Howe Anita Y M, Rodrigo Chaturaka, Cunningham Evan B, Douglas Mark W, Dietz Julia, Grebely Jason, Popping Stephanie, Sfalcin Javier Alejandro, Parczewski Milosz, Sarrazin Christoph, de Salazar Adolfo, Fuentes Ana, Sayan Murat, Quer Josep, Kjellin Midori, Kileng Hege, Mor Orna, Lennerstrand Johan, Fourati Slim, Di Maio Velia Chiara, Chulanov Vladimir, Pawlotsky Jean-Michel, Harrigan P Richard, Ceccherini-Silberstein Francesca, Garcia Federico
British Columbia Centre for Disease Control, British Columbia, Canada.
School of Medical Sciences, UNSW Sydney, Sydney, Australia.
JHEP Rep. 2022 Feb 24;4(5):100462. doi: 10.1016/j.jhepr.2022.100462. eCollection 2022 May.
BACKGROUND & AIMS: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure.
SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated.
The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4.
Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized.
Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses.
直接抗病毒（DAA）方案可使超过95%的慢性丙型肝炎病毒（HCV）感染者获得治愈。然而，在一些治疗失败的患者中，可能会出现耐药相关替代突变（RASs），这限制了再次治疗的选择，并存在耐药病毒传播的风险。在本研究中，我们评估了经历DAA治疗失败的患者中RAS的流行情况和分布，包括新型NS5A RASs以及与RAS选择相关的临床因素。
SHARED是一个由临床医生和科学家组成的研究HCV耐药性的国际联盟。从22个国家收集了3355例患者的HCV序列相关元数据。检测病毒学失败患者中的NS3、NS5A和NS5B RASs，包括新型NS5A替代突变。研究临床和人口统计学特征与RAS选择之间的关联。
DAA治疗后，RASs的频率从其自然流行率上升：索磷布韦治疗的患者中，NS3的RASs频率从37%升至60%，NS5A从29%升至80%，NS5B从15%升至22%；达塞布韦治疗的患者中，NS5B的RASs频率从24%升至37%。在730例病毒学失败患者中，大多数接受的是第一代DAA治疗，94%的患者在≥1类DAA中存在耐药：31%为单类耐药，42%为双类耐药（主要针对蛋白酶和NS5A抑制剂），21%为三类耐药。包含≥2个高耐药RASs的不同模式很常见。在1a、3和4型基因型中发现了新的潜在NS5A RASs和适应性变化。DAA治疗失败后，肝硬化老年患者以及感染1b和4型基因型的患者中RAS选择更为频繁。
DAA治疗失败后，HCV耐药很常见。先前未被识别的替代突变不断出现且仍未得到充分表征。
尽管直接抗病毒药物能有效治愈大多数丙型肝炎患者，但有时治疗会选择出耐药病毒，导致抗病毒药物无效或仅部分有效。DAA治疗失败的患者中多药耐药很常见。老年患者和晚期肝病患者更有可能选择耐药病毒。需要国际社会和各国政府共同努力，制定管理耐药性和预防耐药病毒传播的最佳方法。
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