Treatment options for patients with hepatitis C virus (HCV) infection who fail to respond to peginterferon and ribavirin have been limited in the past, particularly for patients with genotype-1 infection. The May 2011 approval of direct-acting antiviral agents (DAAs) boceprevir and telaprevir, both protease inhibitors, in combination with peginterferon and ribavirin led to dramatic improvements in sustained virologic response (SVR) rates in genotype-1 patients who were naive to treatment as well as those who relapsed after prior peginterferon/ribavirin therapy.1-4 In contrast, treatment-experienced patients who had been less responsive to prior peginterferon/ribavirin therapy, particularly null responders, had low SVR rates even after 48 weeks of therapy.3-5 Recent phase II data suggest that interferon-free combinations of DAAs from different classes can lead to SVR rates that exceed 90% after only 12 weeks of therapy in null responders to prior interferon-based therapy without a protease inhibitor.6-8
A 50-year-old male presents to your practice to discuss the potential of starting treatment for genotype-1a HCV infection. In 2009 he had a null response to peginterferon/ribavirin, with his viral load dropping only 1 log at 12 weeks, from 10 million IU/mL pretreatment to 1.2 million IU/mL. His baseline liver biopsy at that time showed stage 2 fibrosis. He reported missing no doses but found the therapy difficult to tolerate. He experienced fatigue and increasingly painful injection-site reactions. Most importantly, he found it difficult to concentrate at his full-time job as a contractor and had to turn over major projects to his partner.
He feels reasonably well now, with only occasional right upper quadrant pain. He takes lisinopril 20 mg for hypertension and ibuprofen 800 mg on an as-needed basis. On physical exam he is a slightly overweight male, with a weight of 120 kg. His vitals are otherwise stable with blood pressure of 130/88 mmHg. Other than mild hepatomegaly, his exam is normal.
Laboratory tests show: hemoglobin14 g/dL, platelet count of 169,000/mm3, aspartate aminotransferase 112 U/L, alanine aminotransferase 115 U/L, total bilirubin 1.2 mg/dL. His Fibroscan® demonstrates liver stiffness of 12 kPa. An ultrasound shows mild hepatomegaly and fatty infiltration, with mild splenomegaly.
You review his results and explain to him that he likely has advanced fibrosis.
Concerned about his advanced fibrosis, the patient wants to start treatment now. Due to his previous interferon intolerability, he asks for a regimen without a peginterferon/ribavirin backbone. You discuss with him the preliminary SVR rates of all-oral therapies in null responders. He elects to enroll in one of six phase III trials examining the efficacy of ABT-450/ritonavir (a protease inhibitor boosted with ritonavir), in combination with ABT-267 (a NS5A inhibitor) and ABT-333 (a nonnucleoside polymerase inhibitor), and ribavirin.
The patient completes the 12-week regimen and tolerated it well. Of particular importance to the patient, he was able to continue working throughout the treatment. His most recent follow-up confirms that he has achieved SVR12.
Currently approved regimens for genotype-1 patients with prior null response include boceprevir, telaprevir, sofosbuvir (a polymerase inhibitor), or simeprevir (a protease inhibitor), all in combination with peginterferon and ribavirin.9-12 Patients with interferon intolerability or ineligibility need other interferon-free options, however. Product labeling for sofosbuvir allows it be administered without interferon but still in combination with ribavirin for 24 weeks in patients with interferon ineligibility, yet results from the ELECTRON trial show only a 10% SVR12 in patients with prior null response when treated for just 12 weeks.11,13
Table. SVR Rates in Null Responders After 12 Weeks of Interferon-Free Direct-Acting Antiviral Combinations for Chronic Hepatitis C6-8
Preliminary phase II studies of emerging all-oral DAA combinations for 12 weeks demonstrate high SVR rates in null responders to prior peginterferon/ribavirin-based therapy as shown in the Table.6-8 In addition, these treatments were well tolerated.6-8
This patient’s treatment experience and outcome heralds a new era of anti-HCV therapy, where combinations of DAAs will lead to high SVR rates with treatment durations truncated to up to one quarter that of previous therapies and with markedly improved side effect profiles. Large phase III trials have been fully enrolled and will determine the potential of these therapies, but phase II findings strongly suggest that the era of interferon-based therapies is rapidly coming to a close. Furthermore, HCV-infected individuals who have traditionally been the most difficult to treat will have highly effective treatment options. These findings suggest a bright future for the treatment of patients with HCV.
Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection.
N Engl J Med. 2011;364:2417-2428.
Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
Vierling JM, Davis M, Flamm S, et al. Boceprevir for chronic HCV genotype 1 infection in patients with prior treatment failure to peginterferon/ribavirin, including prior null response. J Hepatol. 2014;60:748-756.
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.
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
Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology. 2014;146:736-743.
Victrelis [package insert]. Whitehouse Station, NJ: Schering Corporation; February 2014.
Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; October 2013.
Sovaldi [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2013.
Olysio [package insert]. Titusville, NJ: Janssen Products, LP; December 2013
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.