Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem?

Abstract

Treatment of hepatitis C virus (HCV) infection has evolved greatly through the recent decade. The availability of direct-acting antiviral agents (DAAs) targeting the functional proteins of HCV has resulted in the introduction of DAA-based combination therapies, providing an optimal rate of treatment success. Among the DAAs, NS5A inhibitors are used in most of the introduced and approved HCV antiviral regimens. Resistance-associated substitutions (RASs) are amino acid substitutions in HCV protein sequences that result in decreased antiviral efficacy of the HCV DAAs. Among the HCV RASs, the NS5A RASs were found to effectively modify and decrease treatment response to NS5A inhibitor-containing regimens. As a baseline predictor of treatment response, NS5A RAS draws attention for pretreatment testing in targeted patient groups. Given NS5A RASs are either naturally-occurring or DAA-selected, the application of NS5A RAS testing can be considered in two settings of NS5A inhibitor-naïve patients and NS5A inhibitor-experienced patients. Less than 5% of NS5A inhibitor-naïve patients harbor naturally-occurring NS5A RAS with high resistance level (> 100X resistance fold-change). In NS5A inhibitor-naïve patients, NS5A RAS testing accompanied by treatment optimization cannot increase treatment response more than 2%-3%, while in NS5A inhibitor-experienced patients, > 75% are found to have NS5A RASs > 100X and NS5A RAS testing in this group of patients seems to be reasonable. This editorial will address the debate on the application of NS5A RAS testing and will discuss if the NS5A RAS testing has any role in clinical management of hepatitis C.

Prevalence of Naturally-Occurring NS5A and NS5B Resistance-Associated Substitutions in Iranian Patients With Chronic Hepatitis C Infection

“…Although NS5A inhibitors are effective in low concentrations, there are concerns about the existence of a low barrier to the selection of resistance mutations that decrease susceptibility to NS5A inhibitors. Generally, the NS5A RASs could result in >2 resistance fold-change, and some of them which cause >100 resistance fold-change are known as RASs > 100X ( Issur and Götte, 2014 ; Sharafi and Alavian, 2018 ). For instance, just a single nucleotide substitution in codon 93 can change its related amino acid (from Y to H, C, and N) in NS5A protein and leads to resistance to most of the NS5A inhibitors ( Issur and Götte, 2014 ; Nakamoto et al, 2014 ; Sharafi and Alavian, 2018 ).…”

“…Generally, the NS5A RASs could result in >2 resistance fold-change, and some of them which cause >100 resistance fold-change are known as RASs > 100X ( Issur and Götte, 2014 ; Sharafi and Alavian, 2018 ). For instance, just a single nucleotide substitution in codon 93 can change its related amino acid (from Y to H, C, and N) in NS5A protein and leads to resistance to most of the NS5A inhibitors ( Issur and Götte, 2014 ; Nakamoto et al, 2014 ; Sharafi and Alavian, 2018 ). However, the viral genotype and subtype should be considered as an important factor to define the fold-change ( Wang et al, 2013 ; Issur and Götte, 2014 ; Nakamoto et al, 2014 ; World Health Organization, 2017 ; Brandão et al, 2018 ; Hezode et al, 2018 ; Sharafi and Alavian, 2018 ; Ghany et al, 2019 , 2020 ).…”

“…For instance, just a single nucleotide substitution in codon 93 can change its related amino acid (from Y to H, C, and N) in NS5A protein and leads to resistance to most of the NS5A inhibitors ( Issur and Götte, 2014 ; Nakamoto et al, 2014 ; Sharafi and Alavian, 2018 ). However, the viral genotype and subtype should be considered as an important factor to define the fold-change ( Wang et al, 2013 ; Issur and Götte, 2014 ; Nakamoto et al, 2014 ; World Health Organization, 2017 ; Brandão et al, 2018 ; Hezode et al, 2018 ; Sharafi and Alavian, 2018 ; Ghany et al, 2019 , 2020 ). In this study, baseline RASs were investigated in 72 HCV-1a patients, and 63 HCV-3a patients, which are the most prevalent HCV genotypes in Iran and were used to be known as “difficult-to-treat genotypes” ( Bittar et al, 2010 ; Fridell et al, 2011 ; Hernandez et al, 2013 ; Walker et al, 2015 ; de Rueda et al, 2017 ; Paolucci et al, 2017 ; Zeuzem et al, 2017 ; Grandal et al, 2018 ).…”

“…In cirrhotic patients with HCV-1a infection, 12 (16.7%) had a previous history of IFN-based treatment while it was 17 (27%) in cirrhotic patients with HCV-3a infection. Although the high rate of SVR (>90%) has led to a reduction in the number of studies on baseline resistance before initiating DAA-based treatments, many investigations of baseline RASs showed the impact of NS5A RASs on the virologic outcome for NS5A inhibitor-containing regimens such as DCV/SOF, and LDV/SOF ( Wang et al, 2013 ; Brandão et al, 2018 ; Sharafi and Alavian, 2018 ; Sharafi et al, 2019 ). The European Association for the Study of Liver Diseases (EASL) recommended that the identification of baseline RASs to DAAs including LDV/SOF and DCV/SOF for HCV genotypes such as 1a could be useful to decide on extending treatment duration or if needed adding RBV ( Pawlotsky et al, 2020 ).…”

Real-world observational experience with direct-acting antivirals for hepatitis C: baseline resistance, efficacy, and need for long-term surveillance

“…Most patients were DAA treatment-naive and the data cannot be extrapolated to those with a history of failure to DAA-based regimens, especially NS5A inhibitors. [23]…”