Prevalence of HCV Resistance-associated Substitutions Among Treatment-failure Patients Receiving Direct-acting Antiviral Agents

Zhenqiu Liu; Xianhua Mao; Kangkang Yu; Chen Suo; Li Jin; Tiejun Zhang; Xingdong Chen


J Viral Hepat. 2020;27(6):585-592. 

In This Article

Abstract and Introduction


Direct-acting antiviral (DAA) failure, which is mainly associated with the selection of resistance-associated substitutions (RASs), is not rare in HCV treatment. RAS data collected from published literature and RAS prevalence were integrated using meta-analysis. DAA-failure-associated RASs were identified by comparing their prevalence between DAA-failure and DAA-naïve patients. Prevalences of emerging RASs that occurred during treatment were also estimated. A total of 2932 DAA-naïve patients and 1466 DAA-failure patients were included. Significant differences in the prevalence of RASs were found in 76 scenarios that involved 34 RASs (11 in NS3, 18 in NS5A and 5 in NS5B), 4 genotypes (GTs) (GT1a, GT1b and GT3–4) and 14 DAAs (6 NS3 protease inhibitors [PIs], 6 NS5A inhibitors and 2 NS5B inhibitors). For NS3, the DAA-failure-associated RASs included V36L, Y56H, Q80K/R, R155K, A156T and D168A/E/L/T/V/Y. Substitutions at R155 and D168 were dominant for most NS3 PIs. For NS5A, DAA-failure-associated RASs included K24R, Q30R, L31M, and P32L in GT1a; R30Q/H, L31F/I/M/V, P58S, and Y93H in GT1b; A30K, L31M and Y93H in GT3; and M31V and Y93H in GT4. Y93H was the most prevalent RAS for NS5A inhibitors. DAA-failure-associated RASs were found at only five positions in NS5B. The majority of DAA-failure patients relapsed. A significant difference was detected for only four RAS sites between relapse patients and nonresponse/breakthrough patients. The RAS prevalence in DAA-failure patients varied among the HCV GTs and DAA regimens. The identified treatment-selected resistance patterns for broadly used DAA regimens will enable the selection of optimized retreatment options.


Hepatitis C virus (HCV) affects more than 180 million people worldwide and is a leading cause of liver disease, including decompensated cirrhosis and hepatocellular carcinoma.[1,2] These complications caused >475 000 deaths in 2015, and in contrast with the HIV, malaria and tuberculosis epidemics, HCV infections have caused an increasing number of deaths in recent years.[3,4] Fortunately, a watershed moment came in 2014 with the advent of direct-acting antivirals (DAAs), which achieved sustained virologic responses (SVRs) or cures in a high proportion (>95%) of patients and have few adverse events.[5–7] However, after the initial excitement, dominated by the perception that HCV had been defeated, the sobering reality was that substantial challenges remained.[8] DAA resistance, which mostly leads to treatment failure, is still an issue for the management of HCV patients.[9,10]

Virologic failure is always associated with the selection of resistance-associated substitutions (RASs), whether they are present at baseline or are acquired during treatment.[10] Many studies have reported that DAAs have reduced efficacy for patients carrying baseline RASs, which may lead to treatment failure.[11–13] The American Association for the Study of Liver Diseases (AASLD) has recommended baseline testing for RASs in several scenarios.[14] The adverse impact of these RASs might therefore be ameliorated by increasing the treatment duration or by optimizing DAA regimens.[8] However, a considerable proportion of treatment failures is caused by RASs that are acquired during treatment.[15–17] Even if we assume that the rate of treatment failure is as low as 2% among previously untreated patients who adhere to an optimal first-line regimen, the number of patients who will need retreatment is considerable because of the enormous number of patients who are treated for HCV worldwide.[8,18] Little is known about the RASs of HCV in response to DAAs due to the relatively small number of patients with treatment failure. Knowledge on the characterization of RASs is therefore critical for resistance-guided retreatment for HCV-infected patients with first-treatment failure.[19]