Daclatasvir plus sofosbuvir for HCV infection: An oral combination therapy with high antiviral efficacy (2014)

COMMENTARY ON:Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. N Engl J Med. 2014 Jan 16;370(3):211–221. doi: 10.1056/NEJMoa1306218. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.http://www.ncbi.nlm.nih.gov/pubmed/24428467Abstract:BACKGROUND: All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3.METHODS: In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60mg orally once daily plus sofosbuvir at a dose of 400mg orally once daily, with or without ribavirin, for 24weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12weeks (82 previously untreated patients) or 24weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25IU per milliliter) at week 12 after the end of therapy.RESULTS: Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea.CONCLUSIONS: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.).IntroductionThere have been major advancements these past years with large numbers of trials with various direct-acting antivirals (DAAs) oral regimens showing increased SVR rates, favourable tolerability, and shortened treatment duration [1Jacobson I.M. Gordon S.C. Kowdley K.V. Yoshida E.M. Rodriguez-Torres M. Sulkowski M.S. et al.Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment option.N Engl J Med. 2013; 368: 1867-1877Crossref PubMed Scopus (919) Google Scholar, 2Kowdley K.V. Lawitz E. Poordad F. Cohen D.E. Nelson D.R. Zeuzem S. et al.Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.N Engl J Med. 2014; 370: 222-232Crossref PubMed Scopus (237) Google Scholar, 3Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar, 4Zeuzem S. Soriano V. Asselah T. Bronowicki J.P. Lohse A.W. Müllhaupt B. et al.Faldaprevir and deleobuvir for HCV genotype 1 infection.N Engl J Med. 2013; 369: 630-639Crossref PubMed Scopus (199) Google Scholar, 5Schinazi R. Halfon P. Marcellin P. Asselah T. HCV direct-acting antiviral agents: the best interferon-free combinations.Liver Int. 2014; 34: 69-78Crossref PubMed Scopus (204) Google Scholar]. These DAAs target multiple viral sites: NS3/4a protease, NS5B polymerase, and NS5A. HCV regimens in Phase II or III, or already approved in 2014 are listed in Table 1. This paper will comment on the recently published phase IIb trial with daclatasvir plus sofosbuvir for HCV Infection, reporting spectacular results [[3]Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar].Table 1HCV regimens in phase II or III trials in 2014 or already approved. Open table in a new tab DaclatasvirDaclatasvir is a first-in-class HCV NS5A replication complex inhibitor [[6]Gao M. Nettles R.E. Belema M. Snyder L.B. Nguyen V.N. Fridell R.A. et al.Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.Nature. 2010; 465: 96-100Crossref PubMed Scopus (835) Google Scholar]. Daclatasvir is active at picomolar concentrations in vitro in HCV replicons expressing a broad range of HCV genotypes and acts in an additive to synergistic fashion with interferon (IFN) and other DAAs. The resistance profile of daclatasvir reveals inhibitor sensitivity maps to the N terminus of domain 1 of NS5A. NS5A inhibitors could block hyperphosphorylation of NS5A, which is believed to play an essential role in the viral replication cycle.SofosbuvirSofosbuvir is a nucleotide analogue HCV NS5B polymerase inhibitor [[7]Asselah T. Sofosbuvir for the treatment of hepatitis C virus.Expert Opin Pharmacother. 2013; 15: 121-130Crossref PubMed Scopus (54) Google Scholar]. Polymerase inhibitors interfere with viral replication by binding to the NS5B RNA-dependent RNA polymerase. Nucleoside inhibitors (NI) mimic the natural substrates of the polymerase and are incorporated into the RNA chain causing direct chain termination. NI require conversion to an active triphosphate form. As the active site of NS5B is highly conserved, NI have generally a pan-genotypic efficacy. However, single amino acid substitutions in every position of the active site may result in loss of function of NI, but resistance to NI is typically very low.Daclatasvir plus sofosbuvir study design and resultsIn this open-label study, 44 HCV genotype 1 (G1) naïve patients and 44 HCV-G2 or G3 patients were initially randomly assigned to daclatasvir (60 mg QD) plus sofosbuvir (400 mg QD), with or without ribavirin (RBV), for 24 weeks [[3]Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar]. The study was expanded to include 123 additional HCV-G1 patients who were randomly assigned to daclatasvir plus sofosbuvir, with or without RBV, for 12 weeks (82 naïve patients) or 24 weeks (41 with previous failure with telaprevir or boceprevir plus PegIFN–RBV) (Fig. 1A). Patients with cirrhosis were excluded.Overall, 211 patients received treatment. Among HCV-G1 infected patients, 98% of 126 naïve patients and 98% of 41 patients who failed with protease inhibitors had an SVR at week 12 after the end of therapy (SVR12) (Fig. 1B). A total of 92% of 26 patients with HCV-G2 and 89% of 18 patients with HCV-G3 had a SVR12. All patients had an HCV RNA level of less than 25 IU/ml by week 4.We have to be cautious regarding the results reported for HCV genotype 3, the SVR rate was of 89% after 24 weeks of daclatasvir plus sofosbuvir. This SVR appears to be similar to SVR obtained with sofosbuvir plus ribavirin given during 24 weeks in genotype 3 non-cirrhotic patients [[8]Zeuzem S. Dusheiko G. Salupere R. Mangia A. Flisiak R. Hyland R.H. et al.Sofosbuvir plus ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial.Hepatology. 2013; 58: 733ACrossref Scopus (12) Google Scholar].A highly efficient regimen, even in “difficult to cure” patientsDaclatasvir plus sofosbuvir was associated with high rates of SVR among patients with characteristics that were previously known to be associated with a poor response [[9]Estrabaud E. Vidaud M. Marcellin P. Asselah T. Genomics and HCV infection: progression of fibrosis and treatment response.J Hepatol. 2012; 57: 1110-1125Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar]. Impressively, this regimen was highly efficient in “difficult to cure” patients. All patients with prior failure with protease inhibitors had an SVR. Among these patients, 71% had previous virologic breakthrough or non-response, 80% were infected with subtype 1a, 98% had a non-CC IFNL3 genotype (previously IL28B).Virologic breakthrough and relapse was rare and was not observed in any of the 193 patients infected with HCV genotype 1 or 2, despite pre-existing daclatasvir-resistant variants in 27 patients. Of the 5 patients infected with HCV-G1 or G2 without SVR12 after treatment, 3 had missing data at week 12 but had an SVR24 (including 1 who returned after the database lock) and 2 were lost to follow-up. Among the 18 patients with HCV-G3 infection, virologic relapse occurred in 1 of 5 patients with a pre-existing daclatasvir resistant variant, and in a second patient, who did not have pre-existing daclatasvir-resistant variants, an HCV RNA level below 25 IU/ml was detected at weeks 8 and 10. Because of low virus levels during treatment and an SVR12, the role of viral variants could not be assessed. Sofosbuvir-resistant variants were not detected in any of the patients.Ribavirin does not appear to be useful for this DAAs combinationIn this study, response rates were similar among patients treated with or without RBV. These findings may reflect the antiviral potency and high resistance barrier of the daclatasvir–sofosbuvir combination and suggest that RBV is not required with every oral DAA regimen. Of course, RBV is associated with anemia, and is teratogenic, and therefore RBV-sparing regimen are desirable. However, we cannot exclude, that in cost-effectiveness strategies, RBV may have a role.Take home messages and perspectivesFinally, once-daily, oral treatment with daclatasvir plus sofosbuvir was associated with high SVR rates in HCV-G1, 2, or 3 naïve patients and in HCV-G1 patients with previous failure to protease inhibitors. The development of resistance appears uncommon with daclatasvir plus sofosbuvir.Also, in the same issue of the NEJM, a phase IIb study with a 12-week DAAs combinations of protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the non-nucleoside polymerase inhibitor dasabuvir (also known as ABT-333), and RBV were associated with high rates of SVR among HCV-G1 naïve patients and among patients with failure to prior PegIFN-RBV therapy [[3]Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar]. This ABT-450 regimen has shown excellent results in phase III [10Feld J.J. Kowdley K.V. Coakley E. Sigal S. Nelson D.R. Crawford D. et al.Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.N Engl J Med. 2014; 370: 1594-1603Crossref PubMed Scopus (732) Google Scholar, 11Zeuzem S. Jacobson I.M. Baykal T. Marinho R.T. Poordad F. Bourlière M. et al.Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.N Engl J Med. 2014; 370: 1604-1614Crossref PubMed Scopus (501) Google Scholar, 12Poordad F. Hezode C. Trinh R. Kowdley K.V. Zeuzem S. Agarwal K. et al.ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis.N Engl J Med. 2014; 370: 1973-1982Crossref PubMed Scopus (750) Google Scholar]. The fixed dose combination of sofosbuvir and ledipasvir (NS5A inhibitor) has also demonstrated excellent results in phase III [13Afdhal N. Zeuzem S. Kwo P. Chojkier M. Gitlin N. Puoti M. et al.Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection.N Engl J Med. 2014; 370: 1889-1898Crossref PubMed Scopus (1410) Google Scholar, 14Afdhal N. Reddy K.R. Nelson D.R. Lawitz E. Gordon S.C. Schiff E. et al.Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.N Engl J Med. 2014; 370: 1483-1493Crossref PubMed Scopus (1155) Google Scholar, 15Kowdley K.V. Gordon S.C. Reddy K.R. Rossaro L. Bernstein D.E. Lawitz E. et al.Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.N Engl J Med. 2014; 370: 1879-1888Crossref PubMed Scopus (984) Google Scholar].Furthermore, the Cosmos study – evaluating simeprevir (protease inhibitor) plus sofosbuvir with or without RBV in GT1-naive subjects and prior null-responders – reported also impressive results [16Sulkowski M. Jacobson I.M. Ghalib R. Rodriguez-Torres M. Younossi Z. Corregidor A. et al.Once-daily simeprevir plus sofosbuvir with or without ribavirin in HCV genotype 1 prior null responders with Metavir F0–2: COSMOS study subgroup analysis.J Hepatol. 2014; (Abstract 07)PubMed Google Scholar, 17Lawitz E. Ghalib R. Rodriguez-Torres M. Younossi Z.M. Corregidor A. Sulkowski M.S. et al.Simeprevir plus sofosbuvir with/without ribavirin in HCVgenotype 1 prior null-responder/treatment-naive patients (COSMOS study): primary endpoint (SVR12) results in patients with Metavir F3–4 (Cohort 2).J Hepatol. 2014; 60 (Abstract O165)Google Scholar]. It is a Phase IIa, randomized, open-label study that evaluated 2 cohorts of patients. Cohort 1 (n = 80) randomized prior null-responders with Metavir scores F0–F2 and cohort 2 (n = 87) evaluated prior null-responder and naïve G1 individuals with F3–F4 scores.Data from cohort 1 demonstrated that 93% and 96% of patients with Metavir F0–F2 scores treated with simeprevir and sofosbuvir with or without ribavirin, respectively, for 12 weeks achieved SVR12.In cohort 2, 93% of participants assigned to simeprevir/sofosbuvir either alone or with RBV for 12 weeks achieved SVR12; among those treated for 24 weeks, SVR12 rates were 93% and 100%, respectively.In genotype 1a patients with the Q80K polymorphism at baseline, 89% and 83% achieved SVR after 12 weeks of treatment with and without ribavirin, respectively. The most common adverse events in both treatment arms were fatigue, headache, nausea, and insomnia. Two patients discontinued treatment due to adverse events.We have to recall that several of these phase 2 studies have limitations: mainly the small number of patients limits an exact evaluation of efficacy and the possibility to detect adverse events. Also, patients with cirrhosis are excluded, and they might be less likely than those without cirrhosis to have a response, and also at higher risk of side effects. Again, HCV-G4 patients are neglected, and we have to recall that they represent around 40 million worldwide, and account for the majority of new infection, with no access to therapy, or in the best cases PegIFN plus RBV for 48 weeks with above 40% of SVR [[18]Asselah T. De Muynck S. Broet P. Masliah-Planchon J. Blanluet M. Bieche I. et al.IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C.J Hepatol. 2011; 56: 527-532Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar].In conclusion, these fantastic data from different published trials encourage us to remain very optimistic. We do hope that the majority of HCV infected patients will become “easy-to-cure” and there will be more facilities to access treatment.Conflict of interestTarik Asselah is a speaker and investigator for AbbVie BMS, Boehringer-Ingelheim, Janssen, Gilead, Roche, and MSD. COMMENTARY ON: Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang SP, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM; AI444040 Study Group. N Engl J Med. 2014 Jan 16;370(3):211–221. doi: 10.1056/NEJMoa1306218. Copyright © (2014) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/24428467 Abstract: BACKGROUND: All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. METHODS: In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60mg orally once daily plus sofosbuvir at a dose of 400mg orally once daily, with or without ribavirin, for 24weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12weeks (82 previously untreated patients) or 24weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa-ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of <25IU per milliliter) at week 12 after the end of therapy. RESULTS: Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of 126 previously untreated patients and 98% of 41 patients who did not have a sustained virologic response with HCV protease inhibitors had a sustained virologic response at week 12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89% of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High rates of sustained virologic response at week 12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who received ribavirin and those who did not (94% and 98%, respectively). The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. (Funded by Bristol-Myers Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number, NCT01359644.). IntroductionThere have been major advancements these past years with large numbers of trials with various direct-acting antivirals (DAAs) oral regimens showing increased SVR rates, favourable tolerability, and shortened treatment duration [1Jacobson I.M. Gordon S.C. Kowdley K.V. Yoshida E.M. Rodriguez-Torres M. Sulkowski M.S. et al.Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment option.N Engl J Med. 2013; 368: 1867-1877Crossref PubMed Scopus (919) Google Scholar, 2Kowdley K.V. Lawitz E. Poordad F. Cohen D.E. Nelson D.R. Zeuzem S. et al.Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1.N Engl J Med. 2014; 370: 222-232Crossref PubMed Scopus (237) Google Scholar, 3Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar, 4Zeuzem S. Soriano V. Asselah T. Bronowicki J.P. Lohse A.W. Müllhaupt B. et al.Faldaprevir and deleobuvir for HCV genotype 1 infection.N Engl J Med. 2013; 369: 630-639Crossref PubMed Scopus (199) Google Scholar, 5Schinazi R. Halfon P. Marcellin P. Asselah T. HCV direct-acting antiviral agents: the best interferon-free combinations.Liver Int. 2014; 34: 69-78Crossref PubMed Scopus (204) Google Scholar]. These DAAs target multiple viral sites: NS3/4a protease, NS5B polymerase, and NS5A. HCV regimens in Phase II or III, or already approved in 2014 are listed in Table 1. This paper will comment on the recently published phase IIb trial with daclatasvir plus sofosbuvir for HCV Infection, reporting spectacular results [[3]Sulkowski M.S. Gardiner D.F. Rodriguez-Torres M. Reddy K.R. Hassanein T. Jacobson I. et al.Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.N Engl J Med. 2014; 370: 211-221Crossref PubMed Scopus (986) Google Scholar].Table 1HCV regimens in phase II or III trials in 2014 or already approved. Open table in a new tab