Premkumar Madhumita, Gupta Ekta, Sandhu Anchal, Sharma Prerna, Nain Jasvinder, Taneja Sunil, Verma Nipun, De Arka, Duseja Ajay, Grover Gagandeep S, Dhiman Radha K
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
Department of Virology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India.
J Clin Exp Hepatol. 2025 Nov-Dec;15(6):102601. doi: 10.1016/j.jceh.2025.102601. Epub 2025 May 28.
The National Viral Hepatitis Control Program (NVHCP) has a cure rate of 91.6% when using direct-acting antivirals (DAAs)-sofosbuvir with an NS5A inhibitor (ledipasvir, daclatasvir or velpatasvir) ± ribavirin in the Punjab hub-and-spoke model of hepatitis C virus (HCV) elimination.
We collected the clinical and virological data for the ∼8.4% treatment failure cases. Sanger nucleotide sequencing was performed to identify the resistance-associated substitutions (RAS) following treatment failure. We ascertained the clinical and virological predictors of treatment failure under the NVHCP.
Between April 2019 and December 2023, 50865 patients with HCV were treated; median age 41.6 years, 65% men, 85.8% without cirrhosis, 8.5% treatment experienced, median viral load (x10) of 4.1 (2.9-7.8),71.3% genotype (GT)-3, with cure rate of 89.5%. On multivariable analysis, age (aOR 1.5, 95% CI: 1.3-1.9, = 0.021), presence of cirrhosis (aOR1.8, 95% CI: 1.3-2.5, < 0.001), and poor drug compliance (aOR 0.3, 95% CI: 0.2-0.6, < 0.001) predicted treatment failure. We enrolled a difficult-to-treat group of 640 persons for virological testing, aged 39.2 ± 15.1 years, median HCV viral load (x10) of 1.98 (1.5-2.4). Of these, 56.6% were treatment-experienced, 11.1% were prior defaulters, with predominant GT3 (73.3%) and GT1 (18.7%) with coinfection rates of 3.8% and 4.4% for hepatitis B virus (HBV) and human immunodeficiency virus (HIV), respectively. Presumed modes of transmission in this subgroup were unsafe injections (57%), and injection drug use (32.8%). A total of 243 patient samples underwent RAS testing, with 45 patients having detectable variants, and finally 31 RAS mutations were detected in the NS5A gene, with no clinically significant resistance observed in the NS5B gene. In GT-3, the RAS observed were A30K, L31 M/R, A62S, A62T, and Y93H. In GT-1, the RAS observed were M28A, H58P, G30 H/R, H58D, and Y93K. Among these Y93K, L30R, G30 H/R confer resistance to velpatasvir; such patients received retreatment with voxilaprevir-containing regimens.
Patient factors like compliance and the presence of cirrhosis predicted treatment failures. RAS do not appear to be a primary factor for treatment failure in a public health setting.
NCT03488485 available from https://clinicaltrials.gov/study/NCT03488485.
在旁遮普省丙型肝炎病毒（HCV）消除的中心辐射模式中，国家病毒性肝炎控制项目（NVHCP）使用直接作用抗病毒药物（DAA）索磷布韦联合NS5A抑制剂（来迪派韦、达卡他韦或维帕他韦）±利巴韦林时，治愈率为91.6%。
我们收集了约8.4%治疗失败病例的临床和病毒学数据。治疗失败后进行桑格核苷酸测序以鉴定耐药相关替代突变（RAS）。我们确定了NVHCP下治疗失败的临床和病毒学预测因素。
2019年4月至2023年12月期间，50865例HCV患者接受了治疗；中位年龄41.6岁，65%为男性，85.8%无肝硬化，8.5%有治疗史，中位病毒载量（×10）为4.1（2.9 - 7.8），71.3%为基因（GT）-3型，治愈率为89.5%。多变量分析显示，年龄（调整后比值比[aOR]1.5，95%置信区间[CI]：1.3 - 1.9，P = （此处原文有误，推测为P）0.021）、肝硬化的存在（aOR1.8，95%CI：1.3 - 2.5，P < 0.001）以及药物依从性差（aOR 0.3，95%CI：0.2 - 0.6，P < 0.001）可预测治疗失败。我们纳入了640名难以治疗的患者进行病毒学检测，年龄39.2±15.1岁，HCV中位病毒载量（×10）为1.98（1.5 - 2.4）。其中，56.6%有治疗史，11.1%曾有治疗中断，主要为GT3（73.3%）和GT1（18.7%），乙型肝炎病毒（HBV）和人类免疫缺陷病毒（HIV）合并感染率分别为3.8%和4.4%。该亚组推测的传播方式为不安全注射（57%）和注射吸毒（32.8%）。共243份患者样本进行了RAS检测，45例患者检测到可检测的变异，最终在NS5A基因中检测到31个RAS突变，在NS5B基因中未观察到具有临床意义的耐药性。在GT - 3型中，观察到的RAS为A30K、L31M/R、A62S、A62T和Y93H。在GT - 1型中，观察到的RAS为M28A、H58P、G30H/R、H58D和Y93K。其中Y93K、L30R、G30H/R对维帕他韦耐药；这些患者接受了含伏西瑞韦方案的再治疗。
依从性和肝硬化的存在等患者因素可预测治疗失败。在公共卫生环境中，RAS似乎不是治疗失败的主要因素。临床试验注册编号：NCT03488485，可从https://clinicaltrials.gov/study/NCT03488485获取。
