Dietz Julia, Graf Christiana, Berg Christoph P, Port Kerstin, Deterding Katja, Buggisch Peter, Peiffer Kai-Henrik, Vermehren Johannes, Dultz Georg, Geier Andreas, Reiter Florian P, Bruns Tony, Schattenberg Jörn M, Durmashkina Elena, Gustot Thierry, Moreno Christophe, Trauth Janina, Discher Thomas, Fischer Janett, Berg Thomas, Kremer Andreas E, Müllhaupt Beat, Zeuzem Stefan, Sarrazin Christoph
Medical Clinic 1, Department of Medicine, Goethe University, Frankfurt, Germany.
German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany.
JHEP Rep. 2024 Mar 25;6(7):101072. doi: 10.1016/j.jhepr.2024.101072. eCollection 2024 Jul.
Data on the prevalence and characteristics of so-called rare HCV genotypes (GTs) in larger cohorts is limited. This study investigates the frequency of rare GT and resistance-associated substitutions and the efficacy of retreatment in a European cohort.
A total of 129 patients with rare GT1-6 were included from the European resistance database. NS3, NS5A, and NS5B were sequenced and clinical parameters and retreatment efficacies were collected retrospectively.
Overall 1.5% (69/4,656) of direct-acting antiviral (DAA)-naive and 4.4% (60/1,376) of DAA-failure patients were infected with rare GT. Although rare GTs were almost equally distributed throughout GT1-6 in DAA-naive patients, we detected mainly rare GT4 (47%, 28/60 GT4; of these n = 17, subtype 4r) and GT3 (25%, 15/60 GT3, of these n = 8, subtype 3b) among DAA-failures. A total of 62% (37/60) of DAA failures had not responded to first-generation regimes and the majority was infected with rare GT4 (57%, 21/37). In contrast, among patients with failure to pangenotypic DAA regimens (38%, 23/60), infections with rare GT3 were overrepresented (57%, 13/23). Although NS5A RASs were uncommon in rare GT2, GT5a, and GT6, we observed combined RASs in rare GT1, GT3, and GT4 at positions 28, 30, 31, which can be considered as inherent. DAA failures with completed follow-up of retreatment, achieved a high SVR rate (94%, 45/48 modified intention-to-treat analysis; 92%, 45/49 intention-to-treat). Three patients with GT4f, 4r, or 3b, respectively, had virological treatment failure.
In this European cohort, rare HCV GT were uncommon. Accumulation of specific rare GT in DAA-failure patients suggests reduced antiviral activities of DAA regimens. The limited global availability of pangenotypic regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.
Data on the prevalence and characteristics of rare HCV genotypes (GT) in larger cohorts are still scarce. This study found low rates of rare HCV GTs among European HCV-infected patients. In direct-acting antiviral (DAA)-failure patients, rare GT3 subtypes accumulated after pangenotypic DAA treatment and rare GT4 after first generation DAA failure and viral resistance was detected at NS5A positions 28, 30, and 31. The limited global availability of pangenotypic DAA regimens for first line therapy as well as multiple targeted regimens for retreatment could result in HCV elimination targets being delayed.
关于较大队列中所谓罕见丙型肝炎病毒（HCV）基因型（GT）的患病率及特征的数据有限。本研究调查了欧洲队列中罕见GT及耐药相关替代位点的频率，以及再治疗的疗效。
从欧洲耐药数据库纳入了129例具有罕见GT1-6的患者。对NS3、NS5A和NS5B进行测序，并回顾性收集临床参数和再治疗疗效。
总体而言，初治直接抗病毒药物（DAA）的患者中1.5%（69/4656）以及DAA治疗失败的患者中4.4%（60/1376）感染了罕见GT。虽然在初治DAA的患者中罕见GT在GT1-6中分布几乎均等，但在DAA治疗失败的患者中，我们主要检测到罕见GT4（47%，28/60为GT4；其中n = 17，4r亚型）和GT3（25%，15/60为GT3，其中n = 8，3b亚型）。62%（37/60）的DAA治疗失败患者对第一代方案无反应，且大多数感染了罕见GT4（57%，21/37）。相比之下，在泛基因型DAA方案治疗失败的患者中（38%，23/60），罕见GT3感染占比过高（57%，13/23）。虽然NS5A耐药相关替代位点在罕见GT2、GT5a和GT6中不常见，但我们在罕见GT1、GT3和GT4的28、30、31位点观察到了联合耐药相关替代位点，可认为是固有存在的。完成再治疗随访的DAA治疗失败患者实现了较高的持续病毒学应答率（94%，45/48改良意向性分析；92%，45/49意向性分析）。分别有3例GT4f、4r或3b患者出现病毒学治疗失败。
在这个欧洲队列中，罕见HCV GT并不常见。DAA治疗失败患者中特定罕见GT的积累表明DAA方案的抗病毒活性降低。一线治疗泛基因型方案在全球的可及性有限以及再治疗的多种靶向方案可能导致丙型肝炎病毒消除目标延迟。
关于较大队列中罕见HCV基因型（GT）的患病率及特征的数据仍然匮乏。本研究发现欧洲HCV感染患者中罕见HCV GT的发生率较低。在直接抗病毒药物（DAA）治疗失败的患者中，泛基因型DAA治疗后罕见GT3亚型积累，第一代DAA治疗失败后罕见GT4积累，并且在NS5A的28、30和31位点检测到病毒耐药。一线治疗泛基因型DAA方案在全球的可及性有限以及再治疗的多种靶向方案可能导致丙型肝炎病毒消除目标延迟。
