Development of rare resistance‐associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two‐hit mechanism

Uchida, Yuzo; Kouyama, Jun‐ichi; Naiki, Kayoko; Sugawara, Kayoko; Inao, Mie; Imai, Yumiko; Nakayama, Nobuaki; Mochida, Satoshi

doi:10.1111/hepr.12673

Cited by 34 publications

(51 citation statements)

References 16 publications

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“…Study characteristics were summarised in Tables and . Fifty‐six studies were included, with a total of 5522 patients with HCC, while 27 studies enrolled non‐HCC patients as control groups. Fifty‐three (95%) studies were observational cohorts (45 retrospective and eight prospective) and three studies were clinical trials.…”

Section: Resultsmentioning

confidence: 99%

Systematic review with meta‐analysis: effectiveness of direct‐acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma

Lockart

Alavi

et al. 2019

Aliment Pharmacol Ther

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Summary Background Direct‐acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection is highly curative and tolerable. Among patients with hepatocellular carcinoma (HCC), optimal timing of DAA therapy remains unclear. Data on efficacy of DAA therapy in patients with HCC would inform this decision‐making. Aim To evaluate response to DAA therapy among patients diagnosed with HCV infection and HCC. Methods Bibliographic databases and conference abstracts were searched. Meta‐analysis was conducted to pool sustained virologic response (SVR) estimates. Results Fifty‐six studies with 5522 patients with HCV and HCC were included. Overall SVR was 88.3% (95% CI 86.1‐90.4). Twenty‐seven studies included patients with prior or present HCC (n = 3126) and patients without HCC (n = 49 138), in which SVR was 88.2% (95% CI 85.0‐91.4) and 92.4% (95% CI 91.1‐93.7) among patients with and without HCC, respectively (odds ratio: 0.54, 95% CI 0.43‐0.68, P < .001). In the subgroup analyses, higher SVR was seen in patients who received curative HCC management (SVR 90.4%, 95% CI 88.3‐92.4), or treated with sofosbuvir + NS5A inhibitor DAAs (SVR 96.9%, 95% CI 94.3‐99.4), or in patients with HCV genotype 1 infection (SVR 92.0%, 95% CI 88.1‐95.6). Conclusion Response to DAA therapy was lower in patients with HCC compared to those without HCC, regardless of cirrhosis status. Among HCC patients, there was an impact of proportion with curative HCC management on DAA therapy response.

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Section: Resultsmentioning

confidence: 99%

Systematic review with meta‐analysis: effectiveness of direct‐acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma

Lockart

Alavi

et al. 2019

Aliment Pharmacol Ther

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“…Uchida et al . reported that NS5A R30Q/H/l and NS5A Y93H mutations at baseline determined the therapeutic efficacy of DCV/ASV, but rare NS5A RAVs (P29 del and P32 del ) developed frequently in patients with previous SMV therapy . The D168E RAV in NS3 was detected in the patient who failed therapy in our cohort after the discontinuation of DCV/ASV.…”

Section: Discussionmentioning

confidence: 59%

Outcomes of treatment with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation

Honda¹,

Sugawara²,

Watanabe

et al. 2017

Hepatology Research

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“…We also failed to detect NS5A amino acid substitutions in 20 patients treated with SMV/PEG-IFN/RBV. Uchida et al [16] also detected the same NS5A deletions in three of five DCV/ASV failures. Ultra-sequencing analysis did not detect the NS5A deletion in SMV/PEG-IFN/RBV failure [16].…”

Section: Discussionmentioning

confidence: 85%

“…Uchida et al [16] also detected the same NS5A deletions in three of five DCV/ASV failures. Ultra-sequencing analysis did not detect the NS5A deletion in SMV/PEG-IFN/RBV failure [16]. We speculated that previous triple therapy including SMV potentiates the occurrence of rare NS5A deletions during DCV administration, although the precise mechanism needs to be studied.…”

Section: Discussionmentioning

confidence: 85%

Long-Term Follow-Up of Resistance-Associated Substitutions in Hepatitis C Virus in Patients in Which Direct Acting Antiviral-Based Therapy Failed

Yoshida

Hoang

Tamori

et al. 2017

IJMS

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We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.

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Development of rare resistance‐associated variants that are extremely tolerant against NS5A inhibitors during daclatasvir/asunaprevir therapy by a two‐hit mechanism

Cited by 34 publications

References 16 publications

Systematic review with meta‐analysis: effectiveness of direct‐acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma

Systematic review with meta‐analysis: effectiveness of direct‐acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma

Outcomes of treatment with daclatasvir and asunaprevir for recurrent hepatitis C after liver transplantation

Long-Term Follow-Up of Resistance-Associated Substitutions in Hepatitis C Virus in Patients in Which Direct Acting Antiviral-Based Therapy Failed

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