The availability of new treatments for hepatitis C virus (HCV) has led many patients, particularly those who had failed prior treatment with peginterferon/ribavirin, to return to clinical care. In the United States, peginterferon and ribavirin combination therapy was the standard of care from 2001 to 2011, and patients with partial or null response to this regimen had few highly effective treatment options. The patient in this case study, like many similar patients, has been waiting for new treatments. The question is, how do we select the best treatment option for him?
Mr. A is a 52-year-old man with HCV genotype-1a infection and stage 2 fibrosis. He had a prior null response to therapy with peginterferon and ribavirin and wanted to explore starting a new direct-acting antiviral (DAA) regimen.
As part of his evaluation the patient was tested for the Q80K polymorphism in the NS3 protease region of the HCV genome. Simeprevir in combination with peginterferon and ribavirin, one of the regimens approved in 2013, should be avoided in patients with genotype-1a infection who are positive for this polymorphism due to lower sustained virologic response (SVR) rates than patients who have wild-type virus at this location.1 The patient tested positive for the Q80K polymorphism.
The patient’s treatment options were discussed, including approved regimens and available clinical trials. The patient indicated he was open to participating in a clinical trial using experimental, non–FDA-approved therapies.
Given this patient’s past treatment experience and positive Q80K mutation status, the interferon-free regimens appropriate for this patient and currently in clinical testing include:
- Sofosbuvir (nucleotide NS5B polymerase inhibitor) + simeprevir (NS3/4A protease inhibitor)
- Sofosbuvir + ledipasvir (NS5A inhibitor) or sofosbuvir + daclatasvir (NS5A inhibitor)
- ABT450/ritonavir/ombitasvir (NS3/4A protease inhibitor/pharmacologic booster/NS5A inhibitor) + dasabuvir (nonnucleoside NS5B polymerase inhibitor) + ribavirin
The patient was enrolled in a clinical trial testing sofosbuvir plus daclatasvir for 12 weeks. He reported few adverse effects while taking this two-pill, once-daily regimen and achieved SVR.
Patients who have failed prior peginterferon/ribavirin with a partial or null response generally do not respond as well to retreatment with peginterferon/ribavirin in combination with a single DAA agent. For example, in the studies of simeprevir plus peginterferon/ribavirin, the SVR rate was 80% in patients who were treatment-naive, 67% in prior partial responders, and 45% in partial null responders.1 While these SVR rates are superior to retreatment with peginterferon/ribavirin, interferon-free, oral DAA combination regimens can be expected to yield even higher SVR rates with fewer adverse effects and shorter duration of treatment. In patients with genotype 1a and the Q80K polymorphism, the addition of simeprevir to peginterferon/ribavirin was not more effective than the addition of a placebo pill.1 As such, I would not recommend that this patient be re-treated with interferon-based therapy.
In multiple phase II and phase III studies, interferon-free, oral DAA regimens achieved SVR in more than 90% of prior peginterferon/ribavirin treatment-experienced patients who were treated for 12 weeks.2-6 Importantly, prior treatment with peginterferon/ribavirin did not appear to be linked to lower SVR. Indeed, many of the traditional predictors of poor response to interferon-based treatment, such as IL28B genotype and race/ethnicity, did not have a major impact on SVR.2-5,7
This case discusses a noncirrhotic patient. However, in patients who failed prior peginterferon-based therapy, cirrhosis appears to be associated with slightly higher rates of virologic relapse after the completion of 12 weeks of therapy and some studies suggest that the risk of posttreatment virologic failure may be lower if treatment is continued for 24 weeks. Interestingly, with the extension of therapy to 24 weeks, the SVR rate in treatment-experienced cirrhotic patients was similar to that observed in treatment-naive noncirrhotic patients.2,8
The presence of a naturally occurring polymorphism at position 80 in the HCV NS3 protease region leading to the replacement of the amino acid glutamine (Q) with the amino acid lysine (K)–known as Q80K–may have some impact on the clinical approach to treatment of this patient.9 This variant is not typically found in patients with genotype 1b infection but can be detected in as many as 48% of patients with genotype 1a infection in the United States.1 Testing for Q80K is commercially available in the United States.
This variant confers reduced susceptibility to the NS3 protease inhibitor, simeprevir. In phase III studies of simeprevir plus peginterferon/ribavirin in treatment-naive patients (QUEST 1 and QUEST 2), those with Q80K did not appear to benefit from the addition of simeprevir compared with placebo.10,11 Treatment-experienced patients with Q80K showed some benefit in the PROMISE trial, but SVR rates in this group were substantially lower than in those without the variant.12 These findings led to the recommendation by the FDA [OlysioPI-1] and the American Association for the Study of Liver Diseases/Infectious Disease Society of America to consider alternative therapies in such patients.1,13
EXPLORE A FIGURE: Effect of Q80K Polymorphism on SVR12 in Prior Nonresponders with Genotype-1a Infection and Metavir F0 to F2 Receiving Simeprevir + Sofosbuvir ± Ribavirin in the COSMOS Trial6
In the COSMOS study of simeprevir plus sofosbuvir, however, combined data from the study’s two cohorts show that the SVR rate among genotype-1 patients who are positive for Q80K was 88% (51/58) compared with 94% in patients without Q80K (68/72).6,14 Interestingly, of the 167 patients treated in COSMOS, no patients had virologic breakthrough during treatment, and six patients had virologic relapse.6 Furthermore, four of the six patients with virologic relapse were Q80K positive, and five of six were treated for 12 weeks.6 SVR12 rates from the cohort that included genotype-1a patients similar to this patient—prior null responders with Metavir stage F0 to F2—are shown in the Figure.6
It is important to note that since the Q80K polymorphism is in the HCV protease region, it does not have any impact on the likelihood of response to HCV NS5A inhibitors, such as daclatasvir, ledipasvir, or ombitasivir.9 In ION 1, a phase III trial evaluating sofosbuvir plus ledipasvir in treatment-experienced patients, with and without ribavirin, SVR12 rates ranged from 94% to 99%.2 In the phase III SAPPHIRE-II trial, 96% of prior nonresponders achieved SVR12 with ABT450/ritonavir/ombitasvir + dasabuvir.4
Data from a phase II randomized, open-label trial of daclatasvir, an HCV NS5A inhibitor, in combination with sofosbuvir, with and without ribavirin, in HCV genotype 1, 2, or 3 were recently published.3 The initial cohort of treatment-naive patients was randomized to one of three treatment arms: sofosbuvir for 1 week followed by daclatasvir and sofosbuvir for 23 weeks; daclatasvir and sofosbuvir for 24 weeks; or, daclatasvir and sofosbuvir plus ribavirin for 24 weeks.3 A later cohort of genotype-1 patients, which included patients who were treatment-naive and also nonresponders to prior boceprevir or telaprevir triple therapy, was enrolled and randomized to receive daclatasvir and sofosbuvir, with or without ribavirin, for either 12 (treatment-naive) or 24 weeks (treatment-experienced).3 Overall, 98% of patients with genotype-1 infection achieved SVR12 regardless of prior treatment status, including 98% and 100% for genotypes 1a and 1b, respectively.3 Response rates were similar whether or not ribavirin was included in the regimen.3
This case demonstrates that patients who failed prior treatment with peginterferon and ribavirin will have many treatment options available. While many factors, such as race and IL28B status, will have minimal bearing on treatment decisions, clinicians should consider the presence or absence of the Q80K polymorphism in patients with genotype-1a infection when considering which DAA regimens to use.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; December 2013.
Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370:1483-1493.
Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211-221.
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370:1604-1614.
Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014;370:1983-1992.
Lawitz E, Sulkowski MS, Ghalib R, 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. [Epub ahead of print]
Sulkowski M, Jacobson IM, Ghalib R, et al. Once-daily simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV genotype 1 prior null responders with METAVIR F0-2: COSMOS study subgroup analysis. Abstract O7. Presented at: 49th EASL; April 9-13, 2014; London, England.
Poordad F, Hezode C, Trinh R, et al. ABT-450r–ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014;370:1973-1982;
Berger KL, Triki I, Cartier M, et al. Baseline hepatitis C virus (HCV) NS3 polymorphisms and their impact on treatment response in clinical studies of the HCV NS3 protease inhibitor faldaprevir. Antimicrob Agents Chemother. 2014; 58:698-705.
Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2014;384:403-413.
Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014. [Epub ahead of print]
Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014;146:1669-1679.
American Society for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for testing, managing, and treating Hepatitis C. January 2014. Accessed 7/22/14 at: http://www.hcvguidelines.org/sites/default/files/full_report.pdf.
ClinicalTrials.gov. A study of TMC435 in combination with PSI-7977 (GS7977) in chronic hepatitis C genotype 1-infected prior null responders to peginterferon/ribavirin therapy or HCV treatment-naive patients (COSMOS). Accessed 8/19/14 at: http://clinicaltrials.gov/show/NCT01466790.