July 3, 2013

Gastroenterology
Volume 145, Issue 1 , Pages 245-247, July 2013

Pratima Sharma

Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan

published online 29 May 2013.

Philip S. Schoenfeld, Section Editor, John Y. Kao, Associate Section Editor

Full Text

Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013;368:34–44.

Approval of telaprevir and boceprevir in May 2011, the first-generation NS3/4A serine protease inhibitors important for viral replication, represented a major breakthrough and revolutionized the hepatitis C virus (HCV) treatment. Both these drugs are highly specific to HCV genotype 1, have complex dosing, significant side effects, and drug–drug interactions that limit their use in many subgroups of patients, including those with cirrhosis and posttransplant recurrent HCV. Moreover, their low genetic barrier to viral resistance prevents their use in interferon-free regimens. Many second- and third-generation directly acting antiviral agents (DAA) with less complex dosing, a tolerable side effect profile, and fewer drug–drug interactions are in various phases of development.

In the January 3, 2013, issue of the New England Journal of Medicine, Gane et al examined the safety and efficacy of sofosbuvir, an oral active site NS5B uridine nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV genotypes 1, 2, or 3. This study included patients (age > 18 years) with chronic HCV infection without cirrhosis and hepatitis B or human immunodeficiency co-infection (N Engl J Med 2013;368:34–44).

This phase 2a, open-label trial randomized treatment naïve HCV genotype 2 and 3 patients (n = 40; 10 patients per group) stratified by HCV genotype (2 vs 3) and interleukin (IL)-28B (CC vs CT or TT) in 1:1:1:1 ratio to receive weight-based ribavirin (RBV) and sofosbuvir (400 mg once daily) for 12 weeks with and without pegylated interferon (PEGIFN)-α 2a. Groups 1–3 received PEGIFN for 4, 8, and 12 weeks, respectively, in addition to 12 weeks of weight-based RBV and sofosbuvir. Group 4 received 12 weeks of weight-based RBV and sofosbuvir only. After completion of dosing in groups 1–4, the protocol was amended to include 2 additional groups of treatment naive HCV genotype 2 or 3 patients (group 5: PEGIFN, weight-based RBV and sofosbuvir for 8 weeks; group 6: Sofosbuvir monotherapy for 12 weeks). An additional 35 HCV genotype 1 patients (10 nonresponder and 25 treatment naïve) received 12 weeks of weight-based RBV and sofosbuvir. Because this study was not designed to evaluate formal statistical hypotheses, sample size calculations were not performed.

All 40 HCV genotypes 2 and 3 patients in groups 1–4 had a sustained virologic response (SVR) at week 24 after treatment. The HCV RNA became undetectable as early as 2 weeks on treatment independent of PEGIFN. All 10 patients who received sofosbuvir, PEGIFN, and RBV for 8 weeks (group 5) also had SVR at 12 weeks after treatment. All 9 patients for whom data were available had an SVR at 24 weeks after treatment. In the sofosbuvir monotherapy arm (group 6), 6 of the 10 patients had SVR at 12 and 24 weeks after the end of treatment. Although a virologic relapse was seen in 4 patients (genotype 3 [n = 2], genotype 2 [n = 2]) at 2 and 4 weeks after the end of treatment, respectively, only 1 of these 4 (genotype 2b) had an S282T mutation on standard population sequencing and deep sequencing in 99% of the sequenced viral genomes. There was no evidence of an S282T mutation or any other mutation at the conserved sites in the other 3 patients with relapse.

In the treatment-naïve HCV genotype 1 group, 21 (84%) had SVR at 24 weeks after treatment with 12 weeks sofosbuvir and weight-based RBV therapy. Of the 4 patients who had a relapse during follow-up, 3 had within 4 weeks and 1 between 12 and 24 weeks after the end of treatment. The S282T mutation was not detected in any of these 3 patients on population sequencing or on deep sequencing. No other mutations at conserved sites were consistently observed among the patients who had a relapse during this study. In the nonresponder HCV genotype 1 group (n = 10), only 1 (10%) had a SVR at 24 weeks after treatment. None of the 9 patients without SVR had any S282T-containing mutations on population sequencing and deep sequencing.

All patients completed treatment without dose reductions. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. There were 3 serious adverse events. One was on treatment (urethral injury in sofosbuvir and RBV group) and 2 were after the end of treatment (furunculosis at 14 days and angina at 24 days). PEGIFN-free groups did not have neutropenia and thrombocytopenia. Sofosbuvir monotherapy was associated with a modest decrease in the hemoglobin level. The authors concluded that sofosbuvir plus RBV for 12 weeks is safe and may be effective in treatment naïve HCV genotype 1, 2, or 3 patients.

Comment

The advancement in the knowledge of HCV life cycle and structural proteins has led to the development of many promising DAA. Telaprevir and boceprevir, linear inhibitors of NS3/4A serine protease, are the first-generation DAA specific to HCV genotype 1 with low genetic barrier to viral resistance and significant drug–drug interactions. These properties restrict their use to only genotype 1 patients in combination with PEGIFN and RBV. There is an unmet need for development of newer DAA with pan-genotypic activity, an adequate safety and tolerability profile, and higher genetic barrier to resistance that would extend the treatment to all HCV patients.

Sofosbuvir, formerly known as GS-7977, is a potent, direct-acting active site NS5B nucleotide polymerase analog inhibitor. It is safe and well-tolerated in clinical studies, taken only once daily, with or without food, and has excellent antiviral activity with broad HCV genotype coverage. Sofosbuvir monotherapy (GS-7977, 400 mg once a day) for 7 days in genotype 1 achieved a 4.7 log10 reduction in viral load and showed a high barrier to resistance (Clin Liver Dis 2013;17:105–110). The SVR rates with and without PEGIFN are very promising in phase II clinical trials including PROTON and ATOMIC trial involving harder to treat HCV genotypes 1, 4, and 6, although >90% were HCV genotype 1 patients (Hepatology 2011;54:472A; J Hepatol 2012;56[S2]:1A).

The PROTON trial of sofosbuvir included 121 treatment-naïve HCV genotype 1 patients without cirrhosis who received once daily PSI-7977 (200 or 400 mg) or placebo with PEGIFN and RBV for 12 weeks followed by an additional 12 weeks or 36 weeks of PEGIFN and RBV based on an extended, rapid virologic response. The preliminary results showed 88% and 91% SVR12 rates for the 200 and 400 mg sofosbuvir groups, respectively, versus 40% for the placebo without any virologic breakthrough during therapy with either sofosbuvir dose. Similar to Gane et al (N Engl J Med 2013;368:34–44), none of the patients had sofosbuvir-related adverse events resulting in treatment discontinuation. The most important finding of this study was that 13 HCV genotype 1 patients with the unfavorable IL-28B TT genotype attained an SVR12 in sofosbuvir group (Hepatology 2011;54:472A).

The ATOMIC trial of 332 HCV genotypes 1, 4, and 6 (>90% HCV genotype 1) treatment-naïve patients without cirrhosis randomized 1:2:3 stratified by IL-28B (CC vs non-CC) and HCV RNA (≤800,000 vs ≥800,000 IU/mL) to sofosbuvir 400 mg once a day, PEGIFN, and RBV for 12 weeks (arm 1, 75% genotype 1a) or for 24 weeks (arm 2, 68% genotype 1a) or for 12 weeks followed by additional 12 weeks of sofosbuvir or sofosbuvir and RBV (arms 3a and 3b, 73% genotype 1a). Among them. 90%–94% achieved an SVR4, with 90% of the patients receiving triple therapy for 12 weeks achieving an SVR12. Of these patients, 4%–12% discontinued treatment owing to adverse events, with 1%–5% discontinuing therapy owing to adverse events related to sofosbuvir. The S282T virologic resistance mutation was not detected in 4 patients who relapsed (J Hepatol 2012;56:1A).

Gane et al in their phase II study (ELECTRON) of sofosbuvir with RBV with and without PEGIFN, showed that 12 weeks of dual therapy with sofosbuvir and weight-based RBV is safe and efficacious with 84% and 100% SVR rates among treatment naïve HCV genotypes 1, 2, and 3 patients, respectively (N Engl J Med 2013;368:34–44). Phase III clinical studies evaluating a 12-week course of the once-daily sofosbuvir in combination with RBV among treatment-naïve HCV genotypes 2 and 3 (FISSION) and a 12-week course of the once-daily sofosbuvir in combination with PEGIFN and RBV among treatment-naïve HCV genotype 1, 4, 5, and 6 patients (NEUTRINO) are underway. A press release from GILEAD on February 4, 2013, stated that both these studies achieved their primary efficacy endpoint of noninferiority compared with standard of care (available from: http://www.gilead.com/pr_1780873; accessed February 18, 2013).

In the current study, only 1 HCV genotype 2 patients in the sofosbuvir monotherapy had an S282-containing mutation. None of the treatment naïve HCV genotype 1 patients who relapsed (n = 4) had S282T-containing mutations. Moreover, all 9 previously treated genotype 1 and non-responders to sofosbuvir and weight based RBV dual therapy did not show any S282T-containing mutations (N Engl J Med 2013;368:34–44). The active site NS5B mutations responsible for resistance to nucleotide inhibitors are more likely to also impair RNA polymerase activity rendering the mutant virus less “fit” compared with the wild-type virus. This is among the plausible explanations for high genetic barrier to viral resistance among the nucleotide inhibitors. Therefore, a combination of nucleotide inhibitors such as sofosbuvir with other DAAs with and without RBV may pave the way for PEGIFN-free regimens. There are numerous ongoing clinical trials in different phases examining the efficacy of all-oral HCV treatment regimens, such as sofosbuvir and daclatasvir with and without RBV (J Hepatol 2012;56:S560), ABT-450, ABT-267, ABT-333, and RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012), daclatasvir and asunaprevir (N Engl J Med 2012;366:216–224; Hepatology 2012;55:742–748), danoprevir and mericitabine with and without RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012), faldaprevir and BI 207127 with and without RBV (presented at the 63rd Annual Meeting of the American Association for the Study of Liver Diseases, Boston, MA; November 9–13, 2012).

In conclusion, these early results along with safety and superior efficacy of sofosbuvir in combination with RBV among all genotypes, makes this drug a very attractive agent for PEGIFN-free oral regimens. However, the safety and efficacy of sofosbuvir-based therapy among prior nonresponders, patients with advance fibrosis and cirrhosis, posttransplant recipients with recurrent hepatitis C, and non-liver solid organ transplant recipients with hepatitis C needs to be established.

Finally, this rapid progress strongly indicates that the myth of HCV patient-specific personalized DAA combinations with shorter duration and superior SVR rates is going to become the standard of care in the near future.

PII: S0016-5085(13)00787-7

doi:10.1053/j.gastro.2013.05.030

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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