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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.

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

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

Background: Sex differences in studies of antiretroviral (ART) drug exposure and treatment outcomes support the hypothesis that some ART combinations may not be well tolerated in women. We evaluated disparities in outcomes between men and women participating in ACTG A5288, an interventional strategy trial for individuals failing a protease inhibitor-based second-line ART regimen in low- and middle-income countries. Methods: Participants were assigned to one of 4 cohorts (A-D) based on resistance profiles and ART history. Cohort A had no lopinavir/ritonavir (LPV/r) resistance and stayed on their second-line regimen, and cohorts B, C, and D had increasing resistance and accessed novel ART regimens. In this secondary analysis, we evaluated sex differences in the primary endpoint, HIV-1 RNA ≤200 copies/mL at week 48; confirmed virologic failure ≥1000 copies/mL (VF); and clinical outcomes and adverse events (intent-to-treat). Results: Women made up 258/545 (47%) of the study population. More women than men were assigned to cohort A. Median follow-up was 72 weeks. Fewer women than men had HIV-1 RNA ≤200 copies/mL at week 48: 39% vs. 49% in cohort A and 83% vs. 89% in cohorts B, C, and D combined. More women experienced VF, grade ≥3 signs and symptoms, but similar grade ≥3 diagnoses or laboratory abnormalities. Conclusions: More women than men entered the study with a resistance profile suggesting that their second-line regimen could have been effective in maintaining virologic suppression. The more frequent occurrence of grade ≥3 signs and symptoms in women suggests that tolerability issues were under recognized in women on protease inhibitor-based therapy.

Background Antiretroviral therapy (ART) initiation during acute and early human immunodeficiency virus infection (AEHI) limits HIV reservoir formation and may facilitate post-ART control but is logistically challenging. We evaluated the performance of AEHI diagnostic criteria from a prospective study of early ART initiation. Methods AIDS Clinical Trials Group A 5354 enrolled adults at 30 sites in the Americas, Africa, and Asia who met any 1 of 6 criteria based on combinations of results of HIV RNA, HIV antibody, Western blot or Geenius assay, and/or the signal-to-cutoff (S/CO) ratio of the ARCHITECT HIV Ag/Ab Combo or GS HIV Combo Ag/Ab EIA. HIV status and Fiebig stage were confirmed by centralized testing. Results From 2017 through 2019, 195 participants were enrolled with median age of 27 years (interquartile range, 23–39). Thirty (15.4%) were female. ART was started by 171 (87.7%) on the day of enrollment and 24 (12.3%) the next day. AEHI was confirmed in 188 (96.4%) participants after centralized testing, 4 (2.0%) participants were found to have chronic infection, and 3 (1.5%) found not to have HIV discontinued ART and were withdrawn. Retrospectively, a nonreactive or indeterminate HIV antibody on the Geenius assay combined with ARCHITECT S/CO ≥10 correctly identified 99 of 122 (81.2%) Fiebig II–IV AEHI cases with no false-positive results. Conclusions Novel AEHI criteria that incorporate ARCHITECT S/CO facilitated rapid and efficient ART initiation without waiting for an HIV RNA result. These criteria may facilitate AEHI diagnosis, staging, and immediate ART initiation in future research studies and clinical practice. Clinical Trials Registration NCT02859558.

Background Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. Methods Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. Results At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA Conclusions HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. Clinical Trials Registration NCT00537394.

OBJECTIVE To evaluate associations between hair antiretroviral hair concentrations as an objective, cumulative adherence metric, with self-reported adherence and virologic outcomes. DESIGN Analysis of cohort A of the ACTG-A5288 study. These patients in resource-limited settings were failing second-line protease inhibitor-based antiretroviral therapy (ART) but were susceptible to at least one nucleoside reverse transcriptase inhibitor (NRTI) and their protease inhibitor, and continued taking their protease inhibitor-based regimen. METHODS Antiretroviral hair concentrations in participants taking two NRTIs with boosted atazanavir (n = 69) or lopinavir (n = 112) were analyzed at weeks 12, 24, 36 and 48 using liquid-chromatography--tandem-mass-spectrometry assays. Participants' self-reported percentage of doses taken in the previous month; virologic failure was confirmed HIV-1 RNA at least 1000 copies/ml at week 24 or 48. RESULTS From 181 participants with hair samples (61% women, median age: 39 years; CD4+ cell count: 167 cells/μl; HIV-1 RNA: 18 648 copies/ml), 91 (50%) experienced virologic failure at either visit. At 24 weeks, median hair concentrations were 2.95 [interquartile range (IQR) 0.49-4.60] ng/mg for atazanavir, 2.64 (IQR 0.73--7.16) for lopinavir, and 0.44 (IQR 0.11--0.76) for ritonavir. Plasma HIV-1 RNA demonstrated inverse correlations with hair levels (rs -0.46 to -0.74) at weeks 24 and 48. Weaker associations were seen with self-reported adherence (rs -0.03 to -0.24). Decreasing hair concentrations were significantly associated with virologic failure, the hazard ratio (95% CI) for ATV, LPV, and RTV were 0.69 (0.56-0.86), 0.77 (0.68-0.87), and 0.12 (0.06-0.27), respectively. CONCLUSION Protease inhibitor hair concentrations showed stronger associations with subsequent virologic outcomes than self-reported adherence in this cohort. Hair adherence measures could identify individuals at risk of second-line treatment failure in need of interventions.

Background Human immunodeficiency virus (HIV) drug resistance profiles are needed to optimize individual patient management and to develop treatment guidelines. Resistance profiles are not well defined among individuals on failing second-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). Methods Resistance genotypes were performed during screening for enrollment into a trial of third-line ART (AIDS Clinical Trials Group protocol 5288). Prior exposure to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs and confirmed virologic failure on a protease inhibitor–containing regimen were required. Associations of drug resistance with sex, age, treatment history, plasma HIV RNA, nadir CD4+T-cell count, HIV subtype, and country were investigated. Results Plasma HIV genotypes were analyzed for 653 screened candidates; most had resistance (508 of 653; 78%) to 1 or more drugs. Genotypes from 133 (20%) showed resistance to at least 1 drug in a drug class, from 206 (32%) showed resistance to at least 1 drug in 2 drug classes, and from 169 (26%) showed resistance to at least 1 drug in all 3 commonly available drug classes. Susceptibility to at least 1 second-line regimen was preserved in 59%, as were susceptibility to etravirine (78%) and darunavir/ritonavir (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+ T-cell counts, and those who had received lopinavir/ritonavir, but was lower among prior nevirapine recipients. Conclusions Highly divergent HIV drug resistance profiles were observed among candidates screened for third-line ART in LMIC, ranging from no resistance to resistance to 3 drug classes. These findings underscore the need for access to resistance testing and newer antiretrovirals for the optimal management of third-line ART in LMIC.

Summary Background Antiretroviral therapy (ART) management is challenging for individuals in resource-limited settings presenting for third-line treatment because of complex resistance patterns, partly due to reduced access to viral load monitoring. We aimed to evaluate use of newer antiretroviral drugs and contemporary management approaches, including population-based sequencing, to select appropriate antiretrovirals, plasma viral load monitoring, and interventions to improve adherence in individuals presenting with second-line viral failure. Methods A5288 was a phase 4, third-line ART strategy study done at 19 urban sites in ten countries that enrolled adult participants with confirmed plasma HIV-1 RNA (viral load) of 1000 copies per mL or more after more than 24 weeks of protease inhibitor-based second-line ART. The primary objective was to use antiretrovirals (raltegravir, etravirine, and ritonavir-boosted darunavir) and diagnostic monitoring technologies, including viral load, genotyping, and adherence support to achieve viral load suppression (defined as ≤200 copies per mL) in 65% or more of participants. ART history and real-time drug resistance genotypes were used to assign participants to one of four cohorts: cohort A (no lopinavir resistance) stayed on second-line ART and cohorts B (B1, best available nucleoside reverse transcriptase inhibitors [NRTIs] plus ritonavir-boosted darunavir plus raltegravir; B2, ritonavir-boosted darunavir plus raltegravir plus etravirine; B3, ritonavir-boosted darunavir, raltegravir, and either tenofovir plus emtricitabine or tenofovir plus lamivudine), C (ritonavir-boosted darunavir plus raltegravir plus tenofovir-emtricitabine or tenofovir plus lamivudine), and D (best available NRTIs plus ritonavir-boosted darunavir plus raltegravir) were defined by increasing levels of resistance and received appropriate regimens, including new antiretrovirals. Participants in Cohort B without detectable hepatitis B surface antigen were assigned by blocked randomisation to cohorts B1 and B2, and those with detectable hepatitis B surface antigen were assigned to cohort B3. The trial is registered with ClinicalTrials.gov , number NCT01641367 . Findings From Jan 10, 2013, to Sept 10, 2015, 545 participants were enrolled. 287 (53%) were assigned to cohort A, 74 (14%) to B1, 72 (13%) to B2, eight (1%) to B3, 70 (13%) to C, and 34 (6%) to D. Overall, 349 (64%, 95% CI 60–68) participants achieved viral suppression at week 48, with proportions varying from 125 (44%) of 287 in cohort A to 65 (88%) of 74 in cohort B1, 63 (88%) of 72 in B2, eight (100%) of eight in B3, 63 (90%) of 70 in C, and 25 (74%) of 34 in D. Participants in cohort A remained on their second-line protease inhibitor, and had the most participants with grade 3 or higher adverse events (147 [51%]). Interpretation Targeted real-time genotyping to select third-line ART can appropriately allocate more costly antiretrovirals to those with greater levels of HIV drug resistance. Funding National Institutes of Health.

BackgroundBroadly neutralizing monoclonal antibodies (bnMAbs) may promote clearance of HIV-1-expressing cells through antibody-dependent cell-mediated cytotoxicity. We evaluated the effect of the CD4-binding site bnMAb, VRC01, on measures of HIV-1 persistence in chronically infected individuals.MethodsA5342 was a phase 1, randomized, double-blind, placebo-controlled, parallel-arm study. Participants on effective antiretroviral therapy (ART) were randomized to receive 2 infusions of VRC01 (40 mg/kg) at entry and week 3, and 2 infusions of placebo (saline) at weeks 6 and 9; or 2 infusions of placebo at entry and week 3, and 2 infusions of VRC01 at weeks 6 and 9.ResultsInfusion of VRC01 was safe and well tolerated. The median fold-change in the cell-associated HIV-1 RNA/DNA ratio from baseline to week 6 was 1.12 and 0.83 for the VRC01 and placebo arms, respectively, with no significant difference between arms (P = .16). There were no significant differences in the proportions with residual plasma viremia ≥1 copies/mL or in phorbol 12-myristate 13-acetate/ionomycin-induced virus production from CD4+ T cells between arms (both P > .05).ConclusionsIn individuals with chronic HIV-1 infection on ART, VRC01 infusions were safe and well tolerated but did not affect plasma viremia, cellular HIV-1 RNA/DNA levels, or stimulated virus production from CD4+ T cells.ClinicalTrials.gov IdentifierNCT02411539

The genomic RNA of the retrotransposon Ty1 is packaged as a dimer into virus-like particles. The 5′ terminus of Ty1 RNA harbors cis-acting sequences required for translation initiation, packaging and initiation of reverse transcription (TIPIRT). To identify RNA motifs involved in dimerization and packaging, a structural model of the TIPIRT domain in vitro was developed from single-nucleotide resolution RNA structural data. In general agreement with previous models, the first 326 nucleotides of Ty1 RNA form a pseudoknot with a 7-bp stem (S1), a 1-nucleotide interhelical loop and an 8-bp stem (S2) that delineate two long, structured loops. Nucleotide substitutions that disrupt either pseudoknot stem greatly reduced helper-Ty1-mediated retrotransposition of a mini-Ty1, but only mutations in S2 destabilized mini-Ty1 RNA in cis and helper-Ty1 RNA in trans. Nested in different loops of the pseudoknot are two hairpins with complementary 7-nucleotide motifs at their apices. Nucleotide substitutions in either motif also reduced retrotransposition and destabilized mini- and helper-Ty1 RNA. Compensatory mutations that restore base-pairing in the S2 stem or between the hairpins rescued retrotransposition and RNA stability in cis and trans. These data inform a model whereby a Ty1 RNA kissing complex with two intermolecular kissing-loop interactions initiates dimerization and packaging.