Infrequent Development of Resistance in Genotype 1–6 Hepatitis C Virus–Infected Subjects Treated With Sofosbuvir in Phase 2 and 3 Clinical Trials

Svarovskaia, Evguenia S.; Dvory‐Sobol, Hadas; Parkin, Neil; Hebner, Christy M.; Gontcharova, Viktoria; Martin, Ross; Ouyang, Wen; Han, Bin; Xu, Simin; Ku, Karin S.; Chiu, Sophia; Gane, Edward; Jacobson, Ira M.; Nelson, David R.; Lawitz, Eric; Wyles, David L.; Bekele, N.; Brainard, Diana M.; Symonds, William T.; McHutchison, John G.; Miller, Michael D.; Mo, Hongmei

doi:10.1093/cid/ciu697

Cited by 200 publications

(162 citation statements)

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“…Across the SOF development program, S282T was not detected by deep sequencing (1% cutoff) in any of the 8598 baseline samples, which is consistent with the findings of previous studies 11, 25, 26. 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.…”

Section: Discussionsupporting

confidence: 84%

“…SOF exhibits a high barrier to resistance in vivo. After in vitro selection, S282T in NS5B was the only substitution selected in all tested GTs, conferring 2.4‐ to 18.1‐fold reduced susceptibility to SOF, while also reducing the viral replication capacity by 89% to 99% when compared with wild type 10, 11, 12…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Treatment‐emergent L159F and V321A have been observed at time of virologic failure in a few patients in SOF phase 2 and 3 clinical trials 11. The 50% effective concentration (EC 50 ) fold reduction of these substitutions to SOF was 1.2‐ to 1.3‐fold for L159F in GT1a, GT1b, and GT3a and 1.3‐fold for V321A in GT3a 11, 12. In an analysis of SOF and LDV/SOF studies, the presence of baseline L159F was shown to be associated with virologic failure in a subset of GT1b patients with advanced liver disease treated for a shorter duration with SOF plus RBV before liver transplantation but not for patients receiving LDV/SOF 17.…”

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confidence: 99%

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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: Discussionsupporting

confidence: 84%

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confidence: 99%

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confidence: 99%

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

Gane

Métivier

Nahass³

et al. 2017

Hepatology Communications

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“…Resistance patterns regarding ledipasvir are similar. The NS5B S282T substitution is the only resistance mutation associated with reduced susceptibility to NS5B nucleotide inhibitors, with sofosbuvir being the paradigmatic molecule; it develops minimally and is unrelated to other NS5B RAVs (21). It was initially detected in the Electron study with sofosbuvir monotherapy in a patient infected with genotype 2 who relapsed at week 4 post-treatment (22).…”

Section: Resistance-associated Variants (Ravs)mentioning

confidence: 99%

Causes of treatment failure for hepatitis C in the era of direct-acting antiviral therapy

Cabezas¹,

Llerena²,

Puente³

et al. 2015

Rev Esp Enferm Dig

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Hepatitis C therapy in the era of the newer direct-acting antiviral agents has radically changed our treatment schemes by achieving very high rates of sustained virological response. However, treatment with direct antiviral agents fails in a subgroup of patients. This group of so-called difficult-to-treat individuals is the subject of this paper, which reviews the causes of virological failure, their clinical implications, and some final recommendations.

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Mechanisms of Resistance to Antiviral Agents

Shafer,

Boivin,

Howe

et al. 2023

ClinMicroNow

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Understanding the mechanisms of viral drug resistance is critical for clinical management of individuals receiving antiviral therapy, for developing new antiviral drugs, and for drug resistance surveillance. This chapter reviews the mechanisms of resistance to antiviral drugs used to treat infections by eight common viruses: herpes simplex, cytomegalovirus, varicella‐zoster virus, human immunodeficiency virus type 1, influenza A and B, hepatitis B, hepatitis C, and severe acute respiratory syndrome coronavirus 2. Drug‐resistant virus subpopulations may exist at low levels in clinical isolates or may arise only during drug exposure. The error‐prone polymerases in RNA viruses render the development of resistance more frequent than in DNA viruses. Drug‐resistant viruses are identified by in vitro passage experiments in which wild‐type viruses are cultured in increasing concentrations of an inhibitory drug and by ex vivo analysis of virus isolates obtained from individuals receiving antiviral therapy.

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Infrequent Development of Resistance in Genotype 1–6 Hepatitis C Virus–Infected Subjects Treated With Sofosbuvir in Phase 2 and 3 Clinical Trials

Abstract: These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness.

Cited by 200 publications

References 41 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

Causes of treatment failure for hepatitis C in the era of direct-acting antiviral therapy

Mechanisms of Resistance to Antiviral Agents

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