Preliminary data suggests that second generation NS5A inhibitors with improved EC50 against genotype 3 may allow clinicians to experience the same success as we have seen with genotype 1.
Paul Y. Kwo, MD
Professor of Medicine, Medical Director of Liver Transplantation, Division of Gastroenterology/Hepatology, Indiana University Department of Medicine
The treatment of hepatitis C has undergone a revolution in the past two years. Historically, genotype 1 has been the most difficult to treat genotype, with genotypes 2 and 3 achieving higher sustained virological response (SVR) rates with pegylated interferon and ribavirin.1 Part of the limitation of achieving high sustained response rates was the side effect profile of the interferon backbone with or without direct acting antiviral agents. In 2013, we witnessed the approval of the first all-oral regimen for genotypes 2 and 3, the nucleotide polymerase inhibitor sofosbuvir with weight-based ribavirin, as well as the recommendation of combining sofosbuvir with the protease inhibitor simeprevir for treatment of genotype 1 hepatitis C infection as an all-oral regimen.2,3 These treatment options for the first time eliminated the backbone of interferon, providing treatment options for those with previous contraindications to hepatitis C therapy and those who had previously failed interferon based therapies, with a side-effect profile that was markedly improved over interferon-based therapies.
In 2014, this momentum continued with FDA approval of the combinations of sofosbuvir/ ledipasvir, paritaprevir/ritonavir/ombitasvir/ dasabuvir with/without ribavirin, and sofosbuvir/simeprevir with/without ribavirin, which has led to SVR rates well over 90 percent in all populations with chronic hepatitis C genotype 1 regardless of disease severity and treatment history. Other studies have demonstrated high sustained response rates for genotypes 2, 4 and 6 with all-oral therapies that mirror the success seen with genotype 1, though some of these studies have small sample sizes. Moreover, other special populations — including HIV/ hepatitis C coinfected individuals and those who have undergone orthotopic liver transplant — no longer achieve SVR at lower rates than treatment-naïve populations.
Despite these successes, genotype 3 hepatitis C, particularly those with cirrhosis who have failed prior therapy, remains a population in need of additional strategies to achieve SVR. The current standard of care for genotype 3 is the nucleotide polymerase inhibitor sofosbuvir with weight-based ribavirin for 24 weeks. This recommendation comes from the Valence study where treatment-naïve and treatment-experienced patients with genotype 3 hepatitis C infection received 24 weeks of sofosbuvir with ribavirin.2 High SVR rates were seen in those who were treatment-naïve without or with cirrhosis (93 percent and 92 percent, respectively), with treatment-experienced, non-cirrhotic patients achieving SVR at a slightly lower rate of 85 percent. However, treatment-experienced genotype 3 cirrhotic patients experienced a lower SVR rate of 60 percent. Worldwide, this group remains the most difficult to treat of all hepatitis C populations.
Additional strategies have been explored for this population. One study retreated these patients with sofosbuvir in combination with our previous backbone peginterferon and ribavirin, and in this small study, 10 of 12 genotype 3 cirrhotic patients achieved an SVR (83 percent).4 Because our current standard of care is with just one direct-acting antiviral agent, another strategy is to combine multiple direct-acting antiviral agents. The logical combination is with a NS5A inhibitor, which like the nucleotide polymerase sofosbuvir is pan-genotypic. Several studies have explored this possibility. A previous report in genotype 3 patients have suggested that 24 weeks of sofosbuvir and the NS5A inhibitor, daclatasvir, could achieve high rates of SVR,5 though those with cirrhosis who were previously treated were not studied.
The combination of sofosbuvir and daclatasvir for a duration of 12 weeks was explored in a recent study that demonstrated high SVR rates in non-cirrhotic genotype 3 patients; however, treatment-naïve and treatment-experienced cirrhotic patients with hepatitis C genotype 3 achieved SVR rates of 58 percent and 69 percent, respectively, not different than SVR rates achieved with our current gold standard.6 Additional trials are ongoing to explore whether longer durations of this combination and/or addition of ribavirin may improve SVR rates with sofosbuvir/daclatasvir (NCT02304159, NCT02319031).
Another NS5A inhibitor, ledipasvir, which is approved for genotype 1 hepatitis C, has also been explored in combination with sofosbuvir for genotype 3 infection. One small study in treatment-experienced genotype 3 cirrhotic patients administered ledipasvir, sofosbuvir and ribavirin for 12 weeks. In this preliminary report, 16 of 22 individuals (73 percent) achieved SVR.7 While these SVR rates are good by historical standards, they do not match the SVR rates seen with other genotypes.
With our currently approved therapies worldwide, our retreatment options for genotype 3 cirrhotic patients require additional strategies to achieve SVR rates comparable to those with genotype 1. Preliminary data suggests that second generation NS5A inhibitors with improved EC50 against genotype 3 may allow clinicians to experience the same success as we have seen with genotype 1. Sofosbuvir in combination with GS-5816, NS5A inhibitor with a lower EC50 for genotype 3 (12 pM) demonstrated high SVR rates of 96 percent (25 of 26 patients) when given with ribavirin for 12 weeks.8 Phase 3 trials are fully enrolled (NCT02201953) that will determine the optimal duration of therapy with GS5816 with results expected by the end of 2015. Results of these trials will hopefully offer treatment options for non-responding cirrhotic genotype 3 patients such that they have the same opportunity to achieve SVR at the same high rates as hepatitis C genotype 1 infected hepatitis C patients who have failed previous therapies.
Source
Dr. Kwo is on the advisory board for and receives research support (at the institutional level) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc., Merck & Co., and Janssen Pharmaceuticals, Inc. He is also on the ACG Board of Trustees.
References
1. Hoofnagle, J.H. and L.B. Seeff, Peginterferon and ribavirin for chronic hepatitis C.[see comment]. N Engl J Med, 2006. 355(23): p. 2444-51.
2. Zeuzem, S., et al., Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med, 2014. 370(21): p. 1993-2001.
3. Lawitz, E., et al., Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet, 2014. 384(9956): p. 1756-65.
4. Lawitz, E., et al., Sofosbuvir in combination with pegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Hepatology, 2013. 58 (SupRefpl 1): p. 1380A.
5. Sulkowski, M.S., I.M. Jacobson, and D.R. Nelson, Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med, 2014. 370(16): p. 1560-1.
6. Nelson, D.R., et al., All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase 3 Study. Hepatology, 2015.
7. Gane, E.J., Robert H. Hyland , Di An , Evguenia S., P.S.P. Svarovskaia , William T. Symonds , John G., and M.C.A. Stedman, High Efficacy of LDV/SOF Regimens for 12 Weeks for Patients with HCV Genotype 3 or 6 Infection. Hepatology, 2014. 60(Late Breaking Abstracts): p. 1274.
8. Pianko, S., Flamm, SL., Shiffman , M.L. et al. High Efficacy of Treatment With Sofosbuvir + GS-5816 ± Ribavirin for 12 Weeks in Treatment-Experienced Patients With Genotype 1 or 3 HCV Infection Hepatology. 60(S1): p. 197.
Dr. Kwo is on the advisory board for and receives research support (at the institutional level) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc., Merck & Co., and Janssen Pharmaceuticals, Inc. He is also on the ACG Board of Trustees.
References
1. Hoofnagle, J.H. and L.B. Seeff, Peginterferon and ribavirin for chronic hepatitis C.[see comment]. N Engl J Med, 2006. 355(23): p. 2444-51.
2. Zeuzem, S., et al., Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med, 2014. 370(21): p. 1993-2001.
3. Lawitz, E., et al., Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet, 2014. 384(9956): p. 1756-65.
4. Lawitz, E., et al., Sofosbuvir in combination with pegIFN and ribavirin for 12 weeks provides high SVR rates in HCV-infected genotype 2 or 3 treatment experienced patients with and without compensated cirrhosis: results from the LONESTAR-2 study. Hepatology, 2013. 58 (SupRefpl 1): p. 1380A.
5. Sulkowski, M.S., I.M. Jacobson, and D.R. Nelson, Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med, 2014. 370(16): p. 1560-1.
6. Nelson, D.R., et al., All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase 3 Study. Hepatology, 2015.
7. Gane, E.J., Robert H. Hyland , Di An , Evguenia S., P.S.P. Svarovskaia , William T. Symonds , John G., and M.C.A. Stedman, High Efficacy of LDV/SOF Regimens for 12 Weeks for Patients with HCV Genotype 3 or 6 Infection. Hepatology, 2014. 60(Late Breaking Abstracts): p. 1274.
8. Pianko, S., Flamm, SL., Shiffman , M.L. et al. High Efficacy of Treatment With Sofosbuvir + GS-5816 ± Ribavirin for 12 Weeks in Treatment-Experienced Patients With Genotype 1 or 3 HCV Infection Hepatology. 60(S1): p. 197.
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