Prevalence and characteristics of naturally occurring sofosbuvir resistance‐associated variants in patients with hepatitis C virus genotype 1b infection

Section: Discussionmentioning

confidence: 99%

Real‐world efficacy and safety of sofosbuvir + ribavirin for hepatitis C genotype 2: A nationwide multicenter study by the Japanese Red Cross Liver Study Group

Akahane¹,

Kurosaki

Itakura

et al. 2018

“…Until recently, because most clinical trials exclude patients who failed to respond to DAAs, retreatment outcomes for patients who had such RAVs have not been elucidated. In patients who failed to respond to DAA‐containing regimens, RAVs in D168E, NS5A F28S, P32 deletion, or NS5B S282 T, which are rarely detected as naturally occurring RAVs, were observed . These RAVs are thought to be cross‐resistant to the same class of DAAs; however, the degree of resistance and the sensitivity to other anti‐HCV reagents have not been clarified.…”

Section: Discussionmentioning

confidence: 99%

“…Genome sequences from long‐term HCV cultures were investigated by direct sequencing, as previously described . Briefly, we used an RNeasy mini kit (Qiagen, Limburg, The Netherlands) to extract total RNA from long‐term HCV cultures.…”

Section: Methodsmentioning

confidence: 99%

Effects of resistance‐associated variants in genotype 2 hepatitis C virus on viral replication and susceptibility to antihepatitis C virus drugs

Suda

Kimura

Shigesawa

et al. 2019

Self Cite

Aims Development of direct‐acting antivirals (DAAs) has made antihepatitis C virus (HCV) treatment highly safe and effective. However, the emergence of resistant‐associated variants (RAVs) after failure of DAA therapy affects retreatment outcomes. In particular, genotype 1 HCV with P32 deletion has been reported to be highly resistant to all approved non‐structural protein (NS)5A inhibitors. However, analysis of RAVs in genotype 2 HCV has been limited. Accordingly, in this study, we evaluated the roles of genotype 2 HCV variants in antiviral drug efficacy. Methods We utilized HCV‐2b/2a (JFH‐1) chimeric virus (genotype 2a), which replicates more robustly than JFH‐1. We constructed various genotype 2a JFH‐1‐based HCV cell culture systems with NS3 (D168E), NS5A (F28S, F28S/M31I, P32 deletion, and Y93H), and NS5B (S282 T) RAVs and analyzed the replication ability and sensitivity to various anti‐HCV reagents. Results Genotype 2a‐based HCV with NS5A–P32 deletion could not replicate even in long‐term cultures. Genotype 2a‐based HCV with NS5A‐F28S/M31I showed significantly higher replication ability than the wild‐type strain, and replication could not be suppressed, even with high concentrations of NS5A inhibitors, including pibrentasvir and velpatasvir (<1000–10 000 fold‐resistance compared with the wild‐type strain). However, genotype 2a‐based HCV with NA5A‐F28S/M31I was sensitive to HCV protease inhibitor, NS5B inhibitor, interferon‐α, and ribavirin. Genotype 2a‐based HCV with NS5B‐S282 T was resistant to sofosbuvir, but was highly sensitive to ribavirin compared with the control. Conclusions When undertaking retreatment for genotype 2a HCV‐infected patients who fail to respond to DAAs, the optimized retreatment should be chosen according to the sensitivity of the emerging RAVs to anti‐HCV drugs.

“…Among patients with SOF/LDV failure, a high rate of C316 mutations was observed in the NS5B region. C316 mutations are reported to be found in 46.9% of Japanese HCV genotype 1b‐infected patients, and it is reported to reduce the SVR rates of genotype 1b patients treated with SOF/LDV …”

Section: Discussionmentioning

confidence: 99%

Favorable outcome of retreatment by direct‐acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure

Tojima

Kakizaki

Takakusagi³

et al. 2019

Aim In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance‐associated substitutions. This study aimed to investigate the outcomes of retreatment with direct‐acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations. Methods We retrospectively analyzed 44 patients re‐treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines. Results The sustained virological response rate with second‐line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third‐ and fourth‐line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second‐line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second‐line treatment failed. Conclusions Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug‐resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.