Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies

Chen, Jianmeng; Florian, Jeffry; Carter, Wendy; Fleischer, Russell; Hammerstrom, Thomas; Jadhav, Pravin; Zeng, Wen; Murray, Jeffrey; Birnkrant, Debra

doi:10.1053/j.gastro.2013.02.039

Cited by 155 publications

(120 citation statements)

References 18 publications

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“…Recent data suggest that absence of detectable virus at 12 weeks after completion of therapy (SVR12) with DAA-based regimens is concordant with SVR24. 20 The concordance of SVR4 with SVR24 and SVR12 has also been suggested with SOF therapy. 21 …”

Section: Goals and Endpoints Of Therapymentioning

confidence: 98%

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Puri

Saraswat

Dhiman

et al. 2016

Journal of Clinical and Experimental Hepatology

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India contributes significantly to the global burden of HCV. While the nucleoside NS5B inhibitor sofosbuvir became available in the Indian market in March 2015, the other directly acting agents (DAAs), Ledipasvir and Daclatasvir, have only recently become available in the India. The introduction of these DAA in India at a relatively affordable price has led to great optimism about prospects of cure for these patients as not only will they provide higher efficacy, but combination DAAs as all-oral regimen will result in lower side effects than were seen with pegylated interferon alfa and ribavirin therapy. Availability of these newer DAAs has necessitated revision of INASL guidelines for the treatment of HCV published in 2015. Current considerations for the treatment of HCV in India include the poorer response of genotype 3, nonavailability of many of the DAAs recommended by other guidelines and the cost of therapy. The availability of combination DAA therapy has simplified therapy of HCV with decreased reliance of evaluation for monitoring viral kinetics or drug related side effects. ( J CLIN EXP HEPATOL 2016;6:119-145) T here have been revolutionary changes in the management of chronic hepatitis C (CH-C) over the last few years. Pegylated interferon alfa (Peg-IFNa) plus ribavirin (RBV) therapy, which till the recent past was the standard of care, has been eclipsed by the arrival of newer directly acting antiviral agents (DAAs). Not only do the DAAs have better efficacy, they are also associated with lower side effects, have better tolerability, a shorter duration of therapy, and have simpler administration.In the recent guidelines issued by the American Association for the study of Liver Diseases (AASLD), in collaboration with the Infectious Diseases Society of America 1 and the European Association for Study of the Liver z (EASL), 2 the role of Peg-IFNa/RBV therapy in the management of HCV has been relegated to second-line, backup status. These newer guidelines, however, cannot be implemented in India as many of the recommended drugs are yet to be marketed in India. Other considerations for the treatment of HCV in India are a predominance of

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Section: Goals and Endpoints Of Therapymentioning

confidence: 98%

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Puri

Saraswat

Dhiman

et al. 2016

Journal of Clinical and Experimental Hepatology

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“…HCV RNA levels were measured using the quantitative Roche COBAS Ò Taqman HCV/HPS assay version 2 (lower limit of quantification 25 IU/ml; limit of detection 9-20 IU/ml). The primary endpoint was changed from SVR24 to SVR12 by a protocol amendment, consistent with evidence of concordance between SVR12 and SVR24 [22].…”

Section: Virologic Endpointsmentioning

confidence: 87%

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

Ferenci

Asselah

Foster

et al. 2015

Journal of Hepatology

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Background & Aims:The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. Methods: Patients were randomly assigned (1:2:2) to PegIFN/ RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). Results: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p <0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. Conclusions: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg. Ó

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“…Secondary endpoints included medication dosing, side effects, transfusion requirements, BMI, gender, previous treatment outcome, genotype, IL28B polymorphism, and final outcome (SVR12). Chen et al recently demonstrated that the positive predictive value of SVR12 for SVR24 was 98 % and negative predictive value was 99 % [15]. As SVR12 was a treatment endpoint for this study, final treatment outcomes could vary slightly.…”

Section: End Pointsmentioning

confidence: 74%

HCV Triple Therapy is Equally effective in African-Americans and Non-African-Americans

Wysocki

Newby

Balart

et al. 2014

J. Racial and Ethnic Health Disparities

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Real-world experience with HCV medications differs from original the index studies. AfricanAmericans (AA) are commonly underrepresented in clinical trials. Therefore, we hypothesized that postmarketing experience with the first generation HCV protease inhibitors (PI) (telaprevir and boceprevir) differs from premarket reports in clinically meaningful ways regarding patient race. We conducted a single-center, retrospective, observational analysis to evaluate the efficacy of HCV triple therapy in a nontrial setting. Clinical response and quantitative laboratory values were compared between AA and non-AA patients throughout the duration of treatment. Patients were included if they started triple therapy treatment after July 2011 and are not a part of any other clinical/pharmaceutical trials. Thirty-five patients with HCV genotype 1 were included in this study-22 non-AA and 13 AAs. AAs had a higher BMI compared to non-AA (33.6 vs 28.8, p=0.046). "High" baseline HCV RNA values (above 800,000 copies) were more prevalent in AA (69.2 %) vs non-AA (63.6 %). AA had less favorable IL28B genotypes; only 7.7 % had type CC compared to 40.9 % of non-AA. SVR12 was achieved 82 % of the time with each PI but there was no significance in type of PI used (p=1.00). Patients with cirrhosis were less likely to achieve SVR12 (40 %) compared to those without cirrhosis (88 %, p = 0.013). Thirty-three percent of the patients who received blood transfusions did not achieve SVR12 while every patient who did not require transfusion achieved SVR12 (p=0.001). All patients with IL28B genotype CC achieved SVR12 (p=0.007). SVR12 did not differ among AA (77 %) and non-AA (86.4 %) (p=0.528).

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Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies

Cited by 155 publications

References 18 publications

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

Indian National Association for Study of the Liver (INASL) Guidance for Antiviral Therapy Against HCV Infection: Update 2016

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection

HCV Triple Therapy is Equally effective in African-Americans and Non-African-Americans

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