CRACC, as well as the killer cell immunoglobulin-like receptors (KIRs) KIR2DL1, KIR2DL3, and KIR2DS4 were robustly predictive of markers of HIV-1 persistence, as measured by total HIV-1 cell-associated DNA, HIV-1 cell-associated RNA, and single copy HIV-RNA assays. To characterize the roles of cell populations defined by multiple markers, we augmented the LASSO analysis with FlowSOM clustering. This analysis found that a less mature NK cell phenotype (CD16+CD56dimCD57-LILRB1-NKG2C-) was associated with lower HIV-1 cell associated DNA. Finally, we found that surface expression of HLA-Bw6 measured by CyTOF was associated with lower HIV-1 persistence. Genetic analysis revealed that this was driven by lower HIV-1 persistence in HLA-Bw4/6 heterozygotes. These findings suggest that there may be a role for NK cells in controlling HIV-1 persistence in individuals on long-term ART, which must be corroborated by future studies.

Brief Report: Insomnia and Risk of Myocardial Infarction Among People With HIV

Abstract: Supplemental Digital Content is Available in the Text. Background: Insomnia 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. Setting: Longitudinal cohort study of PWH at 5 Centers for AIDS Research Network of Integrated Clinical Systems sites. Methods: Clinical 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). Results: Among 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). Conclusions: PWH 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.

Associations between drug and alcohol use, smoking, and frailty among people with HIV across the United States in the current era of antiretroviral treatment.

Abstract: To examine associations between frailty and drug, alcohol, and tobacco use among a large diverse cohort of people with HIV (PWH) in clinical care in the current era.PWH at 7 sites across the United States completed clinical assessments of patient-reported measures and outcomes between 2016 and 2019 as part of routine care including drug and alcohol use, smoking, and other domains. Frailty was assessed using 4 of the 5 components of the Fried frailty phenotype and PWH were categorized as not frail, pre-frail, or frail. Associations of substance use with frailty were assessed with multivariate Poisson regression.Among 9336 PWH, 43% were not frail, 44% were prefrail, and 13% were frail. Frailty was more prevalent among women, older PWH, and those reporting current use of drugs or cigarettes. Current methamphetamine use (1.26: 95% CI 1.07-1.48), current (1.65: 95% CI 1.39-1.97) and former (1.21:95% CI 1.06-1.36) illicit opioid use, and former cocaine/crack use (1.17: 95% CI 1.01-1.35) were associated with greater risk of being frail in adjusted analyses. Current smoking was associated with a 61% higher risk of being frail vs. not frail (1.61: 95% CI 1.41-1.85) in adjusted analyses.We found a high prevalence of prefrailty and frailty among a nationally distributed cohort of PWH in care. This study identified distinct risk factors that may be associated with frailty among PWH, many of which, such as cigarette smoking and drug use, are potentially modifiable.

Bamlanivimab therapy for acute COVID-19 does not blunt SARS-CoV-2–specific memory T cell responses

Abstract: Despite the widespread use of SARS-CoV-2–specific monoclonal antibody (mAb) therapy for the treatment of acute COVID-19, the impact of this therapy on the development of SARS-CoV-2–specific T cell responses has been unknown, resulting in uncertainty as to whether anti–SARS-CoV-2 mAb administration may result in failure to generate immune memory. Alternatively, it has been suggested that SARS-CoV-2–specific mAb may enhance adaptive immunity to SARS-CoV-2 via a “vaccinal effect.” Bamlanivimab (Eli Lilly and Company) is a recombinant human IgG1 that was granted FDA emergency use authorization for the treatment of mild to moderate COVID-19 in those at high risk for progression to severe disease. Here, we compared SARS-CoV-2–specific CD4+ and CD8+ T cell responses of 95 individuals from the ACTIV-2/A5401 clinical trial 28 days after treatment with bamlanivimab versus placebo. SARS-CoV-2–specific T cell responses were evaluated using activation-induced marker assays in conjunction with intracellular cytokine staining. We demonstrate that most individuals with acute COVID-19 developed SARS-CoV-2–specific T cell responses. Overall, our findings suggest that the quantity and quality of SARS-CoV-2–specific T cell memory were not diminished in individuals who received bamlanivimab for acute COVID-19. Receipt of bamlanivimab during acute COVID-19 neither diminished nor enhanced SARS-CoV-2–specific cellular immunity.

Risk factors for atrial fibrillation in a multi-center US clinical cohort of people with HIV infection.

Abstract: To assess atrial fibrillation (AF) risk factors in people with HIV, we identified incident AF in a large clinical cohort of people receiving care. Compared with 970 controls without AF, the 97 with adjudicated incident AF were older, less likely Hispanic, and had more coronary disease, heart failure, and chronic obstructive pulmonary disease. In multivariable analysis, non-use of antiretroviral therapy and prescription of antiretroviral regimens with multiple core agents were associated with increased AF risk.

Tobacco smoking and binge alcohol use are associated with incident venous thromboembolism in an HIV cohort

Abstract: People with HIV (PWH) are at increased risk of cardiovascular comorbidities and substance use is a potential predisposing factor. We evaluated associations of tobacco smoking and alcohol use with venous thromboembolism (VTE) in PWH.

Predictors of SARS-CoV-2 RNA From Nasopharyngeal Swabs and Concordance With Other Compartments in Nonhospitalized Adults With Mild to Moderate COVID-19

Abstract: Abstract Background Identifying characteristics associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding may be useful to understand viral compartmentalization, disease pathogenesis, and risks for viral transmission. Methods Participants were enrolled August 2020 to February 2021 in ACTIV-2/A5401, a placebo-controlled platform trial evaluating investigational therapies for mild-to-moderate coronavirus disease 2019 (COVID-19), and underwent quantitative SARS-CoV-2 RNA testing on nasopharyngeal and anterior nasal swabs, oral wash/saliva, and plasma at entry (day 0, pretreatment) and days 3, 7, 14, and 28. Concordance of RNA levels (copies/mL) across compartments and predictors of nasopharyngeal RNA levels were assessed at entry (n = 537). Predictors of changes over time were evaluated among placebo recipients (n = 265) with censored linear regression models. Results Nasopharyngeal and anterior nasal RNA levels at study entry were highly correlated (r = 0.84); higher levels of both were associated with greater detection of RNA in plasma and oral wash/saliva. Older age, White non-Hispanic race/ethnicity, lower body mass index (BMI), SARS-CoV-2 immunoglobulin G seronegativity, and shorter prior symptom duration were associated with higher nasopharyngeal RNA at entry. In adjusted models, body mass index and race/ethnicity associations were attenuated, but the association with age remained (for every 10 years older, mean nasopharyngeal RNA was 0.27 log10 copies/mL higher; P < .001). Examining longitudinal viral RNA levels among placebo recipients, women had faster declines in nasopharyngeal RNA than men (mean change, −2.0 vs −1.3 log10 copies/mL, entry to day 3; P < .001). Conclusions SARS-CoV-2 RNA shedding was concordant across compartments. Age was strongly associated with viral shedding, and men had slower viral clearance than women, which could explain sex differences in acute COVID-19 outcomes.

Current Antiretroviral Treatment Among People With Hiv In The Us: Findings From The Cnics Cohort.

Abstract: Among 14,049 people with HIV in care in 2019-2020, 96% were treated with antiretroviral therapy (ART). Current antiretroviral treatment patterns highlight high uptake of guideline-recommended ART regimens including second-generation integrase strand transfer inhibitors (dolutegravir, bictegravir) and tenofovir alafenamide, especially in ARV-naïve individuals initiating ART.

Comparative sensitivity of automated (Abbott M2000) and manual plasma HIV-1 RNA PCR assays for the detection of persistent viremia after long-term antiretroviral therapy

Abstract: The ability of automated, FDA-cleared plasma HIV-1 RNA assays to detect low-level viremia, compared to manual, highly sensitive research-only methods, is not well-defined. We therefore tested paired plasma samples from people with HIV-1 (PWH) on long-term antiretroviral therapy (ART) with both the Abbott M2000 RealTime HIV-1 Viral Load assay (Abbott) and a quantitative reverse transcriptase (RT)-initiated PCR assay that has a reported 95% detection limit of 1 HIV-1 RNA copy/ml (single copy assay, SCA).Plasma samples from 309 participants in the AIDS Clinical Trials Group study A5321 were tested by both Abbott and SCA. Participants were mostly men (82%). All were on stable ART for a median of 7 years with HIV-1 RNA <40 copies/mL by Abbott. Pooled plasma from each donor was divided and tested. Abbott results were reported as target detected <40 copies/mL but not quantifiable (target detected <40) or target not detected (TND), and SCA results were classified as HIV-1 RNA detected or not detected.By Abbott, 17% (51/309) of sample results were target detected <40, whereas 83% (258/309) were TND. Of the samples that were target detected <40 by Abbott, 73% (37/51) had HIV-1 RNA detected by SCA. By contrast, 43% of samples that were TND by Abbott (110/258) had HIV-1 RNA detected by SCA (p < 0.001).Plasma samples from PWH with HIV-1 RNA detected but <40 copies/ml by the automated Abbott M2000 assay are likely (73% of 51 samples) to have HIV-1 RNA detected by an optimized manual assay with single copy sensitivity. An Abbott HIV-1 RNA result of target not detected did not exclude low-level viremia: 43% of 258 samples had HIV-1 RNA detected by the single copy assay. These findings indicate that the Abbott M2000 assay cannot exclude the persistence of viremia on ART and thus may have less utility, compared to a manual single copy assay, for assessing the impact of experimental interventions designed to eliminate low-level viremia as a step towards achieving ART-free HIV-1 remission.

1063. Female sex and SARS-CoV-2 Serostatus Predict Nasopharyngeal RNA Clearance during Early COVID-19

Abstract: Predictors of SARS-CoV-2 RNA levels and changes over time during early COVID-19 are not well characterized. 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. 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. 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. 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.

881. Nasal and Plasma SARS-CoV-2 RNA Levels Predict Timing of Symptom Resolution in the ACTIV-2 Trial of Non-hospitalized Adults with COVID-19

Abstract: Abstract 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.

1400. Emergency Department (ED) Use among Persons With HIV (PWH) before and during the COVID-19 Pandemic

Abstract: Abstract 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.

Nasal and Plasma SARS-CoV-2 RNA Levels are Associated with Timing of Symptom Resolution in the ACTIV-2 Trial of Non-hospitalized Adults with COVID-19

Abstract: Abstract Acute COVID-19 symptoms limit daily activities, but little is known about its association with SARS-CoV-2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal (AN) RNA levels and detectable plasma RNA were associated with delayed symptom improvement.

Chronic obstructive pulmonary disease and the risk for myocardial infarction by type in people with HIV

Abstract: Objectives: The relationship between chronic obstructive pulmonary disease (COPD) and cardiovascular disease in people with HIV (PWH) is incompletely understood. We determined whether COPD is associated with risk of myocardial infarction (MI) among PWH, and if this differs for type 1 (T1MI) and type 2 (T2MI). Design: We utilized data from five sites in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, a multisite observational study. Methods: Our primary outcome was an adjudicated MI, classified as T1MI or T2MI. We defined COPD based on a validated algorithm requiring COPD diagnosis codes and at least 90-day continuous supply of inhalers. We conducted time-to-event analyses to first MI and used multivariable Cox proportional hazards models to measure associations between COPD and MI. Results: Among 12 046 PWH, 945 had COPD. Overall, 309 PWH had an MI: 58% had T1MI (N = 178) and 42% T2MI (N = 131). In adjusted models, COPD was associated with a significantly increased risk of all MI [adjusted hazard ratio (aHR) 2.68 (95% confidence interval (CI) 1.99–3.60)] even after including self-reported smoking [aHR 2.40 (95% CI 1.76–3.26)]. COPD was also associated with significantly increased risk of T1MI and T2MI individually, and with sepsis and non-sepsis causes of T2MI. Associations were generally minimally changed adjusting for substance use. Conclusion: COPD is associated with a substantially increased risk for MI, including both T1MI and T2MI, among PWH. Given the association with both T1MI and T2MI, diverse mechanistic pathways are involved. Future strategies to decrease risk of T1MI and T2MI in PWH who have COPD are needed.

Development and integration of IPV-4, a patient-reported screening instrument of intimate partner violence for primary and HIV care

Abstract: ,

2073. Persistent HIV-1 Viremia Despite Intensive Antiviral Therapy Due to Non-responsive Clonal Viral Lineages

Abstract: Abstract 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.