Resistance-Associated Substitutions Prevalent in Hepatitis C Virus

map with hepatitis C virus
map with hepatitis C virus
The efficacy of direct-acting antiviral drugs has been found to be influenced by distinct resistance-associated substitutions in the hepatitis C virus genome.

Among different hepatitis C virus (HCV) genotypes (GTs), there is evidence of 114 distinct resistance-associated substitutions (RASs) in the HCV genome that affect the efficacy of direct-acting antiviral (DAA) agents, according to results from a study published in Clinical Gastroenterology and Hepatology.

Researchers searched publication databases for studies of HCV RNA substitutions that mediate resistance to DAAs. They included 50 studies from 32 countries in their meta-analysis. Using the HCV RNA sequence from the Los Alamos HCV sequence database, the researchers estimated the prevalence of the RASs. Change in the 50% effective concentration of the drugs (EC50 value) was used to determine the degree of resistance to treatment conferred by each RAS.

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The included studies comprised 49,744 patients with HCV infection and 12,612 HCV sequences. The researchers estimated the prevalence of 56 RASs that encoded amino acids and 114 specific RASs.

The results indicated that the average prevalence of RASs was highest in HCV GT6, followed by HCV GT1a, GT2, GT1b, GT3, and GT4.

The highest prevalence of RASs encoded Q80K in NS3-NS4A of HCV GT1a, Y93T in NS5A of GT1a, and C316N in NS5B of GT1b, while the greatest numbers of RASs was seen at D168 in NS3-NS4A, at Y93 in NS5A, and at C316 in NS5B.

After looking at RAS prevalence by region, the researchers found a high prevalence of RASs and mutation burden in Japan, the United States, Germany, Thailand, and the United Kingdom, while they were low in Russia, Brazil, Egypt, and India.

The study included several limitations, including high between-study heterogeneity. The researchers also noted that the RASs included were determined via deep sequencing with a 1% cutoff, which may be too low to confer clinical relevance.

“The presence of baseline RASs confers an adverse impact on DAA efficacy, indicating that patients may benefit from the baseline resistance testing before initiation of DAA regimens,” the researchers wrote.


Liu Z, Mao X, Wu J, et al. World-wide prevalence of substitutions in HCV genome associated with resistance to direct-acting antiviral agents [published online November 1, 2019]. Clin Gastroenterol Hepatol. doi:10.1016/j.cgh.2019.10.046