Complex Pattern of Resistance-Associated Substitutions of Hepatitis C Virus after Daclatasvir/Asunaprevir Treatment Failure

Abstract

Backgrounds & AimsWe aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection.MethodsThis is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing.ResultsThe frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients.ConclusionTreatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

Glecaprevir and pibrentasvir for Japanese patients with chronic hepatitis C genotype 1 or 2 infection: Results from a multicenter, real‐world cohort study

“…Because NS3/4A RAS acquired after treatment with protease inhibitors are generally replaced by wild‐type viruses within 1 year after treatment, we have not shown data for NS3/4A RAS. In a Japanese clinical trial of GLE/PIB, however, the only two HCV subtype 1b patients who did not achieve SVR had an NS5A P32 deletion at baseline, which has rarely been acquired as a treatment‐emergent substitution in patients who have failed a DCV‐containing regimen . Recently, the emergence of P32 deletion was found by deep sequencing after LDV/SOF treatment failure .…”

Real‐world efficacy of elbasvir and grazoprevir for hepatitis C virus (genotype 1): A nationwide, multicenter study by the Japanese Red Cross Hospital Liver Study Group

“…Patients with HCV genotype (GT) 1b, the most common type in Japan, were originally treated with the combination of the non‐structural protein (NS)5A inhibitor daclatasvir (DCV) and the NS3/4A protease inhibitor asunaprevir (ASV) . However, the major drawback of this treatment was that the presence of a resistance‐associated substitution (RAS) at the 168th amino acid of NS3 or the 31st or 93rd amino acid of NS5A markedly decreased the sustained virologic response (SVR) rate . Currently, this combination of drugs is excluded as a treatment option.…”

Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy

“…The DCV and ASV combination therapy was particularly valuable for IFN intolerant or ineligible patients, such as those with depression, LC, the elderly and patients with renal failure, as well as pegylated‐IFN plus ribavirin‐based regimen non‐responders. Although DCV/ASV therapy for 24 weeks improved the efficacy and safety outcomes for patients with HCV infection, approximately 10% of patients could not achieve SVR and, finally, multiple NS5A resistance‐associated variants (RAVs) emerged after DCV/ASV failure . In 2015, sofosbuvir (SOF), an oral nucleotide analog inhibitor of the HCV NS5B polymerase plus ledipasvir (LDV), a second‐in‐class NS5A inhibitor, were approved in Japan.…”