Therapeutic regimens for chronic hepatitis C virus (HCV) based on direct-acting antivirals (DAAs) have led a new treatment revolution, starting with the introduction in 2011 of boceprevir-based and telaprevir-based triple therapy. These first DAA-based regimens improved sustained virologic response (SVR) rates compared with traditional therapy; however, they include interferon, have poor tolerability profiles, and are no longer recommended by the American Association for the Study of Liver Diseases (AASLD).1,2 These regimens are being replaced with regimens built around newly approved DAAs, sofosbuvir or simeprevir.2 Both sofosbuvir and simeprevir are administered in combination with peginterferon and ribavirin for genotype-1 patients, although sofosbuvir allows interferon to be excluded for patients who are interferon ineligible.3,4 The emerging next generation of all-oral DAA-based therapies for genotype-1 patients will exclude interferon (with and without ribavirin), have improved tolerability and ease of administration, and require a shorter duration of therapy.5
Mrs. TS is a very pleasant 61-year-old white female with chronic hepatitis C who was referred from a local gastroenterologist in March 2013 for consideration of treatment with an interferon-free regimen in clinical trials. She had genotype-1a infection and was treatment naive. Two years prior to this visit, a liver biopsy had been performed and showed chronic hepatitis with stage 2 fibrosis. She had no other chronic health conditions. Her examination was normal.
In late 2011, her gastroenterologist had recommended treatment with boceprevir- or telaprevir-based triple therapy, but she declined due to concern about interferon injections and potential side effects. The patient had been reading about emerging interferon-free regimens in clinical trials and wanted to find out whether enrolling in such a trial would be an option for her. She was particularly interested in a specific trial of multiple classes of DAAs.
When Mrs. TS presented for treatment consideration in the setting of a clinical trial, there were a number of important pretreatment considerations that informed the treatment decision:
- Her liver biopsy showed evidence of progression, making her a candidate for treatment
- She was eager to be treated and seemed to be very motivated
- She had genotype-1 infection, which would have required 24 to 48 weeks of telaprevir-based triple therapy, or 28 to 48 weeks of boceprevir-based triple therapy6,7
- She continued to be very concerned about side effects related to interferon and to the protease inhibitors telaprevir and boceprevir; therefore, she wished to be treated with an interferon-free regimen that did not include telaprevir or boceprevir
- She was very knowledgeable and had researched all available clinical trials, specifically identifying a phase III trial evaluating the fixed-dose combination of ABT-450/ritonavir coformulated with ABT-267, dosed once daily, and ABT-333 with or without ribavirin, dosed twice daily
- Her genotype and subtype matched the criteria for the identified trial, PEARL-IV, which is for patients with genotype-1a infection
EXPLORE A TABLE: Patient’s HCV RNA Throughout Therapy and at Week 12 Posttreatment
Based on these considerations, the patient was screened for the PEARL-IV clinical trial. She qualified and was randomized to receive the test regimen with either ribavirin or placebo. She tolerated the regimen well, reporting no side effects. After 12 weeks of treatment, she had no detectable HCV RNA, and after 12 weeks of follow-up, she achieved SVR12. Her viral load during treatment is shown in the Table.
The patient was quite happy after treatment. She was seen 24 weeks later by her primary gastroenterologist and remains virus free.
The first class of interferon-free regimen, sofosbuvir and ribavirin, was recently approved by the FDA for all patients with HCV genotypes 2 and 3 as well as those patients with HCV genotype 1 who are not candidates for interferon.3 In addition to this regimen, a number of other interferon-free regimens are being developed for all HCV genotypes with very high efficacy rates and excellent tolerability profiles.
One such emerging regimen includes the fixed-dose combination of ABT-450/ritonavir coformulated with ABT-267, dosed once daily, and ABT-333 with ribavirin, dosed twice daily, for 12 weeks. The regimen is being evaluated in six international phase III clinical trials enrolling patients with chronic HCV, including treatment-naive and treatment-experienced patients with genotype-1a or -1b infection, with or without cirrhosis.
Findings from the phase IIb clinical trial of this regimen have been recently published. These findings showed that 96% of treatment-naive genotype-1 patients (n = 79) who received 12 weeks of ABT-450/ritonavir + ABT-267 + ABT-333 + ribavirin achieved SVR12.8 In this treatment arm, only 2/79 (3%) discontinued due to adverse events.8 The most commonly reported adverse events were fatigue, headache, nausea, and insomnia.8
Other interferon-free regimens in late-phase testing for treatment-naive genotype-1 infection include:
- Daclatasvir in combination with asunaprevir and BMS-791325, with and without ribavirin
- Sofosbuvir plus simeprevir, with and without ribavirin
- Sofosbuvir plus ledipasvir, with or without and ribavirin
These regimens are also in clinical testing for treatment-experienced infection, as well as infection with genotypes other than genotype 1.
Treatment for chronic HCV infection is rapidly changing. Barriers to treatment and potential cure are being removed through shorter durations of therapy, better tolerability, and increased efficacy with new regimens, particularly those that are interferon-free. Now, more than ever, clinicians need to stay informed on the regimens currently available as well as the regimens emerging in late-phase clinical testing.
Jacobson IM, Pawlotsky J-M, Afdhal NH, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat. 2012;19(suppl 2):1-16.
American Society for the Study of Liver Diseases, Infectious Diseases Society of America. Recommendations for testing, managing, and treating Hepatitis C. January 2014. Accessed 3/21/14 at: http://www.hcvguidelines.org/sites/default/files/full_report.pdf.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2013.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; December 2013.
Afdhal NH, Zeuzem S, Schooley RT, et al. The new paradigm of hepatitis C therapy: integration of oral therapies into best practices. J Viral Hepat. 2013;20:745-760.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; October 2013.
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; February 2014.
Kowdley KV, Lawitz E, Poordad F, et al. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370:222-232.