Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus

Pawlotsky, Jean‐Michel

doi:10.1002/hep.24262

Cited by 293 publications

(288 citation statements)

References 24 publications

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“…This suggests that S282T has a poor fitness in the absence of drug pressure, and S282T is therefore unlikely to be detected at measurable frequency in untreated patients. In comparison, baseline NS3, NS5A, and NS5B non‐nucleoside inhibitor (NNI) RASs has been detected in 10%‐90% of DAA‐naïve patients depending on genotype and subtype27, 28, 29, 30, 31; for example, NS5A L31M has been detected in >50% of GT2a patients 32. Due to the high error rate of HCV polymerase, substitutions at all sites in the HCV genome can exist within the viral quasispecies33, 34; however, the lack of S282T compared with other RASs suggests that not all positions in the HCV genome has the same allowance for genetic variability.…”

Section: Discussionmentioning

confidence: 99%

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

Gane

Métivier

Nahass³

et al. 2017

Hepatology Communications

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S282T in NS5B is the primary amino acid substitution associated with resistance to sofosbuvir (SOF) but has rarely been detected in patients treated with a SOF‐based regimen. Here, the emergence and fitness of the S282T substitution in virologic failure patients administered SOF‐based regimens across the SOF and ledipasvir (LDV)/SOF phase 2 and 3 programs was evaluated. Plasma samples collected at baseline and at virologic failure were amplified and deep sequenced (1% cutoff). To date, over 12,000 patients have been treated in SOF or LDV/SOF phase 2 and 3 studies. Of these, deep sequencing was available at baseline in 8598 patients (62.4% genotype [GT] 1, 10.7% GT2, 20.9% GT3, and 6.0% GT4‐6) and at virologic failure in 901 patients. In the 8598 patients, no S282T substitution was detected at baseline; at virologic failure, 10 of the 901 (1%) patients had S282T detected. The SOF‐based regimen associated with treatment‐emergent S282T was SOF monotherapy in two patients, retreatment with LDV/SOF in prior LDV/SOF failures in three patients, LDV/SOF for 8 weeks in 1 GT1 patient, LDV/SOF for 12 weeks in 1 patient each with GT3, GT4, and GT5, and LDV/SOF + ribavirin for 12 weeks in 1 GT6 patient. Nine of 10 patients with emergent S282T received an SOF‐based retreatment regimen, eight of whom achieved sustained virologic response 12 weeks after treatment and one of whom failed retreatment. Conclusion: The emergence of S282T substitution was rare in patients who fail SOF‐based regimens. Successful retreatment of prior SOF failure patients is possible in the presence of S282T substitution with SOF in combination with various direct‐acting antiviral agents. (Hepatology Communications 2017;1:538–549)

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Section: Discussionmentioning

confidence: 99%

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

Gane

Métivier

Nahass³

et al. 2017

Hepatology Communications

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“…Since the progression of liver disease is essentially due to the local immune responses targeting infected hepatocytes, and as triple-drug treatment failure has not been associated with ALT flares, the selection of PI-resistant variants that have been present for years as minor viral populations may not lead to a shift in immune-dominance resulting in strong intrahepatic cellular immune responses and the associated production of proinflammatory cytokines, which accelerate liver disease progression [8]. Strong NS3-specific T cell immune responses at the baseline may predict a positive outcome for DAA-based therapy, and the presence of pre-existent existing resistance mutations does not play a significant role in the outcome of anti-HCV combined therapy [18].…”

Section: Host Factorsmentioning

confidence: 99%

“…An elevated body mass index and GT1a disease have emerged as the most important factors limiting treatment success in the general population [15]. Markedly higher failure rates are expected when these therapies are used in more difficult-to-treat populations, such as patients with unfavorable genetic markers of IFN-responsiveness and specific subgroups such as African Americans and null responders to prior therapy with pegylated IFN(PEG-IFN)-α and ribavirin (RBV), or patients who have not yet been included in clinical trials, including patients with advanced liver disease, liver transplant recipients, HIV-co-infected individuals, hemodialysis patients, or immunosuppressed patients [8].…”

Section: Host Factorsmentioning

confidence: 99%

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

Kishida¹

2016

MOJI

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“…Nevertheless, triple therapy, particularly for difficult patients, is often limited by safety and tolerability issues, which limit its use, along with a rapid onset of drug-resistance in virological failures. Paradoxically, drug-resistance is considered a hallmark of antiviral drugs, and de facto is both a major cause and consequence of virological failure [5,6].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice

Cento

Tontodonati

Maio

et al. 2015

Digestive and Liver Disease

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The used first generation protease inhibitors may be hampered by virological failure in partially interferon-sensitive patients. Aim: To investigate early hepatitis C virus (HCV)-RNA decay and quasispecies modifications, and disclose viral dynamics underlying failure. Methods: Viraemia decay at early time-points during telaprevir treatment was modelled according to Neumann et al. (1998). NS3-sequences were obtained by population-sequencing and ultradeep-454-pyrosequencing. Results: 13 treatment-experienced (8 non-responders, 5 relapsers), and two cirrhotic naïve patients, received telaprevir + pegylated-interferon-␣ + ribavirin.Viraemia decay was biphasic. In all patients, first-phase was rapid and consistent, with a median [interquartile-range] viraemia decay of 2.8 [2.6-3.2] log IU/ml within 48 h. Second-phase decay was slower, especially in failing patients: 3/3 showed <1 log IU/ml decay between 48 h and 2 weeks, and HCV-RNA >100 IU/ml at week 2. Only one patient experiencing sustained viral response showed similar kinetics.By pyrosequencing, mutational freeze was observed in all 15 patients within the first 24 h, but only in patients with sustained response afterwards. Indeed, 2/2 failing patients showed early resistance, as minor (V36A-T54A: prevalence <26% at 48 h) or major (V36M/A-R155K: prevalence, 99.8% at week 2) variants. Conclusions: Following telaprevir administration, first-phase HCV-RNA decay is consistent with mutational freeze and limited/no viral replication, while second-phase is significantly slower in failing patients (with appearance of resistance), suggesting the usefulness of early HCV-RNA monitoring.© 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus

Cited by 293 publications

References 24 publications

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

The emergence of NS5B resistance associated substitution S282T after sofosbuvir‐based treatment

Mechanisms of Virologic Failure in Hepatitis C and Strategies for Treatment Failure

Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice

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