REAL-WORLD PREDICTORS OF TREATMENT FAILURE AND NS5A RESISTANCE SELECTION IN GENOTYPE 3 HEPATITIS C: A MULTICENTER COHORT WITH LONGITUDINAL SEQUENCING AND IN-SILICO MODELLING
Author(s)
Saima Mushtaq, PhD1, Amjad Khan, PhD2, Aaron G. Lim, DPhil3, Yu Fang, PhD4;
1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, 2Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan, 3Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom, 4Department of Pharmacy Administration and Clinical Pharmacy, Xi’an Jiaotong University, Xi'an, China
1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, 2Department of Pharmacy, Quaid-i-Azam University, Islamabad, Pakistan, 3Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom, 4Department of Pharmacy Administration and Clinical Pharmacy, Xi’an Jiaotong University, Xi'an, China
OBJECTIVES: Direct-acting antivirals (DAAs) have improved hepatitis C virus (HCV) cure rates; however, genotype 3 (GT3) patients particularly those with compensated cirrhosis (CC) and prior NS5A exposure, remain at high risk of treatment failure. This study aimed to determine whether patient characteristics and treatment history predict treatment failure and to investigate how NS5A resistance-associated substitutions (RASs) selection and persistence impact retreatment outcomes.
METHODS: All patients enrolled between 2022 and 2023 at tertiary centers linked to Pakistan’s national hepatitis control programs were included and followed through 2025. Treatment outcomes were compared by prior DAA exposure (treatment-naïve [TN] vs treatment-experienced [TE]) and cirrhosis status (CC vs no CC). Baseline predictors of failure were identified using multivariable logistic regression. NS5A RASs were profiled by Sanger sequencing at failure and re-evaluated up to 24 months. Molecular docking and dynamics simulations assessed the binding stability of inhibitors across mutant NS5A dimers.
RESULTS: A total of 1,390 patients (TN 972; TE 418) completed follow-up. overall SVR was 93% and was higher in TN than TE patients (96% vs 86%). SVR among TN without CC was 99% versus 44% with CC; among TE, 94% without CC versus 53% with CC. Failures (7%) clustered in CC (69% of failures). Independent predictors included cirrhosis (AOR 2.27), obesity (12.33), prior NS5A exposure (0.28), age ≥60 years (0.22), and elevated ALT (0.25). Among failures (n=93), NS5A RASs were frequent: single 31%, double 61%, triple 21%. Y93H was more common in TE than TN (90% vs 61%; p=0.0018) and persisted in 78% of TE+CC at 24 months. In silico analyses showed reduced binding stability for daclatasvir relative to velpatasvir across GT3 mutants.
CONCLUSIONS: In GT3 infection, DAA failure is driven by cirrhosis and prior NS5A exposure. National Programs should implement resistance testing at failure and use resistance-guided, higher-barrier retreatment rather than recycling prior regimens.
METHODS: All patients enrolled between 2022 and 2023 at tertiary centers linked to Pakistan’s national hepatitis control programs were included and followed through 2025. Treatment outcomes were compared by prior DAA exposure (treatment-naïve [TN] vs treatment-experienced [TE]) and cirrhosis status (CC vs no CC). Baseline predictors of failure were identified using multivariable logistic regression. NS5A RASs were profiled by Sanger sequencing at failure and re-evaluated up to 24 months. Molecular docking and dynamics simulations assessed the binding stability of inhibitors across mutant NS5A dimers.
RESULTS: A total of 1,390 patients (TN 972; TE 418) completed follow-up. overall SVR was 93% and was higher in TN than TE patients (96% vs 86%). SVR among TN without CC was 99% versus 44% with CC; among TE, 94% without CC versus 53% with CC. Failures (7%) clustered in CC (69% of failures). Independent predictors included cirrhosis (AOR 2.27), obesity (12.33), prior NS5A exposure (0.28), age ≥60 years (0.22), and elevated ALT (0.25). Among failures (n=93), NS5A RASs were frequent: single 31%, double 61%, triple 21%. Y93H was more common in TE than TN (90% vs 61%; p=0.0018) and persisted in 78% of TE+CC at 24 months. In silico analyses showed reduced binding stability for daclatasvir relative to velpatasvir across GT3 mutants.
CONCLUSIONS: In GT3 infection, DAA failure is driven by cirrhosis and prior NS5A exposure. National Programs should implement resistance testing at failure and use resistance-guided, higher-barrier retreatment rather than recycling prior regimens.
Conference/Value in Health Info
2026-05, ISPOR 2026, Philadelphia, PA, USA
Value in Health, Volume 29, Issue S6
Code
CO17
Topic
Clinical Outcomes
Topic Subcategory
Comparative Effectiveness or Efficacy
Disease
SDC: Gastrointestinal Disorders, SDC: Infectious Disease (non-vaccine)