Search

BackgroundIt is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID.MethodsNon-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo.FindingsParticipants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID.InterpretationAmubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID.FundingNational Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

BackgroundAssessing the breadth and duration of antigen-specific binding antibodies provides valuable information for evaluating interventions to treat or prevent SARS-CoV-2 infection. Multiplex immunoassays are a convenient method for rapid measurement of antibody responses but can sometimes provide discordant results, and antibody positive percent agreement for COVID-19 diagnosis can vary depending on assay type, disease severity, and population sampled. Therefore, we compared two assays marked for research applications, MSD and Bio-Plex Pro, to evaluate qualitative interpretation of serostatus and quantitative detection of antibodies of varying isotypes (IgG, IgM, and IgA) against receptor binding domain (RBD) and nucleocapsid (N) antigens.MethodsSpecimens from ACTIV-2/A5401, a placebo-controlled clinical trial of the SARSCoV-2 monoclonal antibody (mAb) bamlanivimab to prevent COVID-19 disease progression, were used to evaluate the concordance of the Bio-Rad Bio-Plex Pro Human SARS-CoV-2 Serology Assay and the Meso Scale Discovery (MSD) V-PLEX COVID-19 Panel 1 serology assay in detecting and quantifying IgG, IgA, and IgM binding anti-SARS-CoV-2 antibody responses against the RBD and N antigens. Data were disaggregated by study arm, bamlanivimab dose, days post-enrollment, and presence of emerging resistance.ResultsWe observed 90.5% (412 of 455 tests) concordance for anti-RBD IgG and 87% (396 of 455) concordance for anti-N IgG in classifying samples as negative or positive based on assay-defined cutoffs. Antibody levels converted to the WHO standard BAU/mL were significantly correlated for all isotypes (IgG, IgM, and IgA) and SARS-CoV-2 antigen targets (RBD and N) tested that were common between the two assays (Spearman r 0.65 to 0.92, P < 0.0001). Both assays uncovered evidence of diminished host-derived IgG immune responses in participants treated with bamlanivimab compared to placebo. Assessment of immune responses in the four individuals treated with the 700 mg of bamlanivimab with emerging mAb resistance demonstrated a stronger anti-N IgG response (MSD) at day 28 (median 2.18 log BAU/mL) compared to participants treated with bamlanivimab who did not develop resistance (median 1.55 log BAU/mL).ConclusionsThese data demonstrate the utility in using multiplex immunoassays for characterizing the immune responses with and without treatment in a study population and provide evidence that monoclonal antibody treatment in acute COVID-19 may have a modest negative impact on development of host IgG responses.

BackgroundAnti-SARS-CoV-2 monoclonal antibodies (mAbs) have played a key role as an anti-viral against SARS-CoV-2, but there is a potential for resistance to develop. The interplay between host antibody responses and the development of monoclonal antibody (mAb) resistance is a critical area of investigation. In this study, we assessed host neutralizing antibody (nAb) responses against both ancestral virus and those with treatment-emergent E484K bamlanivimab resistance mutations.MethodsStudy participants were enrolled in the ACTIV-2/Advancing Clinical Therapeutics Globally (ACTG) A5401 phase 2 randomized, placebo-controlled trial of bamlanivimab 700 mg mAb therapy (NCT04518410). Anterior nasal and nasopharyngeal swabs were collected for SARS-CoV-2 RNA testing and S gene next-generation sequencing to identify the E484K bamlanivimab resistance mutation. Serum nAb titers were assessed by pseudovirus neutralization assays.ResultsHigher baseline (pre-treatment) nAb titers against either ancestral or E484K virus was associated with lower baseline viral load. Participants with emerging resistance had low levels of nAb titers against either ancestral or E484K nAb at the time of study entry. Participants with emergent E484K resistance developed significantly higher levels of E484K-specific nAb titers compared to mAb-treated individuals who did not develop resistance. All participants who developed the E484K mAb resistance mutation were eventually able to clear the virus.ConclusionEmerging drug resistance after SARS-CoV-2-specific mAb therapy led to a heightened host neutralizing antibody response to the mAb-resistant variant that was associated with eventual viral clearance. This demonstrates the interplay between the antiviral treatment-directed viral evolution and subsequent host immune response in viral clearance.

BackgroundOutpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.MethodsACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.ResultsA total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA ConclusionsWhile safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3-4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

BackgroundHospital readmission trends for persons with human immunodeficiency virus (PWH) in North America in the context of policy changes, improved antiretroviral therapy (ART), and aging are not well-known. We examined readmissions during 2005-2018 among adult PWH in NA-ACCORD.MethodsLinear risk regression estimated calendar trends in 30-day readmissions, adjusted for demographics, CD4 count, AIDS history, virologic suppression (

BackgroundWith the emergence of SARS-CoV-2 variants resistant to monoclonal antibody therapies and limited global access to therapeutics, the evaluation of novel therapeutics to prevent progression to severe COVID-19 remains a critical need.MethodsSafety, clinical and antiviral efficacy of inhaled interferon-β1a (SNG001) were evaluated in a phase II randomized controlled trial on the ACTIV-2/A5401 platform (ClinicalTrials.govNCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized and initiated either orally inhaled nebulized SNG001 given once daily for 14 days (n = 110) or blinded pooled placebo (n = 110) between February 10 and August 18, 2021.FindingsThe proportion of participants reporting premature treatment discontinuation was 9% among SNG001 and 13% among placebo participants. There were no differences between participants who received SNG001 or placebo in the primary outcomes of treatment emergent Grade 3 or higher adverse events (3.6% and 8.2%, respectively), time to symptom improvement (median 13 and 9 days, respectively), or proportion with unquantifiable nasopharyngeal SARS-CoV-2 RNA at days 3 (28% [26/93] vs. 39% [37/94], respectively), 7 (65% [60/93] vs. 66% [62/94]) and 14 (91% [86/95] vs. 91% [83/81]). There were fewer hospitalizations with SNG001 (n = 1; 1%) compared with placebo (n = 7; 6%), representing an 86% relative risk reduction (p = 0.07). There were no deaths in either arm.InterpretationIn this trial, SNG001 was safe and associated with a non-statistically significant decrease in hospitalization for COVID-19 pneumonia.FundingThe ACTIV-2 platform study is funded by the NIH. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1 AI068634, UM1 AI068636 and UM1 AI106701. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

BackgroundCamostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults.MethodsWe conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28.ResultsOf 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA ConclusionsIn a phase 2 study of nonhospitalized adults with mild-to-moderate COVID-19, oral camostat did not accelerate viral clearance or time to symptom improvement, or reduce hospitalizations or deaths. Clinical Trials Registration. ClinicalTrials.gov identifier: NCT04518410.

Plasma vascular endothelial growth factor (VEGF) coreceptor neuropilin-1 (NRP-1) had the largest association with coronary plaque in the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) proteomics analysis. With little known about NRP-1 in people with human immunodeficiency virus (PWH), we explored its relation to other proteins in REPRIEVE and validated our findings through a Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) case-cohort study by assessing its relation to host factors and incident cardiovascular disease and cancer. Within REPRIEVE, NRP-1 was associated with proteins involved in angiogenesis, signal transduction, immunoregulation, and cell migration/adhesion. Within CNICS, NRP-1 was associated with key host factors, including older age and male sex. NRP-1 was associated with an increased hazard of multiple cancers but a decreased prostate cancer risk. Finally, NRP-1 was most strongly associated with mortality and type 2 myocardial infarction. These data suggest that NRP-1 is part of a clinically relevant immunoregulatory pathway related to multiple comorbidities in PWH. Clinical Trials Registration. NCT02344290.

Immunocompromised individuals are disproportionately affected by severe coronavirus disease 2019, but immune compromise is heterogenous, and viral dynamics may vary by the degree of immunosuppression. In this study, we categorized ACTIV-2/A5401 participants based on the extent of immunocompromise into none, mild, moderate, and severe immunocompromise. Moderate/severe immunocompromise was associated with higher nasal viral load at enrollment (adjusted difference in means: 0.47 95% confidence interval, .12-.83 log10 copies/mL) and showed a trend toward higher cumulative nasal RNA levels and plasma viremia compared to nonimmunocompromised individuals. Immunosuppression leads to greater viral shedding and altered severe acute respiratory syndrome coronavirus 2 viral decay kinetics. Clinical Trials Registration. NCT04518410.

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410.

Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04518410.

BackgroundTime to symptom resolution measures were used in outpatient coronavirus disease 2019 (COVID-19) treatment trials without prior validation.MethodsACTIV-2/A5401 trial participants completed a COVID-19 diary assessing 13 targeted symptoms and global experience (overall COVID-19 symptoms, return to pre-COVID-19 health) daily for 29 days. We evaluated concordance of time to sustained (2 days) resolution of all targeted symptoms (TSR) with resolution of overall symptoms and return to health in participants receiving placebo.ResultsThe analysis included 77 high-risk and 81 standard-risk participants with overall median 6 days of symptoms at entry and median age 47 years, 50% female, 82% white, and 31% Hispanic/Latino. Correlation between TSR and resolution of overall symptoms was 0.80 and 0.68, and TSR and return to health, 0.66 and 0.57 for high- and standard-risk groups, respectively. Of the high- and standard-risk participants, 61% and 79%, respectively, achieved targeted symptom resolution, of which 47% and 43%, respectively, reported symptom recurrence. Requiring >2 days to define sustained resolution reduced the frequency of recurrences.ConclusionsThere was good internal consistency between TSR and COVID-19-specific global outcomes, supporting TSR as a trial end point. Requiring >2 days of symptom resolution better addresses natural symptom fluctuations but must be balanced against the potential influence of non-COVID-19 symptoms.Clinical trials registrationNCT04518410.

BackgroundThere is little information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA as a predictor for clinical outcomes in outpatients with mild-to-moderate coronavirus disease 2019 (COVID-19).MethodsAnterior nasal (AN) and plasma SARS-CoV-2 RNA data from 2115 nonhospitalized adults who received monoclonal antibodies (mAbs) or placebo in the ACTIV-2/A5401 trial were analyzed for associations with hospitalization or death.ResultsOne hundred two participants were hospitalized or died through 28 days of follow-up. Higher day 0 (pretreatment) AN RNA was associated with increasing risk of hospitalization/death (risk ratio [RR], 1.24 per log10 copies/mL [95% confidence interval {CI}, 1.04-1.49]) among placebo recipients, ranging from 3% to 16% for

Understanding variant-specific differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral kinetics may explain differences in transmission efficiency and provide insights on pathogenesis and prevention. We evaluated SARS-CoV-2 kinetics from nasal swabs across multiple variants (Alpha, Delta, Epsilon, Gamma) in placebo recipients of the ACTIV-2/A5401 trial. Delta variant infection led to the highest maximum viral load and shortest time from symptom onset to viral load peak. There were no significant differences in time to viral clearance across the variants. Viral decline was biphasic with first- and second-phase decays having half-lives of 11 hours and 2.5 days, respectively, with differences among variants, especially in the second phase. These results suggest that while variant-specific differences in viral kinetics exist, post-peak viral load all variants appeared to be efficiently cleared by the host. Clinical Trials Registration. NCT04518410.

Most clinical trials evaluating coronavirus disease 2019 (COVID-19) therapeutics include assessments of antiviral activity. In recently completed outpatient trials, changes in nasal severe acute respiratory syndrome coronavirus 2 (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 article, 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

BackgroundProspective evaluations of long COVID in outpatients with coronavirus disease 2019 (COVID-19) are lacking. We aimed to determine the frequency and predictors of long COVID after treatment with the monoclonal antibody bamlanivimab in ACTIV-2/A5401.MethodsData were analyzed from participants who received bamlanivimab 700 mg in ACTIV-2 from October 2020 to February 2021. Long COVID was defined as the presence of self-assessed COVID symptoms at week 24. Self-assessed return to pre-COVID health was also examined. Associations were assessed by regression models.ResultsAmong 506 participants, median age was 51 years. Half were female, 5% Black/African American, and 36% Hispanic/Latino. At 24 weeks, 18% reported long COVID and 15% had not returned to pre-COVID health. Smoking (adjusted risk ratio [aRR], 2.41 [95% confidence interval {CI}, 1.34- 4.32]), female sex (aRR, 1.91 [95% CI, 1.28-2.85]), non-Hispanic ethnicity (aRR, 1.92 [95% CI, 1.19-3.13]), and presence of symptoms 22-28 days posttreatment (aRR, 2.70 [95% CI, 1.63-4.46]) were associated with long COVID, but nasal severe acute respiratory syndrome coronavirus 2 RNA was not.ConclusionsLong COVID occurred despite early, effective monoclonal antibody therapy and was associated with smoking, female sex, and non-Hispanic ethnicity, but not viral burden. The strong association between symptoms 22-28 days after treatment and long COVID suggests that processes of long COVID start early and may need early intervention.Clinical trials registrationNCT04518410.

BackgroundSAB-185, a novel fully human IgG polyclonal immunoglobulin product, underwent phase 2 evaluation for nonhospitalized adults with mild-moderate coronavirus disease 2019 (COVID-19).MethodsParticipants received intravenous SAB-185 3840 units/kg (low-dose) or placebo, or 10 240 units/kg (high-dose) or placebo. Primary outcome measures were nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA < lower limit of quantification (LLOQ) at study days 3, 7, and 14, time to symptomatic improvement, and safety through day 28.ResultsTwo-hundred thirteen participants received low-dose SAB-185/placebo (n = 107/106) and 215 high-dose SAB-185/placebo (n = 110/105). The proportions with SARS-CoV-2 RNA < LLOQ were higher for SAB-185 versus placebo at days 3 and 7 and similar at day 14, and significantly higher at day 7 for high-dose SAB-185 versus placebo only, relative risk 1.23 (95% confidence interval, 1.01-1.49). At day 3, SARS-CoV-2 RNA levels were lower with low-dose and high-dose SAB-185 versus placebo: differences in medians of -0.78 log10 copies/mL (P = .08) and -0.71 log10 copies/mL (P = .10), respectively. No difference was observed in time to symptom improvement: median 11/10 days (P = .24) for low-dose SAB-185/placebo and 8/10 days (P = .50) for high-dose SAB-185/placebo. Grade ≥3 adverse events occurred in 5%/13% of low-dose SAB-185/placebo and 9%/12% of high-dose SAB-185/placebo.ConclusionsSAB-185 was safe and generally well tolerated and demonstrated modest antiviral activity in predominantly low-risk nonhospitalized adults with COVID-19. Clinical Trials Registration. NCT04518410.

Brain microglia (MG) may serve as a human immunodeficiency virus 1 (HIV) reservoir and ignite rebound viremia following cessation of antiretroviral therapy (ART), but they have yet to be proven to harbor replication-competent HIV. Here, we isolated brain myeloid cells (BrMCs) from nonhuman primates and rapid autopsy of people with HIV (PWH) on ART and sought evidence of persistent viral infection. BrMCs predominantly displayed microglial markers, in which up to 99.9% of the BrMCs were TMEM119+ MG. Total and integrated SIV or HIV DNA was detectable in the MG, with low levels of cell-associated viral RNA. Provirus in MG was highly sensitive to epigenetic inhibition. Outgrowth virus from parietal cortex MG in an individual with HIV productively infected both MG and PBMCs. This inducible, replication-competent virus and virus from basal ganglia proviral DNA were closely related but highly divergent from variants in peripheral compartments. Phenotyping studies characterized brain-derived virus as macrophage tropic based on the ability of the virus to infect cells expressing low levels of CD4. The lack of genetic diversity in virus from the brain suggests that this macrophage-tropic lineage quickly colonized brain regions. These data demonstrate that MG harbor replication-competent HIV and serve as a persistent reservoir in the brain.

BackgroundDevelopment of safe and effective SARS-CoV-2 therapeutics is a high priority. Amubarvimab and romlusevimab are noncompeting anti-SARS-CoV-2 monoclonal antibodies with an extended half-life.ObjectiveTo assess the safety and efficacy of amubarvimab plus romlusevimab.DesignRandomized, placebo-controlled, phase 2 and 3 platform trial. (ClinicalTrials.gov: NCT04518410).SettingNonhospitalized patients with COVID-19 in the United States, Brazil, South Africa, Mexico, Argentina, and the Philippines.PatientsAdults within 10 days onset of symptomatic SARS-CoV-2 infection who are at high risk for clinical progression.InterventionCombination of monoclonal antibodies amubarvimab plus romlusevimab or placebo.MeasurementsNasopharyngeal and anterior nasal swabs for SARS-CoV-2, COVID-19 symptoms, safety, and progression to hospitalization or death.ResultsEight-hundred and seven participants who initiated the study intervention were included in the phase 3 analysis. Median age was 49 years (quartiles, 39 to 58); 51% were female, 18% were Black, and 50% were Hispanic or Latino. Median time from symptom onset at study entry was 6 days (quartiles, 4 to 7). Hospitalizations and/or death occurred in 9 (2.3%) participants in the amubarvimab plus romlusevimab group compared with 44 (10.7%) in the placebo group, with an estimated 79% reduction in events (P

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.

BackgroundAlthough symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described.ObjectiveTo characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19.DesignRetrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410).SettingMulticenter trial.Patients563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial.MeasurementsParticipants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL to a viral load of 5.0 log10 copies/mL or higher.ResultsSymptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants.LimitationA largely unvaccinated population infected with pre-Omicron variants was evaluated.ConclusionSymptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

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.

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.

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.

BackgroundIdentifying 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.MethodsParticipants 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.ResultsNasopharyngeal 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).ConclusionsSARS-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.

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

Among 14 049 people with human immunodeficiency virus 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 and bictegravir) and tenofovir alafenamide, especially in antiretroviral-naive individuals initiating ART.

BackgroundThe updated Veterans Aging Cohort Study (VACS) Index 2.0 combines general and human immunodeficiency virus (HIV)-specific biomarkers to generate a continuous score that accurately discriminates risk of mortality in diverse cohorts of persons with HIV (PWH), but a score alone is difficult to interpret. Using data from the North American AIDS Cohort Collaboration (NA-ACCORD), we translate VACS Index 2.0 scores into validated probability estimates of mortality.MethodsBecause complete mortality ascertainment is essential for accurate calibration, we restricted analyses to cohorts with mortality from the National Death Index or equivalent sources. VACS Index 2.0 components were ascertained from October 1999 to April 2018. Mortality was observed up to March 2019. Calibration curves compared predicted (estimated by fitting a gamma model to the score) to observed mortality overall and within subgroups: cohort (VACS/NA-ACCORD subset), sex, age 500 copies/mL, CD4 count

BackgroundUnderstanding the spectrum of COVID-19 in people with HIV (PWH) is critical to provide clinical guidance and risk reduction strategies.SettingCenters for AIDS Research Network of Integrated Clinic System, a US multisite clinical cohort of PWH in care.MethodsWe 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.ResultsOf 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

ObjectivesTo 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.DesignObservational study within the CFAR Network of Integrated Clinical Systems cohort in seven cities during 2020.MethodsWe 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.ResultsAmong 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.ConclusionOur 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.

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

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

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.

ObjectiveTo assess differences in anal cancer incidence between racial/ethnic groups among a clinical cohort of men with HIV who have sex with men.DesignClinical cohort study.MethodsWe studied men who have sex with men (MSM) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who initiated antiretroviral therapy (ART) under HIV care in CNICS. We compared anal cancer incidence between Black and non-Black men and calculated hazard ratios controlling for demographic characteristics (age, CNICS site, year of ART initiation), HIV disease indicators (nadir CD4+, peak HIV RNA), and co-infection/behavioral factors including hepatitis B virus (HBV), hepatitis C virus (HCV), tobacco smoking and alcohol abuse.ResultsWe studied 7473 MSM with HIV who contributed 41 810 person-years of follow-up after initiating ART between 1996 and 2014 in CNICS. Forty-one individuals had an incident diagnosis of anal cancer under observation. Crude rates of anal cancer were 204 versus 61 per 100 000 person-years among Black versus non-Black MSM. The weighted hazard ratio for anal cancer in Black MSM (adjusting for demographics, HIV disease factors, and co-infection/behavioral factors) was 2.37 (95% confidence interval: 1.17, 4.82) compared to non-Black MSM.ConclusionsIn this large multicenter cohort, Black MSM were at significantly increased risk for anal cancer compared to non-Black MSM. Further detailed studies evaluating factors impacting anal cancer incidence and outcomes in Black men with HIV are necessary. Inclusion of more diverse study cohorts may elucidate modifiable factors associated with increased anal cancer risk experienced by Black MSM.

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.

Abstract Background SARS-CoV-2 continues to spread and the development of safe and effective therapeutics for the prevention of severe disease remains a priority. BRII-196 and BRII-198 are non-competing anti-SARS-CoV-2 mAbs with YTE triple amino acid substitution in Fc to extend half-life and reduce receptor binding, that are being studied for treatment of COVID-19 in the ACTIV-2 Trial, sponsored by NIAID and led by ACTG. Methods ACTIV-2 evaluates safety/efficacy of investigational agents for treatment of non-hospitalized adults with mild-moderate COVID-19 under a randomized, blinded, controlled adaptive platform. BRII-196/BRII-198 (1000 mg each) as a single dose given as sequential infusions, or placebo to those at high risk of clinical progression (i.e., age ≥ 60 years or presence of other medical conditions) within 10 days of symptom onset and positive test for SARS-CoV-2. The primary endpoint was hospitalization and/or death through day 28. We report Phase 3 BRII-196/BRII-198 trial results per DSMB recommendation following an interim analysis. Results Between January and July 2021, 837 participants (418 active, 419 placebo) from sites in the US (66%), Brazil, South Africa, Mexico, Argentina and the Philippines were randomized and received study product at time of emerging variants. Median age 49 years (Q1, Q3: 39, 58), 51% female, 17% Black/African-American and 49% Hispanic/Latino, with median 6 days from symptom onset. At interim analysis 71% and 97% had a day 28 and 7 visit, respectively. For all available data at interim review, BRII-196/BRII-198 compared to placebo had fewer hospitalizations (12 vs. 45) and deaths (1 vs. 9). At day 28 of follow-up, there was an estimated 78% reduction in hospitalization and/or death (2.4 vs. 11.1%), relative risk 0.22 (95% CI: 0.05, 0.86), P=0.00001 (nominal one-sided). Grade 3 or higher adverse events (AEs) were observed less frequently among BRII-196/BRII-198 participants than placebo (3.8% vs. 13.4%) with no severe infusion reactions or drug related serious AEs. Conclusion BRII-196/BRII-198 was safe, well-tolerated, and demonstrated significant reduction compared to placebo in the risk of hospitalization and/or death among adults with mild-moderate COVID-19 at high risk for progression to severe disease. Disclosures Kara W. Chew, MD, MS, Amgen (Individual(s) Involved: Self): Grant/Research Support; Merck Sharp & Dohme (Individual(s) Involved: Self): Grant/Research Support David Alain Wohl, MD, Gilead Sciences (Individual(s) Involved: Self): Advisor or Review Panel member, Consultant, Research Grant or Support, Scientific Research Study Investigator; Janssen (Individual(s) Involved: Self): Advisor or Review Panel member; Merck (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support; ViiV (Individual(s) Involved: Self): Advisor or Review Panel member, Research Grant or Support Joseph J. Eron, MD, Gilead Sciences (Consultant, Research Grant or Support)Janssen (Consultant, Research Grant or Support)Merck (Consultant)ViiV (Consultant, Research Grant or Support) David A. Margolis, MD MPH, Brii Biosciences (Employee) Courtney Fletcher, Pharm.D., National Institute of Allergy and Infectious Diseases, NIH (Grant/Research Support) Davey Smith, M.D., Linear Therapies, Matrix Biomed, Bayer (Consultant, Shareholder) Eric Daar, Gilead (Consultant, Grant/Research Support)Merck (Consultant)ViiV (Consultant, Grant/Research Support)

Substance use in the U.S. varies by geographic region. Opioid prescribing practices and marijuana, heroin, and methamphetamine availability are evolving differently across regions. We examined self-reported substance use among people living with HIV (PLWH) in care at seven sites from 2017-2019 to understand current regional substance use patterns. We calculated the percentage and standardized percentage of PLWH reporting current drug use and at-risk and binge alcohol use by U.S. Census Bureau geographic region and examined associations in adjusted logistic regression analyses. Among 7,686 PLWH, marijuana use was the most prevalent drug (30%), followed by methamphetamine/crystal (8%), cocaine/crack (7%), and illicit opioids (3%). One-third reported binge alcohol use (32%). Differences in percent of current use by region were seen for marijuana (24-41%) and methamphetamine/crystal (2-15%), with more use in the West and Northeast, and binge alcohol use (26-40%). In adjusted analyses, PLWH in the Midwest were significantly less likely to use methamphetamine/crystal (aOR: 0.13;0.06-0.25) or illicit opioids (aOR:0.16;0.05-0.53), and PLWH in the Northeast were more likely to use cocaine/crack (aOR:1.59;1.16-2.17), compared to PLWH in the West. Understanding differences in substance use patterns in the current era, as policies continue to evolve, will enable more targeted interventions in clinical settings among PLWH.

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.

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.

From 2005 to 2018, among 32013 adults with human immunodeficiency virus entering care, median time to antiretroviral therapy (ART) prescription declined from 69 to 6 days, CD4 count at entry into care increased from 300 to 362 cells/μL, and CD4 count at ART prescription increased from 160 to 364 cells/μL.

BackgroundUnderstanding 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.ObjectiveTo 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.DesignObservational cohort study.SettingThirteen sites from the U.S. North American AIDS Cohort Collaboration on Research and Design.Participants82 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.MeasurementsFive-year all-cause mortality, estimated using the Kaplan-Meier estimator of the survival function.ResultsOverall 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.LimitationMatching 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.ConclusionMortality 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 sourceNational Institutes of Health.