Sofosbuvir-based regimens for HCV treatment achieve high cure rates with low resistance because sofosbuvir's NS5B target has a structural constraint limiting mutations. The specific mechanism is:

• A The active metabolite (sofosbuvir-triphosphate) binds the allosteric thumb site II of NS5B, causing conformational closure resistant to mutation without loss of polymerase function
• B Sofosbuvir's phosphoramidate prodrug chemistry ensures only renal excretion, preventing development of intrahepatic resistance
• C Pan-genotypic activity of sofosbuvir means that even partial resistance to one HCV genotype allows full susceptibility in coinfection
• D Sofosbuvir is a nucleoside analog that mimics uridine; the S282T resistance mutation in the NS5B palm domain dramatically reduces enzymatic fitness, creating a fitness cost for resistance ✓

Explanation

Sofosbuvir is a nucleotide analog prodrug (ProTide technology) targeting HCV NS5B RNA-dependent RNA polymerase at the catalytic palm (active) site. As a nucleoside analog, it is incorporated into HCV RNA where it acts as a chain terminator. The known resistance mutation S282T (in the NS5B thumb domain proximal to the active site) does confer reduced susceptibility to sofosbuvir, but causes a severe enzymatic fitness cost — the mutant NS5B replicates HCV far less efficiently, making S282T-bearing viruses clinically unfit and rarely observed. This structural constraint of the catalytic site explains sofosbuvir's remarkably high genetic barrier, unlike the frequent mutations seen with NS5A inhibitors.

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

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Written and medically reviewed by the StethoPrep medical team.