Systematic review and patient‐level meta‐analysis of SARS‐CoV‐2 viral dynamics to model response to antiviral therapies

Gastine, Silke; Pang, Juanita; Boshier, Florencia A.T.; Carter, Simon J.; Lonsdale, Dagan O.; Cortina‐Borja, Mario; Hung, Ivan F.N.; Breuer, Judy; Kloprogge, Frank; Standing, Joseph F.

SARS‐CoV‐2 viral loads change rapidly following symptom onset so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient‐level meta‐analysis of SARS‐CoV‐2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to‐date. This systematic review identified case reports, case series and clinical trial data from publications between 1/1/2020 and 31/5/2020 following PRISMA guidelines. A multivariable Cox proportional hazards regression model (Cox‐PH) of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed‐effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modelling of respiratory viral dynamics was performed to quantify time dependent drug effects. Patient‐level data from 645 individuals (age 1 month‐100 years) with 6316 viral loads were extracted. Model‐based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions and breast milk were generated. Cox‐PH modelling showed longer time to viral clearance in older patients, males and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, p<0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, p=0.015; AHR = 6.04, p = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analysing antiviral trials has been established.