Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1

Lok, Anna S.; Gardiner, David F.; Lawitz, Eric; Martorell, Claudia; Everson, Gregory T.; Ghalib, Reem; Reindollar, Robert; Rustgi, Vinod K.; McPhee, Fiona; Wind‐Rotolo, Megan; Persson, Anna; Zhu, Kurt; Dimitrova, Dessislava I.; Eley, Timothy; Guo, Tong; Grasela, Dennis M.; Pasquinelli, Claudio

doi:10.1056/nejmoa1104430

Cited by 558 publications

(453 citation statements)

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“…The emergence of novel direct‐acting antivirals (DAAs) against HCV has dramatically increased the number of patients who achieve a sustained virological response (SVR) 3, 4. The elimination of HCV will prevent the progression of chronic hepatitis and associated complications 5.…”

Section: Introductionmentioning

confidence: 99%

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

et al. 2017

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Background and AimPredictive factors for hepatocarcinogenesis following eradication of hepatitis C virus by direct‐acting antivirals (DAAs) are unknown. The aim of the study was to investigate the relationships between liver stiffness (LS) using acoustic radiation force impulse (ARFI) erastograghy and the development of hepatocellular carcinoma (HCC) in patients who achieved sustained virological response (SVR) treated with DAA.MethodsIn this prospective study, we enrolled 263 hepatitis C patients with SVR who underwent ARFI before DAA treatment. Thirty patients had previous HCC.ResultsThe median LS value according to ARFI measurements was 1.34 m/s (range: 0.67–4.35). During the follow‐up period (median: 18.1 months), development of HCC occurred in 19 patients (7.2%; HCC occurrence in 7 patients and HCC recurrence in 12 patients). By multivariate Cox regression analysis, HCC history (hazard ratio [HR]: 10.634; 95% confidence interval [CI]: 4.13–27.37; P = 0.001), older age (HR: 4.638; 95% CI: 1.63–13.61; P = 0.004) and higher total bilirubin levels (HR: 4.189; 95% CI: 1.66–10.60; P = 0.002) were independent predictors for the development of HCC, and higher LS value (≥1.73 m/s) at baseline was an independent predictor for HCC occurrence (HR: 8.350; 95% CI: 1.62–43.09; P = 0.011). The cumulative recurrence of HCC was statistically similar according to the degree of LS in patients who were previously treated for HCC.ConclusionThe LS value at baseline is useful for predicting HCC occurrence. Thus, even if SVR is achieved, patients with higher LS at baseline must be followed carefully for HCC occurrence.

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Section: Introductionmentioning

confidence: 99%

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

et al. 2017

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“…5,6 The first trial to confirm achievement of SVR with an IFN-free regimen was a small study in which 11 previous null responders receiving the NS5A inhibitor, daclatasvir, and the NS3 protease inhibitor, asunaprevir, achieved an SVR rate of 36%. 5 Six patients had virologic breakthrough during therapy with the combination; all were infected with HCV genotype 1a, and resistance mutations to both targeted proteins were found in all cases.…”

Section: Discussionmentioning

confidence: 99%

“…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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confidence: 99%

“…Studies investigating DAA combinations have shown that SVR can be achieved with shorter treatment durations and in the absence of IFN. 5,6 In this phase II trial, we assessed the safety and efficacy of a combination regimen consisting of ledipasvir (LDV), an inhibitor of the nonstructural (NS)5A protein, vedroprevir (VDV; previously known as GS-9451), a reversible noncovalent inhibitor of the HCV NS3/4A serine protease, tegobuvir (TGV), a non-nucleoside inhibitor of the HCV NS5B polymerase, and RBV. Individually, these agents have demonstrated antiviral activity against genotype 1 HCV.…”

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confidence: 99%

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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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“…5 However, to our knowledge, this represents the first successful cure of HCV in which DAA therapy without interferon was used to suppress the virus before OLT in a patient with decompensated liver disease in whom interferon was contraindicated. It should be emphasized that this case was unique because of the very low viral level and the more favorable genotype 1b infection.…”

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confidence: 94%

Oral direct-acting antiviral therapy to prevent reinfection of the liver graft after liver transplantation for hepatitis C virus-related cirrhosis

Kwo

Tector

2013

Liver Transpl

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Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1

Cited by 558 publications

References 21 publications

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

Liver stiffness measurement predicts hepatocellular carcinoma development in patients treated with direct‐acting antivirals

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

Oral direct-acting antiviral therapy to prevent reinfection of the liver graft after liver transplantation for hepatitis C virus-related cirrhosis

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