Antiviral Drug Development against RNA Viruses: Progress, Clinical Translation and Persistent Challenges

Abstract

Antiviral drug development has produced transformative treatments for some RNA-virus infections while leaving major gaps in acute respiratory, haemorrhagic and enteric disease. The unevenness of progress cannot be explained by target availability alone. This critical narrative review examines how viral biology, pharmacological exposure, disease timing, trial design, resistance and health-system access jointly determine whether an antiviral candidate becomes a clinically useful intervention. Peer-reviewed mechanistic studies, randomised trials, methodological papers and authoritative institutional evidence published from 2000 to 13 August 2026 were critically synthesised, with earlier foundational findings considered where necessary. Durable combination treatment for human immunodeficiency virus and curative direct-acting treatment for hepatitis C show what sustained target validation and clinical development can achieve. Conversely, trials of influenza, coronavirus disease 2019, respiratory syncytial virus, dengue and emerging infections demonstrate the difficulty of translating reductions in viral replication into reliable effects on symptoms, hospitalisation, transmission or survival. Contrasting remdesivir outcomes across disease stages, context-dependent results for oral coronavirus antivirals, a promising but geographically limited paediatric respiratory syncytial virus trial, and dengue human-challenge studies illustrate why positive virological or early clinical findings require precise interpretation. Resistance is shaped by drug mechanism, treatment exposure, viral population dynamics and surveillance quality, rather than by a uniform property of all RNA viruses. Apparent broad-spectrum activity may also reflect assay artefacts or non-physiological experimental systems. Priorities include pharmacologically credible discovery platforms, earlier diagnosis and treatment, adaptive trials with prespecified patient-important endpoints, resistance-informed combinations, outbreak-ready trial infrastructure and affordability planned before licensing. The central conclusion is that antiviral innovation is most effective when molecular specificity, clinically relevant timing and equitable implementation are developed as a connected evidence pathway.