A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C

Lawitz, Eric; Gruener, Daniel; Hill, John M.; Marbury, Thomas; Moorehead, Lisa; Mathias, Anita; Cheng, Guofeng; Link, John O.; Wong, Kelly A.; Mo, Hongmei; McHutchison, John G.; Brainard, Diana M.

doi:10.1016/j.jhep.2011.12.029

Cited by 146 publications

(125 citation statements)

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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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“…From the 1 University of California, San Diego, La Jolla, CA; 2 Fundacion de Investigacion de Diego, Santurce, Puerto Rico; 3 Texas Liver Institute, San Antonio, TX; 4 Liver Institute of Virginia, Richmond, VA; 5 Hôpital Cochin, Paris, France; 6 Quality Medical Research, PLLC, Nashville, TN; 7 Gilead Sciences, Inc., Foster City, CA; 8 Inserm 1110, Universite de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and 9 Johns Hopkins University School of Medicine, Baltimore, MD.…”

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“…Individually, these agents have demonstrated antiviral activity against genotype 1 HCV. [7][8][9] In a 3-day monotherapy study, LDV dosed at 90 mg demonstrated significant antiviral activity within the first 12 hours of therapy. At doses of 3 mg or greater, the median maximal reduction in HCV RNA from baseline was >3 log 10 IU/mL in patients infected with HCV genotype 1a; LDV dosed at 30 mg or higher provided >95% of maximal antiviral response.…”

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“…At doses of 3 mg or greater, the median maximal reduction in HCV RNA from baseline was >3 log 10 IU/mL in patients infected with HCV genotype 1a; LDV dosed at 30 mg or higher provided >95% of maximal antiviral response. 7 LDV has been shown to be well tolerated in more than 1,000 patients across six phase II studies. 10 VDV dosed at 200 or 400 mg for 3 days suppressed HCV RNA levels by a median of 3.2-3.6 log 10 IU/mL from baseline in treatment-na€ ıve patients infected with HCV genotype 1a or 1b.…”

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confidence: 99%

“…9 Resistance mutations detected in these studies did not confer cross-resistance to other classes of DAAs. [7][8][9] Given the positive results of combining two DAAs with RBV in previous trials, we hypothesized that the addition of a third DAA with a distinct mechanism of action might result in improved response with a shortened treatment duration. Although the results from the 3-day monotherapy study with LDV suggested that the 30-mg dose or higher resulted in robust viral suppression, the optimal dose of LDV given for a longer period has not been determined.…”

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All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection

et al. 2014

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This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-na€ ıve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n 5 46) or LDV 90 mg QD (Arm 2; n 5 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir. (HEPATOLOGY 2014;60:56-64)

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Direct-acting antivirals for chronic hepatitis C

Jakobsen

Nielsen

Feinberg

et al. 2017

Cochrane Database of Systematic Reviews

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Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

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A phase 1, randomized, placebo-controlled, 3-day, dose-ranging study of GS-5885, an NS5A inhibitor, in patients with genotype 1 hepatitis C

Cited by 146 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

All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection

Direct-acting antivirals for chronic hepatitis C

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