Zhenqiu Liu1, Xianhua Mao1, Jiaqi Wu2, Kangkang Yu3, Qin Yang4, Chen Suo5, Ming Lu6, Li Jin7, Tiejun Zhang8, Xingdong Chen7. 1. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, China. 2. School of Life Science and Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan. 3. Department of Infectious Diseases, Huashan Hospital, Shanghai, China. 4. State Key Laboratory for Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai, China. 5. Department of Epidemiology, School of Public Health, Shanghai, China; Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, China. 6. Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China. 7. State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Shanghai, China; Fudan University Taizhou Institute of Health Sciences, Taizhou, China; Human Phenome Institute, Fudan University, Shanghai, China. 8. Department of Epidemiology, School of Public Health, Shanghai, China; Key Laboratory of Public Health Safety, Fudan University, Ministry of Education, China. Electronic address: tjzhang@shmu.edu.cn.
Abstract
BACKGROUND & AIMS: The efficacy of direct-acting antiviral agents against hepatitis C virus (HCV) infection can be compromised by substitutions in the HCV genome that occur before treatment (resistance-associated substitutions [RASs]). We performed a meta-analysis to determine the prevalence of RASs and their effects. METHODS: We searched publication databases for studies of HCV RNA substitutions that mediate resistance to direct-acting antiviral agents. Findings from 50 studies of the prevalence of RAS in HCV, from 32 countries, were used in a meta-analysis. We retrieved the HCV RNA sequence from the Los Alamos HCV sequence database to estimate the prevalence of the RASs. The degree of resistance to treatment conferred by each RAS was determined based on fold-change in the 50% effective concentration of the drugs. RESULTS: Our final analysis included data from 49,744 patients with HCV infection and 12,612 HCV sequences. We estimated the prevalence of 56 RASs that encoded amino acids and 114 specific RASs. The average prevalence of RASs was highest in HCV genotype (GT) 6, followed by HCV GT1a, GT2, GT1b, GT3, and GT4. The highest prevalence of RASs observed encoded Q80K in NS3 to NS4A of HCV GT1a, Y93T in NS5A of GT1a, and C316N in NS5B of GT1b. The greatest number of RASs were observed at D168 in NS3 to NS4A, at Y93 in NS5A, and at C316 in NS5B. The prevalence of RASs and mutation burdens were high in Japan, the United States, Germany, Thailand, and the United Kingdom; low in Russia, Brazil, Egypt, and India; and intermediate in China, Canada, Australia, Spain, and France. CONCLUSIONS: In a meta-analysis, we found evidence for 114 RASs in HCV of different genotypes. Patients with HCV infection should be tested for RASs before treatment is selected, especially in regions with a high prevalence of RASs.
BACKGROUND & AIMS: The efficacy of direct-acting antiviral agents against hepatitis C virus (HCV) infection can be compromised by substitutions in the HCV genome that occur before treatment (resistance-associated substitutions [RASs]). We performed a meta-analysis to determine the prevalence of RASs and their effects. METHODS: We searched publication databases for studies of HCV RNA substitutions that mediate resistance to direct-acting antiviral agents. Findings from 50 studies of the prevalence of RAS in HCV, from 32 countries, were used in a meta-analysis. We retrieved the HCV RNA sequence from the Los Alamos HCV sequence database to estimate the prevalence of the RASs. The degree of resistance to treatment conferred by each RAS was determined based on fold-change in the 50% effective concentration of the drugs. RESULTS: Our final analysis included data from 49,744 patients with HCV infection and 12,612 HCV sequences. We estimated the prevalence of 56 RASs that encoded amino acids and 114 specific RASs. The average prevalence of RASs was highest in HCV genotype (GT) 6, followed by HCV GT1a, GT2, GT1b, GT3, and GT4. The highest prevalence of RASs observed encoded Q80K in NS3 to NS4A of HCV GT1a, Y93T in NS5A of GT1a, and C316N in NS5B of GT1b. The greatest number of RASs were observed at D168 in NS3 to NS4A, at Y93 in NS5A, and at C316 in NS5B. The prevalence of RASs and mutation burdens were high in Japan, the United States, Germany, Thailand, and the United Kingdom; low in Russia, Brazil, Egypt, and India; and intermediate in China, Canada, Australia, Spain, and France. CONCLUSIONS: In a meta-analysis, we found evidence for 114 RASs in HCV of different genotypes. Patients with HCV infection should be tested for RASs before treatment is selected, especially in regions with a high prevalence of RASs.
Authors: Stephanie Popping; Rosanne Verwijs; Lize Cuypers; Mark A Claassen; Guido E van den Berk; Anja De Weggheleire; Joop E Arends; Anne Boerekamps; Richard Molenkamp; Marion P Koopmans; Annelies Verbon; Charles A B Boucher; Bart J Rijnders; David A M C van de Vijver Journal: Clin Infect Dis Date: 2020-11-05 Impact factor: 9.079