ABSTRACT:

Background: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), precipitated an unprecedented global health crisis, catalysing an accelerated pipeline of antiviral drug development. Despite the emergency deployment of numerous therapeutic agents, the comparative efficacy, safety, and applicability of these interventions across heterogeneous patient populations remain subjects of active investigation. Objectives: This systematic review synthesises evidence from randomised controlled trials (RCTs), meta-analyses, and high quality observational studies on antiviral and immunomodulatory therapies for COVID-19, critically evaluating the evidence base and extrapolating lessons relevant to future pandemic preparedness. Methods: A systematic search of PubMed/MEDLINE, Cochrane Library, Embase, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) was performed for studies published between January 2020 and December 2024. Studies were selected based on pre-specified eligibility criteria aligned with the PRISMA 2020 guidelines. A total of 127 studies were included in the qualitative synthesis, of which 64 contributed to quantitative analysis. Results: Direct-acting antivirals, particularly nirmatrelvir–ritonavir (Paxlovid) and remdesivir, demonstrated robust efficacy in reducing hospitalisation and mortality among high-risk outpatients and hospitalised patients, respectively. Molnupiravir demonstrated more modest and uncertain benefit, with concerns regarding mutagenicity limiting its broader application. Immunomodulatory agents—dexamethasone, baricitinib, and tocilizumab—conferred significant survival benefit in patients with severe-to-critical disease. Monoclonal antibodies showed class-wide vulnerability to emerging SARS-CoV-2 variants, with most losing neutralising potency against Omicron subvariants. Host-directed therapies and combination antiviral regimens represent promising avenues for broad-spectrum pandemic readiness. Conclusions: The COVID-19 pandemic has fundamentally transformed the antiviral drug development landscape. A stratified, disease-phase-specific treatment approach guided by disease severity has emerged as the optimal paradigm. Future pandemic preparedness demands sustained investment in platform technologies, broad-spectrum antivirals, and adaptive clinical trial infrastructure to enable rapid evidence generation for novel pathogens.

Keywords: COVID-19; SARS-CoV-2; antiviral therapy; pandemic preparedness; nirmatrelvir–ritonavir; remdesivir; molnupiravir; immunomodulatory therapy; broad-spectrum antivirals; systematic review