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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.
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Background. Little is known about how race and ethnicity, imperfect (albeit accessible) proxies for structural racism, impact COVID-19 incidence among people with HIV (PWH). We report the cumulative incidence and incidence rate ratios (IRR) for COVID-19 in a long-term multi-site cohort of PWH across the US Figure 1. Cumulative incidence of COVID-19 in the CNICS cohort Methods. We examined COVID-19 cumulative incidence and IRR among PWH in care between 3/1/2020 and 12/31/2020 at seven sites in the CFAR Network of Integrated Clinical Systems (CNICS) cohort. We define COVID-19 incident case as having a laboratory-confirmed (RT-PCR/Ag) SARS-CoV-2 positive result or diagnosis verified by chart review. Reinfections were excluded. Results are presented as monthly and quarterly cumulative incidence and IRR with 95% CI stratified by CD4 count, self-reported race/ethnicity, and site. Follow-up was censored on the earliest of diagnosis of COVID-19 disease, loss to follow up, or 12/31/2020 Results. Among 15,780 PWH in care in the CNICS cohort during the study period, 62% were non-white, with a median (IQR) age of 52 (IQR 40-59), 95% were on antiretroviral therapy, 17% had a CD4 count less than 350, and 6% less than 200. Overall, 651 PWH tested positive for COVID-19 for a cumulative incidence of 4.13%. COVID-19 cumulative incidence increased from 0.77% at the end of the first quarter to 4.12% by the end of December 2020. At the peak of the pandemic in December 2020, the cumulative incidence in Black PWH was 1.68 fold higher than in white PWH (p=.033) and 2.35 fold higher in Hispanics than in whites (P< .0001), figure 1. Similarly, the IRR for COVID-19 was 1.71 (95% CI 1.42-2.07) for Black and 2.40 (95% CI 1.91-3.01) for Hispanic PWH relative to white. Although there was variation across sites, reflecting geographic differences in pandemic waves and access to COVID-19 testing, overall individual trends remained the same. COVID-19 cumulative incidence was similar across CD4 cell count strata Conclusion. Our results suggest effects of structural racial disparities on COVID-19 incidence in this diverse population of PWH across the US, with higher and disproportionate rates of COVID-19 in Black and Hispanic PWH. Incidence estimates are conservative because testing was not uniform, and no systematic testing was conducted.
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The world was unprepared for coronavirus disease 2019 (COVID-19) and remains ill-equipped for future pandemics. While unprecedented strides have been made developing vaccines and treatments for COVID-19, there remains a need for highly effective and widely available regimens for ambulatory use for novel coronaviruses and other viral pathogens. We posit that a priority is to develop pan-family drug cocktails to enhance potency, limit toxicity, and avoid drug resistance. We urge cocktail development for all viruses with pandemic potential both in the short term (<1 to 2 years) and longer term with pairs of drugs in advanced clinical testing or repurposed agents approved for other indications. While significant efforts were launched against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro and in the clinic, many studies employed solo drugs and had disappointing results. Here, we review drug combination studies against SARS-CoV-2 and other viruses and introduce a model-driven approach to assess drug pairs with the highest likelihood of clinical efficacy. Where component agents lack sufficient potency, we advocate for synergistic combinations to achieve therapeutic levels. We also discuss issues that stymied therapeutic progress against COVID-19, including testing of agents with low likelihood of efficacy late in clinical disease and lack of focus on developing virologic surrogate endpoints. There is a need to expedite efficient clinical trials testing drug combinations that could be taken at home by recently infected individuals and exposed contacts as early as possible during the next pandemic, whether caused by a coronavirus or another viral pathogen. The approach herein represents a proactive plan for global viral pandemic preparedness.
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Background: Severe COVID-19 can result in pneumonia, with many patients (pts) requiring hospitalization andoxygen support. Severe COVID-19 may also be complicated by acute respiratory distress syndrome, sepsis andseptic shock, and/or multiorgan failure. Many of these pts have features consistent with cytokine release syndrome(CRS) and its associated hyperinflammation. Given their immunomodulatory effects, Janus kinase (JAK) inhibitorshave been suggested as a potential therapeutic option in pts with severe COVID-19. Ruxolitinib-a potentJAK1/JAK2 inhibitor approved for treating myelofibrosis, polycythemia vera, and steroid-refractory acute graft-vs.-host disease (GvHD;US only)-has been associated with reduced levels of inflammatory cytokines in disorderswhere cytokine dysregulation plays a role, including GvHD and secondary hemophagocytic lymphohistiocytosis.Additionally, findings from a small, randomized, phase 2 study (N = 43;Cao Y et al., J Allergy Clin Immunol 2020)showed that treatment with ruxolitinib plus standard of care (SOC) reduced CRS-associated hyperinflammation inpts with severe COVID-19 vs placebo plus SOC, with significant improvement seen in chest computed tomography(CT) features. Although no statistically significant differences were observed, ruxolitinib-treated pts also had anumerically shorter median time to clinical improvement, a lower proportion requiring intensive care/mechanicalventilation, and reduced mortality, with ruxolitinib having a favorable safety profile. Methods: RUXCOVID ( NCT04362137 ) is a global, randomized (2:1), double-blind, placebo-controlled, 29-day, phase 3 study evaluating the efficacy and safety of ruxolitinib plus SOC compared with placebo plus SOC in pts withCOVID-19. Pts are eligible for the study if they are ≥ 12 years old, have confirmed COVID-19, are hospitalized, andmeet ≥ 1 of the following: pulmonary infiltrates (by chest x-ray or CT scan), respiratory frequency ≥ 30 breaths/min, requirement of supplemental oxygen, oxygen saturation (SpO ) ≤ 94% on room air, or arterial oxygen partialpressure (PaO )/fraction of inspired oxygen (FiO ) < 300 mm Hg (1 mm Hg = 0.133 kPa). Pts with a need forintensive care or intubation are not eligible. Pts will be randomized to ruxolitinib 5 mg twice daily or placebo andtreated for 14 days. Pts may be treated for an additional 14 days if no improvement occurs and the potential benefitoutweighs the potential risk per investigator assessment. The primary endpoint is the proportion of pts who die, develop respiratory failure (require mechanical ventilation), or require intensive care by day 29. Secondaryendpoints include improvement in clinical status, in-hospital outcomes, change in National Early Warning Score, change in SpO :FiO ratio, mortality rate, change in inflammatory biomarkers, and safety. Target enrollment is 402pts. Sponsored by Novartis Pharmaceuticals and Incyte.