The Phase 3 REDPINE trial examined antiviral effects of remdesivir in hospitalized adults with COVID-19 who had impaired kidney function. The virology analyses reported here aimed to quantify treatment-associated changes in SARS-CoV-2 viral load, evaluate outcomes in immunocompromised participants (including those with solid organ transplantation [SOT]), and screen for emergent polymerase substitutions associated with altered remdesivir susceptibility.
REDPINE was a randomized, placebo-controlled phase 3 clinical trial in participants hospitalized for COVID-19 with impaired renal function. A total of 243 participants were enrolled and treated. Among these, 42 participants had undergone SOT and were receiving immunosuppressive medication before and during the study. Participants received remdesivir or placebo for a 5-day treatment course.
Nasopharyngeal swabs were collected at baseline and through Day 29 for virologic assessments. Analyses included quantitative SARS-CoV-2 RT-qPCR to measure viral load, next-generation sequencing (NGS) to detect viral genomic substitutions, and site-directed mutagenesis assessed in a SARS-CoV-2 replicon system to characterize the functional impact of substitutions on remdesivir susceptibility.
Remdesivir treatment produced significantly greater reductions from baseline in viral load on Day 5 and Day 7 compared with placebo (P ≤ 0.034). These findings indicate measurable antiviral activity of remdesivir in this population of patients with impaired kidney function when evaluated by nasopharyngeal RT-qPCR.
Within the remdesivir-treated group, participants with prior SOT demonstrated significantly smaller reductions in viral load from baseline on Days 5, 7, and 14 compared with participants without SOT (all P < 0.05). This pattern indicates delayed viral clearance in immunosuppressed SOT recipients relative to non-SOT participants despite remdesivir treatment.
Mathematical modeling of viral load kinetics was performed for participants with kidney transplants. The model predicted that extending remdesivir treatment from 5 days to 10 days would accelerate viral decline, estimating a greater than 13-day faster time to viral load decline with the longer regimen. The report provides this model-based prediction but does not include prospective clinical outcome data to confirm the modeled benefit of the extended duration.
NGS detected emergent substitutions in the viral RNA-dependent RNA polymerase (Nsp12) in four participants treated with remdesivir. The substitutions observed were E136V, M794I, and C799F, and they were identified 9 days after cessation of remdesivir treatment. Three of the four participants with emergent substitutions had undergone SOT.
Site-directed mutagenesis of these Nsp12 substitutions in a SARS-CoV-2 replicon system demonstrated low-level reduced in vitro susceptibility to remdesivir, with changes in half-maximal effective concentration (EC50) of up to ≤3.4-fold. These findings indicate rare post-treatment emergence of polymerase substitutions associated with modest reductions in remdesivir susceptibility. The source does not report clinical consequences directly attributable to these substitutions.
In participants with impaired kidney function, remdesivir showed demonstrable antiviral activity as measured by nasopharyngeal viral load reductions on Days 5 and 7. Immunocompromised SOT recipients had delayed viral clearance despite receiving remdesivir, and modeling suggested that an extended 10-day remdesivir course might shorten time to viral decline in transplanted patients. Emergence of Nsp12 substitutions conferring low-level reduced susceptibility was rare and was observed predominantly in SOT recipients. The report presents virologic and in vitro susceptibility data but does not provide direct evidence of clinical outcome improvements with extended therapy; the modeling result is a prediction rather than a prospectively tested regimen.
This study is registered at ClinicalTrials.gov as NCT04745351 and EudraCT registration no. 2020-005416-22.
Conflict of interest disclosures reported in the source include multiple authors who are employees and stockholders of Gilead Sciences, Inc.; other authors disclosed research funding, consulting relationships, or advisory roles with various industry organizations as detailed in the original report.