Objective: Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) under development for HIV-1 treatment. We aimed to evaluate the pharmacokinetics (PK) of islatravir and its active form, islatravir-triphosphate, in blood and mucosal tissues. Design: This was an exploratory substudy of a randomized, double-blind, placebo-controlled, multicenter, Phase 2a study of once-monthly islatravir in adults at low likelihood of HIV-1 exposure (NCT04003103). Methods: Participants were randomly assigned 2 : 2 : 1 to receive 6 once-monthly oral doses of islatravir 60 mg, islatravir 120 mg, or placebo. Plasma, peripheral blood mononuclear cell (PBMC), and cervical, vaginal, and rectal tissue samples were collected at Weeks 1, 4, 24, and 32. Samples were assayed by liquid chromatography with tandem mass spectrometry. Intercompartmental ratios and regression analyses were assessed. Results: The analyses included 44 participants who received islatravir 60 mg or 120 mg (73% assigned female at birth; median age 30 years). Following 6 once-monthly doses, islatravir-triphosphate trough concentrations were comparable across homogenized mucosal tissue samples and isolated rectal cells. Median venous whole blood islatravir (total of islatravir and key anabolites) to mucosal tissue islatravir-triphosphate concentration ratios ranged from 0.565 to 1.490 four weeks after the sixth islatravir dose. Adjusted R 2 coefficients between islatravir concentrations in venous whole blood and islatravir-triphosphate concentrations in rectal, cervical, and vaginal tissues across sampling times were 0.67, 0.76, and 0.75, respectively. Conclusions: The favorable tissue distribution of islatravir and islatravir-triphosphate following oral administration supports the evaluation of NRTTIs for HIV-1 preexposure prophylaxis.

INTRODUCTION:Drug-induced liver injury affects some people living with HIV (PWH) during antiretroviral therapy (ART). We examined associations of polygenic risk scores (PRS) with liver injury during ART. METHODS:We derived PRS using summary statistics from the Veterans Affairs Million Veteran Program (MVP) and the Penn Medicine BioBank (PMBB). We constructed PRS for individuals of African (AFR) and European (EUR) ancestry in 3,619 treatment-naïve participants from ART-naive studies of the Advancing Clinical Therapeutics Globally (ACTG) network. Liver injury was defined as incident grade 3 or greater alanine aminotransferase (ALT) within 48 weeks. Associations were evaluated by multivariable regression models. RESULTS:Clinical variables associated with higher baseline ALT values included hepatitis B or C virus infection, increasing BMI and age, and male sex. In analyses of liver injury among 1,897 EUR participants (28 cases, 1869 controls) and 1722 AFR participants (21 cases, 1701 controls), HBV was associated with liver injury in both EUR and AFR participants, and HCV in EUR participants (p < 0.001 for each). PRSALT was not independently associated with incident liver injury in either EUR or AFR participants. CONCLUSION:No association was observed between baseline PRSALT and subsequent liver injury following initiation of ART.

Background:Intact proviral DNA (IPD) is a measure of the replication-competent HIV reservoir. Little is known about how IPD levels compare in people with HIV (PWH) who initiate antiretroviral therapy (ART) during acute HIV infection (AHI), chronic infection (CHI) or as HIV controllers (CON). Methods:Participants with sustained plasma HIV RNA < 50 copies/mL on ART had longitudinal measurements of intact, defective and total proviral DNA in blood samples. Results:Twenty-nine participants were evaluated: 14 CHI, 7 AHI and 8 CON. PWH-CON had lower IPD than PWH-AHI or PWH-CHI during ART. PWH-CON also had low intact and total provirus levels before initiating ART. During years 2-5 of ART, IPD decay half-life was 1.0 years in PWH-AHI, 1.6 years in PWH-CHI and 3.2 years in PWH-CON (P = .01 for PWH-CON vs PWH-AHI). Defective provirus levels did not decrease in PWH-AHI and PWH-CHI. Conclusions:During the initial years of ART, PWH treated during acute and chronic infection have decay in intact but not defective proviruses. PWH controllers have low intact and total provirus levels before and during ART, suggesting interactions between host and virus shape the proviral landscape. Variable proviral decay patterns in these populations provide insight into approaches to achieve ART-free HIV remission.

mRNA technology might accelerate development of an urgently needed preventive human immunodeficiency virus (HIV) vaccine. We evaluated the safety and immunogenicity of three mRNA-encoded envelope trimers, including two doses of soluble and membrane-anchored forms, in a randomized, open-label, phase 1 clinical trial. Vaccines were generally well tolerated, although 6.5% (7 of 108) of participants developed urticaria, a higher proportion than seen with other mRNA vaccines. mRNA-encoded trimers induced strong envelope-specific B and T cell responses. Immunization with membrane-anchored trimers, intended to obscure epitopes at the trimer base targeted by nonneutralizing antibodies, reduced the frequency of base-binding serum antibodies in comparison with soluble trimers. Three immunizations elicited autologous tier 2 serum neutralizing antibodies in 80% of vaccinees receiving the membrane-anchored trimers, in contrast to only 4% receiving the soluble trimer. Thus, with demonstration of more favorable safety, mRNA-encoded membrane-anchored HIV envelope trimers represent a promising platform for HIV vaccine clinical development.

BACKGROUND:Islatravir, a nucleoside reverse transcriptase translocation inhibitor, exhibits high potency against human immunodeficiency virus type 1 (HIV-1), with a long intracellular half-life. The safety, tolerability, and pharmacokinetics of once-monthly oral islatravir were evaluated in adults at low risk of acquiring HIV-1. METHODS:In this double-blind, placebo-controlled trial, participants were randomized 2:2:1 to receive 6 once-monthly doses of islatravir 60 mg, islatravir 120 mg, or placebo. Objectives included assessing safety, tolerability, and pharmacokinetic profiles of islatravir in plasma and its active metabolite, islatravir triphosphate (ISL-TP), in peripheral blood mononuclear cells (PBMCs). RESULTS:Of 242 participants (islatravir 60 mg, n = 97; islatravir 120 mg, n = 97; placebo, n = 48), most were aged ≤45 years (90.1%), female (67.4%), and White (52.9%). Proportions of participants experiencing ≥1 adverse event (AE) were similar in the islatravir (60 mg: 68.0%; 120 mg: 64.9%) and placebo (75.0%) arms. AEs were generally mild to moderate, with infection-related AEs comparable across arms. Lymphocyte count decreased in the islatravir arms, with mean percentage changes of -21.3% ± 20.1% (60 mg) and -35.6% ± 22.8% (120 mg) versus +4.4% ± 25.9% (placebo) at week 24. Median intracellular PBMC ISL-TP concentrations remained above the prespecified pharmacokinetic threshold for HIV-1 prophylaxis (0.050 pmol/106 cells) through 4 weeks after the first dose and ≥8 weeks after the last dose. CONCLUSIONS:Oral islatravir 60 mg and 120 mg once monthly demonstrated similar tolerability and AE profiles to placebo, except for dose-dependent decreases in total lymphocyte counts. A partial recovery in total lymphocyte counts was observed. In most participants, both islatravir doses achieved PBMC ISL-TP exposure levels projected to be effective for once-monthly oral HIV-1 preexposure prophylaxis. CLINICAL TRIALS REGISTRATION:NCT04003103.

Background: The mRNA platform is under investigation for many vaccines, including HIV-1 vaccines. Objective: To evaluate the safety and tolerability of 3 investigational HIV-1 trimer mRNA vaccines. Design: Safety analysis of mRNA vaccination in a phase 1, randomized, open-label trial. (ClinicalTrials.gov: NCT05217641) Setting: Ten research sites in the United States. Participants: 108 volunteers aged 18 to 55 years without HIV-1. Intervention: Investigational HIV-1 BG505 MD39.3 trimer mRNA vaccines (gp140 soluble trimer, gp151 membrane-bound trimer, and gp151 CD4KO membrane-bound trimer) at doses of 100 and 250 mcg at 0, 2, and 6 months. Measurements: Solicited and unsolicited adverse reactions and events reported during the 12 months after the first vaccination. Results: Participants (n = 108) were randomly assigned to 6 vaccine groups. Mild to moderate local and systemic solicited events were common. Eighty participants reported 190 unsolicited adverse events (AEs); 30 were considered to be related to a study product. Most (73%) related AEs were mild, and the rest were moderate. Among related AEs, urticaria was reported by 7 of 108 participants (7% [95% CI, 3% to 13%]), 4 of whom had unresolved, intermittent urticaria at 12 months. In post hoc analyses, demographic characteristics, history of allergy or medication use, and COVID-19 were not associated with urticaria. In a comparison of participants with versus without urticaria, 100% (7 of 7; CI, 65% to 100%) versus 37% (37 of 101; CI, 28% to 46%) reported previous Moderna COVID-19 vaccination, 29% (2 of 7; CI, 8% to 64%) versus 76% (77 of 101; CI, 67% to 84%) reported previous Pfizer-BioNTech COVID-19 vaccination, and 0% (0 of 7; CI, 0% to 35%) versus 5% (5 of 101; CI, 2% to 11%) reported no previous mRNA COVID-19 vaccination. Limitations: Lack of a placebo group, open-label study, and post hoc evaluation of urticarial risk. Conclusion: Urticarial reactions associated with experimental HIV-1 mRNA vaccines were observed in this trial. Studies to investigate the mechanism and approaches to mitigate these reactions are underway to further advance HIV-1 vaccine research. Primary Funding Source: National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Twelve weeks of dipyridamole increased extracellular adenosine levels and decreased T cell activation in people with human immunodeficiency virus (HIV). In this analysis, we investigated the effect of dipyridamole on HIV-specific T cell responses. We compared changes in Gag- and Env-specific T cell responses using intracellular cytokine staining, following 12 wk of dipyridamole treatment vs placebo. We evaluated whether frequencies of polyfunctional HIV-specific T cells were associated with purines in the adenosine pathway and with measures of HIV persistence and chronic inflammation. There was a significant decrease in CD4+ polyfunctional T cell responses to Gag (-62.6% vs -23.0%; P < 0.001) and Env (-56.1% vs -6.0%; P < 0.001) in the dipyridamole arm. In the dipyridamole group, lower frequencies of polyfunctional Env-specific CD4+ T cells were associated with higher plasma levels of adenosine (r = -0.85, P < 0.01) and inosine (r = -0.70, P = 0.04). Higher adenosine levels induced by dipyridamole treatment is associated with decreased HIV-specific CD4+ T cell polyfunctional responses in people with HIV on antiretroviral therapy.

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.

Access to safe and effective antiretroviral therapy (ART) is a cornerstone in the global response to the HIV pandemic. Among people living with HIV, there is considerable interindividual variability in absolute CD4 T-cell recovery following initiation of virally suppressive ART. The contribution of host genetics to this variability is not well understood. We explored the contribution of a polygenic score which was derived from large, publicly available summary statistics for absolute lymphocyte count from individuals in the general population (PGSlymph) due to a lack of publicly available summary statistics for CD4 T-cell count. We explored associations with baseline CD4 T-cell count prior to ART initiation (n=4959) and change from baseline to week 48 on ART (n=3274) among treatment-naïve participants in prospective, randomized ART studies of the AIDS Clinical Trials Group. We separately examined an African-ancestry-derived and a European-ancestry-derived PGSlymph, and evaluated their performance across all participants, and also in the African and European ancestral groups separately. Multivariate models that included PGSlymph, baseline plasma HIV-1 RNA, age, sex, and 15 principal components (PCs) of genetic similarity explained ∼26-27% of variability in baseline CD4 T-cell count, but PGSlymph accounted for <1% of this variability. Models that also included baseline CD4 T-cell count explained ∼7-9% of variability in CD4 T-cell count increase on ART, but PGSlymph accounted for <1% of this variability. In univariate analyses, PGSlymph was not significantly associated with baseline or change in CD4 T-cell count. Among individuals of African ancestry, the African PGSlymph term in the multivariate model was significantly associated with change in CD4 T-cell count while not significant in the univariate model. When applied to lymphocyte count in a general medical biobank population (Penn Medicine BioBank), PGSlymph explained ∼6-10% of variability in multivariate models (including age, sex, and PCs) but only ∼1% in univariate models. In summary, a lymphocyte count PGS derived from the general population was not consistently associated with CD4 T-cell recovery on ART. Nonetheless, adjusting for clinical covariates is quite important when estimating such polygenic effects.

Vesatolimod is a Toll-like receptor-7 (TLR7) agonist in clinical development as part of a combination regimen for human immunodeficiency virus (HIV) cure. Influenza-like symptoms associated with TLR7-mediated immune activation have been reported in clinical trials of vesatolimod. Therefore, a broader understanding of the safety profile of vesatolimod and association with dose and mechanism of action will help inform future clinical studies. In this analysis, data on flu-like adverse events of interest (AEIs) were pooled from eight clinical studies in which 606 participants either received single or multiple doses of vesatolimod (0.3–12 mg; n = 505) or placebo (n = 101). Vesatolimod pharmacokinetics, inflammatory responses, and pharmacodynamics were assessed. The incidence of flu-like AEIs was higher with vesatolimod versus placebo (19

Antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection. ART previously consisted of concomitant administration of many drugs, multiple times per day. Currently, ART generally consists of two- or three-drug regimens once daily as fixed-dose combinations. Drug monitoring may be necessary to ensure adequate concentrations are achieved in the plasma over the dosing interval and prevent further HIV resistance formation. Additionally, nonadherence remains an issue, highlighting the need to ensure sufficient ART exposure. Towards this effort, we developed and validated a highly selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of a panel of nine antiretrovirals: abacavir, bictegravir, cabotegravir, dolutegravir, doravirine, emtricitabine, lamivudine, raltegravir, and tenofovir in human plasma. Using only 50 mu L of plasma, a simple protein precipitation with acetonitrile with internal standards followed by reconstitution in 50 uL (high) or 400 uL (low) was performed. Analyte separation was achieved using a multistep UPLC gradient mixture of (A: 0.1% formic acid in water and B: acetonitrile) and a Waters CORTECS T3 (2.1 x100 mm) column. The method was comprehensively validated according to the United States Food and Drug Administration Bioanalytical Guidelines over two clinically relevant ranges (1-250 ng/mL and 100-5000 ng/mL) with excellent linearity (R-2 > 0.99 for all). The assay run time was 7.5 min. This method achieves acceptable performance of trueness (89.7-104.1%), repeatability, and precision (CV <15%), and allows for simultaneous quantification of guideline-recommended ART regimens. This method can be utilized for the therapeutic monitoring of antiretrovirals in human plasma.

Objective: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses. Design: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia. Methods: HIV DNA was measured at week 48 of ART in 5 million CD4(+) T cells by sensitive qPCR assays targeting HIV gag and pol. Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env, gag, nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines. Results: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I (n = 6), II (n = 43), III (n = 56), IV (n = 23), and V (n = 60). Median age was 27 years (interquartile range 23-38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels (P < 0.001). Week 48 HIV DNA mostly did not correlate with concurrent CD4(+) or CD8(+) T cell HIV-specific immune responses (rho range -0.11 to +0.19, all P > 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest. Conclusion: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.

Background On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. Methods MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P < .065 and P < .039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420. Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration . NCT04047420.

Widespread availability of antiretroviral therapies (ART) for HIV-1 have generated considerable interest in understanding the pharmacogenomics of ART. In some individuals, ART has been associated with excessive weight gain, which disproportionately affects women of African ancestry. The underlying biology of ART-associated weight gain is poorly understood, but some genetic markers which modify weight gain risk have been suggested, with more genetic factors likely remaining undiscovered. To overcome limitations in available sample sizes for genome-wide association studies (GWAS) in people with HIV, we explored whether a multi-ancestry polygenic risk score (PRS) derived from large, publicly available non-HIV GWAS for body mass index (BMI) can achieve high cross-ancestry performance for predicting baseline BMI in diverse, prospective ART clinical trials datasets, and whether that PRSBMI is also associated with change in BMI over 48 weeks on ART. We show that PRSBMI explained ∼5-7% of variability in baseline (pre-ART) BMI, with high performance in both European and African genetic ancestry groups, but that PRSBMI was not associated with change in BMI on ART. This study argues against a shared genetic predisposition for baseline (pre-ART) BMI and ART-associated weight gain.

Fourteen people with human immunodeficiency virus type 1 had longitudinal measurements of intact, defective, and total proviral DNA over the course of two decades of antiretroviral therapy. Three patterns of intact proviral DNA decay were revealed: (1) biphasic decline with markedly slower second-phase decline, (2) initial decline that transitions to a zero-slope plateau, and (3) initial decline followed by later increases in intact proviral DNA. Defective proviral DNA levels were essentially stable. Mechanisms of slowing or reversal of second-phase decay of intact proviral DNA may include the inability to clear cells with intact but transcriptionally silent proviruses and clonal expansion of cells with intact proviruses.

Fourteen people with HIV-1 on two decades of antiretroviral therapy had longitudinal measurements of intact, defective, and total proviral DNA. Three patterns of intact proviral DNA decay were revealed: 1) biphasic decline with markedly slower second phase decline; 2) initial decline that transitions to a zero-slope plateau; and 3) initial decline followed by later increases in intact proviral DNA. Defective proviral DNA levels were essentially stable. Mechanisms of slowing or reversal of second phase decay of intact proviral DNA may include the inability to clear cells with intact but transcriptionally silent proviruses and clonal expansion of cells with intact proviruses.

BackgroundBreakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals. MethodsTo explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746). ResultsWe observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints. ConclusionRobust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic.

ImportanceCurrent data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders.ObjectiveTo identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection.Design, Setting, and ParticipantsThis secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023.ExposuresComorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment.Main Outcomes and MeasuresCoprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection.ResultsA total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001).Conclusions and RelevanceIn this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.