Hepatitis C RAVs are Not a Barrier to Retreatment

Posted on June 6, 2015

Study published in the journal Hepatology suggests that sofosbuvir plus peginterferon and ribavirin for 12 weeks is effective and safe in patients who have not achieved SVR with prior regimens of one or more direct-acting antiviral (DAA) agents plus peginterferon and ribavirin. High rates of SVR12 are achieved regardless of the presence of resistance associated variants (RAVs) to the previous agents (Pol S, et al. Hepatology. 2015 Apr 6. doi: 10.1002/hep.27836. [Epub ahead of print]).

  • The anti-HCV regimen of sofosbuvir (Gilead Sciences, Foster City, CA, USA) plus peginterferon and ribavirin is approved in the United States and Europe for the treatment of patients with genotype 1 HCV infection

Although SVR rates in clinical trials involving new and investigational DAAs have generally been high, not all patients have achieved SVR with these regimens. Antiviral resistance is a growing area of concern among clinicians who treat hepatitis (hepcblog.amjmed.com/hep-c-news/dr-e-lebovics-post-easl-2015-hcv-interview). The results of an open-label trial to evaluate the efficacy and safety of 12 weeks of sofosbuvir plus peginterferon and ribavirin in patients with genotype 1 HCV infection who did not achieve SVR12 in clinical trials of Gilead first-generation investigational protease inhibitors (investigational DAAs; GS-9451 or GS-9256—with or without the non-nucleoside polymerase inhibitor tegobuvir and/or the NS5A inhibitor ledipasvir), were recently published online in the journal Hepatology (Pol S, et al. Hepatology. 2015 Apr 6. doi: 10.1002/hep.27836. [Epub ahead of print]).

  • 80 patients were enrolled at 40 clinical sites in the United States, Europe, and New Zealand to receive 12 weeks of treatment with sofosbuvir 400 mg once daily, peginterferon-alfa 180 mg/week, and weight-based ribavirin. All 80 patients completed the full 12 weeks of treatment.
    • The primary efficacy end point of this study was SVR (HCV RNA <25 IU/mL) 12 weeks after the end of treatment (SVR12).
  • The majority of patients (75%) were male and most (82%) were white. The mean age was 55 years (ranging from 21 to 72 years). No patient had documented cirrhosis by either biopsy or non-invasive assessment at the time of entry into the prior Gilead studies. Liver status was not reassessed at the time of retreatment.
  • All but one patient had received peginterferon as a part of their previous regimen.
  • Most patients (93%) harbored at least one class of RAV at baseline; 40% had resistance to one class, 40% had two-class resistance, and 13% had three-class resistance. Three patients (4%) were observed to have sofosbuvir treatment-emergent variants (TEVs) at baseline. No S282T was observed at baseline.

Patients experienced rapid reductions in HCV RNA after beginning treatment. No subjects experienced on treatment virologic failure during the 12 weeks of treatment.

  • Overall, 63 of 80 patients (79%; 95% confidence interval 68-87%) achieved SVR12
  • The presence at baseline of HCV variants conferring resistance to NS3 protease inhibitors, NS5A inhibitors, and non-nucleotide or nucleotide NS5B polymerase inhibitors—as well as any combination of these agents—did not decrease the likelihood of patients’ achieving SVR12
    • SVR12 was achieved by 9 of the 10 (90%) patients with three-class resistance, 26 of the 32 patients (81%) with two-class resistance, and 26 of the 32 (81%) with one class resistance at baseline.
    • Of the three patients with observed sofosbuvir TEVs at baseline, two achieved SVR.
  • Blacks and patients with non-CC IL28B alleles had lower rates of SVR12 (64% and 74%, respectively) than non-blacks and those with CC IL28B alleles (81% and 100%, respectively).
  • SVR12 rates were similar in most other groups (male vs female, high vs low BMI, HCV genotype 1a vs 1b).
  • Patients with baseline viral load ≥6 log10 IU/mL had a lower rate of SVR12 than patients with viral load <6 log10 IU/mL, but only eight patients were in the latter group.
  • No patients relapsed after post-treatment week 12.
  • Of the 17 patients who did not achieve SVR12, three had no baseline RAVs, three had one class of RAVs at baseline, eight had two classes of RAVs at baseline, and three patients had three classes of RAVs at baseline.
    • No S282T was detected in the patients that relapsed during sofosbuvir treatment, and no ribavirin TEVs emerged in those patients who relapsed.

Overall, 71 of 80 of patients (89%) experienced at least one treatment-emergent adverse event. Most of these patients only experienced events that were mild to moderate in severity.

  • The most common adverse events were fatigue (43%), headache (35%), and nausea (24%).
  • No patient discontinued all study treatment, but two patients discontinued peginterferon prematurely due to adverse events (lymphopenia and neutropenia) and one patient discontinued ribavirin prematurely due to anemia.
  • A total of 33 patients (41%) had Grade 3 and eight (10%) had Grade 4 laboratory abnormalities

In this open-label study, 12 weeks of treatment with sofosbuvir plus peginterferon and ribavirin resulted in a high rate of SVR12 in patients without cirrhosis who had not achieved SVR in prior trials involving peginterferon/ribavirin plus a protease inhibitor with and without other DAAs. The study authors concluded the following: “non-cirrhotic patients who did not achieve SVR after treatment with DAA combinations including a protease inhibitor and ribavirin with or without peginterferon achieved high rates of SVR12 when retreated with peginterferon, ribavirin, and sofosbuvir, regardless of the presence of RAVS to the previous agents.”

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