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Lancet Respir Med 10:278C288. CPT-FPV, while 68 received sotrovimab. The study demonstrated that CPT-FPV was non-inferior to sotrovimab in preventing hospitalization within 14 and 28 days. No significant differences between the two treatment arms were observed in emergency room visits, oxygen supplementation, or mortality. Although there were no significant disparities in radiological, virological, or inflammatory marker outcomes, sotrovimab exhibited a more pronounced reduction in IL-6 levels during days 2C5 and lower MCP-1 levels on day 14. High neutralizing titer convalescent plasma and favipiravir demonstrated non-inferior to sotrovimab in preventing hospitalization, emergency room visit, oxygen supplementation, and mortality in mild-to-moderate ACA COVID-19. The evidence may be a choice for treatment for new variants despite the need for further study. (The trial protocol was registered in the Thai clinical trials registry no. 20220319002.) IMPORTANCE This pivotal study reveals that high neutralizing titer COVID-19 convalescent plasma therapy (CPT) combined with favipiravir (FPV) is non-inferior to sotrovimab in preventing hospitalization and severe outcomes in outpatients with mild-to-moderate COVID-19 and high-risk comorbidities. It underscores the potential of CPT-FPV as a viable alternative to neutralizing monoclonal antibodies like sotrovimab, especially amid emerging variants with spike protein mutations. The studys unique approach, comparing a monoclonal antibody with CPT, demonstrates the efficacy of early intervention using high neutralizing antibody titer CPT, even in populations with a significant proportion of elderly patients. These findings are crucial, considering the alternative treatment challenges, especially in resource-limited countries, posed by the rapidly mutating SARS-CoV-2 virus and the need for adaptable therapeutic strategies. KEYWORDS: convalescent plasma, sotrovimab, monoclonal antibody, mild COVID-19, SARS-CoV-2, randomized controlled trial, outpatient COVID-19, non-severe COVID-19 INTRODUCTION The COVID-19 pandemic has had a devastating impact on global health, resulting in unprecedented levels of mortality and morbidity. To combat the severity of the disease, various oral antiviral agents have been developed and proven effective in preventing severe cases of COVID-19, namely, nirmatrelvir/ritonavir and molnupiravir (1 C 3). In Thailand, amid the surge of the delta and omicron variants, favipiravir (FPV) has been extensively deployed as the standard treatment for mild-to-moderate cases of COVID-19, adhering to the Thai COVID-19 clinical practice guidelines. This approach was necessitated by the constrained availability of novel therapeutic options (4). A real-world study within Thailand, alongside a meta-analysis, underscored the advantages of FPV treatment, revealing notable clinical improvements, diminished rates of clinical deterioration, enhanced viral clearance, decreased dependency on supplemental oxygen therapy, and reduced mortality (5 C 7). However, a randomized controlled trial ACA (RCT) conducted among obese Hispanic individuals failed to Tpo demonstrate the efficacy of FPV treatment in mild-to-moderate COVID-19 (8). Given its non-linear pharmacokinetics and auto-inhibition properties, FPVs efficacy remains a topic of controversy and perpetuates a treatment gap, especially among certain ethnic groups characterized by overweight and obesity (9, 10). Sotrovimab (VIR-7831) was a neutralizing monoclonal antibody (NmAb), which many RCTs demonstrated preventing hospitalization in outpatient COVID-19; however, there were many gaps in NmAb treatment, including the high cost and difficulty of access (11 C 15). While most monoclonal antibodies lose their ability to neutralize the omicron variant in laboratory tests due to mutations in the receptor-binding motif, data indicate that sotrovimab remains effective in preventing COVID-19 progression, particularly in the omicron BA.2 sublineage (16, 17). The escape spike protein mutation led to NmAb resistance, while the rapid emergence of spike protein mutations in new variants hindered NmAb efficacy for COVID-19 treatment. The short-lived utility of NmAb contributed to hesitation in developing costly alternatives. The COVID-19 convalescent plasma (CCP) transfusion was reported to treat MERS-CoV, SARS-CoV-1, and influenza virus (18). CCP ACA therapy acts as passive immunization with a well-safety profile, although the result of convalescent plasma therapy (CPT) in various clinical trials was mixed (19). Many negative CPT trials were conducted in hospitalized and ICU-admitted patients with severe COVID-19. The REMAP-CAP, CONCOR-1, ACA RECOVERY, PLACID, and RECOVER could not demonstrate the benefit of CCP in decreasing mortality, time to hospitalized discharge, organ and respiratory support free day, intubation rate, and ICU length of stay in severe and critical COVID-19 patients (19.