Does Ribavirin Still Have a Role in Sofosbuvir and Velpatasvir Therapy for Patients With HCV Genotype 3 Infection and Cirrhosis?
2018; Elsevier BV; Volume: 155; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2018.09.003
ISSN1528-0012
Autores Tópico(s)Hepatitis B Virus Studies
ResumoSee “Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis,” by Esteban R, Pineda JA, Calleja JL, et al on page 1120. See “Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis,” by Esteban R, Pineda JA, Calleja JL, et al on page 1120. This month’s issue of Gastroenterology features an important paper from Esteban et al1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar that attempts to address remaining questions regarding the treatment of hepatitis C virus (HCV) GT3, which has been the “problem child” in the era of direct-acting antiviral (DAA) therapy. GT3 is the second most common HCV genotype worldwide and is the dominant genotype in southern Asia.2Messina J.P. Humphreys I. Flaxman A. et al.Global distribution and prevalence of hepatitis C virus genotypes.Hepatology. 2015; 61: 77-87Crossref PubMed Scopus (1134) Google Scholar Perhaps at least partially because of the “viral” steatosis associated with it, GT3 is the most pathogenic HCV genotype, with a greater risk of progressive fibrosis, cirrhosis, and hepatocellular carcinoma.3Bassendine M.F. Sheridan D.A. Bridge S.H. et al.Lipids and HCV.Semin Immunopathol. 2013; 35: 87-100Crossref PubMed Scopus (78) Google Scholar, 4Nkontchou G. Ziol M. Aout A. et al.HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis.J Viral Hepat. 2011; 18: e516-e522Crossref PubMed Scopus (140) Google Scholar, 5McCombs J. Matsuda T. Tonnu-Mihara I. et al.The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry.JAMA Intern Med. 2014; 174: 204-212Crossref PubMed Scopus (100) Google Scholar, 6Kanwal F. Kramer J.R. Ilyas J. et al.HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV.Hepatology. 2014; 60: 98-105Crossref PubMed Scopus (215) Google Scholar Interferon therapy (including pegylated forms), initially without and then in combination with ribavirin, has superior efficacy in patients with GT2 and GT3 compared with GT1, the dominant HCV genotype in the United States and Europe. Moreover, GT2 and GT3 require only 24 weeks of treatment with pegylated interferon and ribavirin compared with 48 weeks of treatment for GT1, with responses to interferon-based regimens somewhat lower for GT3 than GT2.7Hadziyannis S.J. Sette Jr., H. Morgan T.R. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2757) Google Scholar, 8Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5905) Google Scholar, 9Zeuzem S. Hultcrantz R. Bourliere M. et al.Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3.J Hepatol. 2004; 40: 993-999Abstract Full Text Full Text PDF PubMed Google Scholar Early studies of the pangenotypic nucleotide polymerase inhibitor sofosbuvir (SOF) indicated similar kinetics of viral decline with GT2 and GT3, consistent with its equivalent in vitro potency across all genotypes. In the landmark phase II study showing the capacity of an interferon-free SOF-based regimen to cure HCV infection, a 12-week course of SOF and ribavirin yielded a sustained virologic response (SVR) in 10 of 10 patients with GT2 or GT3, including 6 with GT3.10Gane E.J. Stedman C.A. Hyland R.H. et al.Once daily sofosbuvir (GS-7977) plus ribavirin in patients with HCV genotypes 1, 2, and 3: the ELECTRON trial.Hepatology. 2012; 56: 306A-307AGoogle Scholar, 11Gane E.J. Stedman C.A. Hyland R.H. et al.Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.N Engl J Med. 2013; 368: 34-44Crossref PubMed Scopus (638) Google Scholar The design of the subsequent phase III development program was based on the hypothesis that SOF and ribavirin would have similar efficacy across both GT2 and GT3 and that 12 weeks of treatment would be sufficient to treat both genotypes. The reality that emerged from the phase III trials was different. Twelve weeks of SOF and ribavirin yielded an SVR in >90% of GT2 patients but a substantially lower proportion of GT3 patients, with lower response rates in patients with prior interferon treatment or cirrhosis, most profoundly when the 2 factors were combined. There was some improvement in SVR with extension of therapy to 16 from 12 weeks in treatment experienced patients.12Lawitz E. Mangia A. Wyles D. et al.Sofosbuvir for previously untreated chronic hepatitis C infection.N Engl J Med. 2013; 368: 1878-1887Crossref PubMed Scopus (1438) Google Scholar, 13Jacobson I.M. Gordon S.C. Kowdley K. et al.Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options.N Engl J Med. 2013; 368: 1867-1877Crossref PubMed Scopus (926) Google Scholar When SOF + ribavirin was approved in late 2013 with a treatment duration of 12 weeks for GT2 patients and 24 weeks for GT3, it was clear that further advances were needed to improve SVR rates for GT3 patients in comparison with GT2 patients as well as in comparison with the first-generation dual or triple DAA regimens approved for GT1 in 2014 through early 2016. The first-generation DAA regimen of daclatasvir and SOF, approved for GT3 in 2015, featured an NS5A inhibitor that is somewhat less active against GT3 than against GT1 in vitro, and conferred SVR in 96% of noncirrhotic GT3 patients when given for 12 weeks, but only 63% of those with cirrhosis.14Nelson D.R. Cooper J.N. Lalezari J.P. et al.All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study.Hepatology. 2015; 61: 1127-1135Crossref PubMed Scopus (551) Google Scholar The pivotal ASTRAL-3 study of SOF and the NS5A inhibitor velpatasvir (VEL) in GT3 patients led to the inclusion of GT3 in the first approval of a pangenotypic regimen for all HCV genotypes in 2016.15Foster G.R. Afdhal N. Roberts S.K. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (650) Google Scholar VEL possessed equivalent in vitro potency against GT3 as other genotypes, and provided broader coverage against the NS5A resistance-associated substitutions (RASs) than previously approved members of the class, including those at the 28, 30, and 31 positions of NS5A. Its major Achilles heel is the Y93H substitution, against which its in vitro potency is substantially reduced.16Harrington P.H. Komatsu T.E. Deming D. et al.Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: regulatory analyses and perspectives.Hepatology. 2018; 67: 2430-2448Crossref PubMed Scopus (32) Google Scholar In the ASTRAL-3 study, SVR rates across 4 treatment groups varied from 89% in treatment-experienced cirrhotics to 98% in treatment-naïve noncirrhotics, with treatment-naïve cirrhotics and treatment-experienced noncirrhotics at 93% and 91%, respectively.15Foster G.R. Afdhal N. Roberts S.K. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (650) Google Scholar Further analysis revealed that patients with baseline RASs had SVR rates of 88% compared with 97% in those lacking such RASs, with the Y93H RAS predominantly responsible for the disparity. Whether ribavirin could have improved SVR rates in baseline RASs was not addressed. It was only the ASTRAL-4 study in decompensated cirrhotic patients that randomized patients to SOF/VEL (12 or 24 weeks) versus SOF/VEL plus ribavirin (12 weeks), demonstrating a pronounced numerical advantage for ribavirin in GT3 patients.17Curry M.P. O’Leary J.G. Bzowej N. et al.Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis.N Engl J Med. 2015; 373: 2618-2628Crossref PubMed Scopus (597) Google Scholar The paper by Esteban et al1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar represents an admirable effort to fill the gap left by the absence of ribavirin in any of the treatment arms of the ASTRAL-3 study, including patients with cirrhosis. With >200 patients with compensated cirrhosis randomized to receive either SOF/VEL or SOF/VEL plus ribavirin, SVR rates were 91% (92/101) and 96% 99/103), respectively. Treatment-experienced patients fared equally well without ribavirin, attaining an SVR of 96% in both treatment groups, whereas treatment-naïve patients achieved SVR in 89% without ribavirin versus 96% with ribavirin. This difference from the ASTRAL-3 study, in which treatment-naïve cirrhotics fared better than treatment-experienced cirrhotics with SOF/VEL, is likely due to chance, because it is difficult to posit an explanation for why SOF/VEL would be more effective in treatment-experienced than treatment-naïve patients. Predictably, the incidence of adverse effects was higher in the ribavirin group. The findings of Esteban et al1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar support the hypothesis inferred from ASTRAL-3 and implied by the ASTRAL-4 data—namely, that the addition of ribavirin to SOF/VEL would augment response in some GT3 patients with cirrhosis. The greatest disparity between the 2 treatment arms was in patients with baseline RASs, with 84% of SOF/VEL patients (16/19) having SVR versus 96% of those without RASs (76/79) achieving an SVR. In contrast, 95% of baseline RAS-positive patients (21/22) receiving SOF/VEL and ribavirin achieved an SVR, compared with 99% without RASs (78/79). Two of 4 baseline Y93H-positive patients failed therapy in the SOF/VEL group versus only 1 of 9 patients with Y93H at baseline in the ribavirin arm.1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar Esteban et al1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar acknowledge that their study demonstrates numerical but not statistically significant differences, pointing out the challenges of conducting a study that would fulfill the latter goal. These investigators underscore a flexible approach to using either SOF/VEL or SOL/VEL plus ribavirin in GT3 cirrhotics “based on local treatment guidelines, availability of RAS testing, and/or ability to monitor for ribavirin toxicity,” to which one might add patient’s likely ability to tolerate ribavirin. Nevertheless, the cumulative data from all studies, including this latest one, lead to the conclusion that, at the least, GT3 cirrhotic patients with baseline Y93H have suboptimal results with SOF/VEL alone. The goal of optimization and “leaving no patient behind” has led the authors of both the American Association for the Study of Liver Diseases/Infectious Diseases Society of America and European Association for the Study of the Liver (EASL) guidelines to issue at times disparate recommendations in the GT3 cirrhotic population incorporating 2 even newer pangenotypic regimens.18AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: www.hcvguidelines.org. Updated September 21, 2017.Google Scholar, 19EASL Recommendations on treatment of hepatitis C 2018.J Hepatol. 2018; 69: 461-511Abstract Full Text Full Text PDF PubMed Scopus (1241) Google Scholar A principal difference between the guidelines is the avoidance by EASL of a dependence upon resistance testing in any GT3 patients (see Table 1 for complete GT3 recommendations). For treatment naïve GT3 cirrhotic patients, both documents recommend glecaprevir/pibrentasvir for 12 weeks as 1 option, with the American Association for the Study of Liver Diseases/Infectious Diseases Society of America recommending RAS testing before SOF/VEL and the addition of ribavirin or the use of SOF/VEL/voxilaprevir (VOX) if Y93H is present. In contrast, the EASL document recommends SOF/VEL/voxilaprevir for 12 weeks, omitting SOF/VEL despite the 96% to 98% rates of SVR in GT3 patients with cirrhosis for SOF/VEL in POLARIS-3 (8 weeks) and ASTRAL-3 (12 weeks).15Foster G.R. Afdhal N. Roberts S.K. et al.Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection.N Engl J Med. 2015; 373: 2608-2617Crossref PubMed Scopus (650) Google Scholar, 20Jacobson I.M. Lawitz E. Gane E.J. et al.Efficacy of 8 weeks of sofosbuvir, velpatasvir and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials.Gastroenterology. 2017; 153: 113-122Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Interestingly, the EASL position not to use SOF/VEL is nowhere reflected in the conclusions of Esteban et al,1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar despite the lower SVR rate for SOF/VEL in these patients in their study. As suggested by Esteban et al,1Esteban R. Pineda J.A. Calleja J.L. et al.Efficacy of sofosbuvir and velpatasvir, with and without ribavirin, in patients with Hepatitis C virus genotype 3 infection and cirrhosis.Gastroenterology. 2018; 155: 1120-1127Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar SOF/VEL does seem a viable approach if RAS testing is available and baseline Y93H is absent. For the less common interferon-experienced GT3 cirrhotic patients not yet treated with a DAA, neither guideline recommends SOF/VEL, preferring other regimens. Finally, both guidelines recommend only SOF/VEL/voxilaprevir for 12 weeks for GT3 patients with a history of NS5A inhibitor experience; this highly effective GT3 regimen seems to be unimpacted by baseline RASs and is uncommonly associated with treatment-emergent RASs. The triple regimen would, in fact, seem preferable to SOF/VEL in any situation in which ribavirin might be under consideration except for decompensated cirrhotics in whom protease inhibitors should not be used. The guidelines for the treatment of GT3 surpass in complexity the recommendations for other genotypes, even without taking into account the possibility that the baseline A30K variant in GT3 may affect the efficacy of glecaprevir and pibrentasvir—the other front-line recommended regimen in GT3, the NS5A component of which pibrentasvir is highly active against the Y93H RAS—in treatment-naive noncirrhotic patients treated for the recommended 8 weeks.16Harrington P.H. Komatsu T.E. Deming D. et al.Impact of hepatitis C virus polymorphisms on direct-acting antiviral treatment efficacy: regulatory analyses and perspectives.Hepatology. 2018; 67: 2430-2448Crossref PubMed Scopus (32) Google Scholar, 21Zeuzem S. Foster G.R. Wang S. et al.Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection.N Engl J Med. 2018; 378: 354-369Crossref PubMed Scopus (286) Google Scholar These considerations, particularly in treatment experienced or cirrhotic patients, constitute a counterargument to suggestions that genotyping of HCV patients is no longer needed.Table 1AASLD/IDSA and EASL Guideline Recommendations for Treatment of GT3AASLD/IDSA18AASLD/IDSA HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: www.hcvguidelines.org. Updated September 21, 2017.Google ScholarEASL19EASL Recommendations on treatment of hepatitis C 2018.J Hepatol. 2018; 69: 461-511Abstract Full Text Full Text PDF PubMed Scopus (1241) Google ScholarTreatment naïve, no cirrhosisSOF/VEL 12 wkSOF/VEL 12 wkGLE/PIB 8 wka“Insufficient evidence to recommend testing for RASs or extension of therapy in the setting of A30K at this time, but the effect of the A30K mutation should continue to be explored in real world cohorts.”GLE/PIB 8 wkTreatment naïve, cirrhosisSOF/VEL 12 wkbIf Y93H present, SOF/VEL + ribavirin or SOF/VEL/VOX.SOF/VEL/VOX 12 wkGLE/PIB 12 wkGLE/PIB 12 wkTreatment experienced, no cirrhosisSOF/VEL 12 wkcIf Y93H present, SOF/VEL + ribavirin, SOF/VEL/VOX (each 12 wk), or GLE/PIB 16 wk.SOF/VEL 12 wk—GLE/PIB 12 wkTreatment experienced, cirrhosisSOF/VEL/VOX, 12 wkSOF/VEL/VOX 12 wkEBR/GZR + SOF, 12 wkGLE/PIB 16 wkPrior DAA failureSOF/VEL/VOX 12 wkdAdd ribavirin for NS5A inhibitor failure with cirrhosis.SOF/VEL/VOX 12 wkGLE/PIB/SOF 12 wkeCan be used if “predictors of lower response” or “very difficult-to-cure”.NOTE. Protease inhibitors are contraindicated in patients with decompensated cirrhosis.AASLD, American Association for the Study of Liver Diseases; DAA, direct-acting antiviral; DCV, daclatasvir; EASL, European Association for the Study of the Liver; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; IDSA, Infectious Diseases Society of America; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.a “Insufficient evidence to recommend testing for RASs or extension of therapy in the setting of A30K at this time, but the effect of the A30K mutation should continue to be explored in real world cohorts.”b If Y93H present, SOF/VEL + ribavirin or SOF/VEL/VOX.c If Y93H present, SOF/VEL + ribavirin, SOF/VEL/VOX (each 12 wk), or GLE/PIB 16 wk.d Add ribavirin for NS5A inhibitor failure with cirrhosis.e Can be used if “predictors of lower response” or “very difficult-to-cure”. Open table in a new tab NOTE. Protease inhibitors are contraindicated in patients with decompensated cirrhosis. AASLD, American Association for the Study of Liver Diseases; DAA, direct-acting antiviral; DCV, daclatasvir; EASL, European Association for the Study of the Liver; EBR, elbasvir; GLE, glecaprevir; GZR, grazoprevir; IDSA, Infectious Diseases Society of America; PIB, pibrentasvir; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir. Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and CirrhosisGastroenterologyVol. 155Issue 4PreviewIn phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. Full-Text PDF
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