The approval of simeprevir and sofosbuvir in late 2013, the release of new treatment guidelines from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) in early 2014, and the ongoing accumulation of clinical trial data from emerging direct-acting antiviral agents and regimens substantially expands the base of knowledge and evidence from which treatment decisions are made. The increased complexity applies to treatment-naive as well as to treatment-experienced patients. In the case that follows, the range of current options for treatment-experienced patients is reviewed.
Mrs. E is a 55-year-old treatment-experienced female with genotype 1a infection who presented for consultation on initiating treatment with one of the newly approved . Seven years ago she had a partial response to peginterferon and ribavirin combination therapy. Although she experienced fatigue and mild anemia, she acknowledged she was not averse to including peginterferon and ribavirin again in her next regimen. About 5 years ago, she had a liver biopsy, which showed histologic cirrhosis. At the office visit, patient’s current status was assessed and she was found to have compensated cirrhosis.
Table. Suggested Hepatitis C Virus Therapeutic Regimens from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America HCV Treatment Guidelines1
Due to Mrs. E’s compensated cirrhosis status, proceeding with treatment now rather than waiting for other new therapies to be approved was considered the best course of action.1 Treatment options were presented to the patient, including the regimens recommended in the AASLD/IDSA guidelines as shown in the Table, as well as the option of a clinical trial.1 The patient expressed disinterest in participating in a clinical trial but instead wanted to start one of the new regimens.
After discussing the pros and cons of the various options, Mrs. E selected simeprevir plus peginterferon/ribavirin. Her insurance carrier would not cover the sofosbuvir plus simeprevir option, which is not approved by the FDA but is the recommended regimen in the 2014 AASLD/IDSA guidelines for hepatitis C virus. However, an alternative regimen is a regimen that includes simeprevir/peginterferon/ribavirin, which was approved by her insurance carrier (see Table).
Prior to starting therapy with simeprevir plus peginterferon/ribavirin, she was assessed for the Q80K polymorphism and found to be negative. In pooled clinical trial data, genotype-1a patients who had the Q80K polymorphism had substantially lower sustained virologic response (SVR) rates compared with those who did not have the polymorphism.2 Patients who are positive for the polymorphism should consider an alternative therapy.2 Mrs. E was also assessed for contraindications to simeprevir and potential interactions with drugs metabolized by CYP3A4 or drugs that are substrates for OATP1B1/3 and P-gp transport.2 Given the lack of contraindications and interfering drugs, she was cleared to begin therapy.
The three regimens suggested in the AASLD/IDSA guidelines for prior nonresponders to peginterferon/ribavirin (ie, null responders and partial responders) are shown in the Table.1 The regimen preferred by AASLD/IDSA is the combination of sofosbuvir and simeprevir, with or without ribavirin, for 12 weeks, regardless of the subtype of interferon eligibility of the patient.1 This recommendation is based on preliminary findings from the COSMOS trial, which reported a 4-week SVR rate among prior null responders that exceeded 90%.3 This regimen, however, can be used only off-label because the FDA has not approved the use of sofosbuvir and simeprevir in combination.
Alternative regimens for prior nonresponders, as shown in the Table, include 1) simeprevir in combination with peginterferon and ribavirin for 12 weeks followed by an additional 36 weeks of only peginterferon and ribavirin, and 2) sofosbuvir in combination with peginterferon and ribavirin for 12 weeks, with the option of an additional 12 weeks of peginterferon/ribavirin, which could be potentially considered for patients with multiple predictors of nonresponse.1
Simeprevir in combination with peginterferon/ribavirin was evaluated in the phase IIb randomized placebo-controlled ASPIRE trial.4 The study population included patients with null response or partial response to prior peginterferon/ribavirin therapy as well as patients who relapsed. Overall, prior partial responders who received simeprevir 150 mg plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin for an additional 36 weeks had an SVR rate of 65% compared with 9% for patients who received only peginterferon/ribavirin.4 SVR rates were lower, however, for patients with genotype-1a infection compared with genotype-1b: 44% and 77%, respectively.2 Adverse effects were similar in the simeprevir/peginterferon/ribavirin and placebo/peginterferon/ribavirin arms and were consistent with the historical safety profile of peginterferon/ribavirin.4
Sofosbuvir plus peginterferon/ribavirin has not been studied in peginterferon/ribavirin-experienced patients.1,5 The FDA, however, has allowed that the efficacy of sofosbuvir plus peginterferon/ribavirin in prior nonresponders may be extrapolated from its efficacy among patients with factors predictive of poor response in the phase III NEUTRINO trial, a single-arm open-label study.1,5-7 For example, patients with genotype 1 infection, non-CC IL28B status, high viral load, and F3/F4 liver disease achieved an SVR rate of 71%.8 Adverse effects in the NEUTRINO trial were similar to that expected with peginterferon/ribavirin combination therapy.6
This case demonstrates that treatment-experienced patients with genotype 1 hepatitis C virus have multiple options. When choosing among these options, clinicians should consider the most recent AASLD/IDSA treatment guidelines, as well as factors such as insurance coverage, clinical trial data, and patient demographics and preferences.
American Society for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for testing, managing, and treating Hepatitis C. January 2014. Accessed 5/14/14 at: http://www.hcvguidelines.org/sites/default/files/full_report.pdf.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; December 2013.
Jacobson IM, Ghalib RH, Rodriguez-Torres M, et al. SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naive and prior null responder patients: the COSMOS study. Abstract LB-3. Presented at: AASLD 2013; November 1-5, 2013; Washington, DC.
Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology. 2014;146:430-441.
U.S. Food and Drug Administration. FDA Antiviral Drugs Advisory Committee Meeting: Background Package for NDA 204671 Sofosbuvir (GS-7977). October 13, 2013. Accessed 5/14/14 at: http://1.usa.gov/1kx5ehH.
Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; December 2013.
U.S. Food and Drug Administration. Introductory Remarks: Sofosbuvir NDA 204671. Accessed 5/15/14 at: http://1.usa.gov/TCL50f.