Sofosbuvir is a nucleotide analogue inhibitor of HCV NS5B RNA-dependent RNA polymerase used in HCV DAA regimens. Its pan-genotypic activity and resistance profile is explained by:

• A Sofosbuvir binds an allosteric thumb site on NS5B that is highly conserved across genotypes; resistance requires changes at this site that also impair enzyme function
• B Sofosbuvir inhibits NS5A phosphoprotein in addition to NS5B, providing multi-target coverage across genotypes
• C Sofosbuvir is a prodrug (ProTide technology) that, after intracellular activation to sofosbuvir triphosphate, is incorporated into nascent HCV RNA as a chain terminator; the NS5B active site is highly conserved across genotypes and resistance (S282T mutation) severely reduces viral replication fitness ✓
• D Sofosbuvir activates host innate immune pathways that are equally effective regardless of HCV genotype

Explanation

Sofosbuvir uses ProTide technology (phosphoramidate prodrug approach) to deliver sofosbuvir monophosphate directly into hepatocytes, bypassing the first phosphorylation step. Intracellular kinases convert it to sofosbuvir triphosphate, which competes with UTP for incorporation into HCV RNA; once incorporated, it lacks a 3'-OH group and causes obligate chain termination. The NS5B active site (nucleoside binding site) is highly conserved across all HCV genotypes, explaining pan-genotypic activity. The primary resistance mutation S282T in NS5B strikingly reduces viral replication fitness by ~20-fold, meaning resistant viruses are substantially less fit and rarely emerge clinically. This makes sofosbuvir the backbone of virtually all modern HCV regimens.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.