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New Studies of Interferon and Ribavirin-free Treatment of Hepatitis C at ID week 2013

Interferon has been an component of all treatment for Hepatitis C (HCV) for more than 20 years. It also has been a major cause of limited treatment success because it causes numerous adverse events, requires injection and has variable activity against different HCV genotypes and in patients with different genetic backgrounds. Adding ribavirin to interferon improves responses, but contributes additional adverse effects, especially anemia, and increases pill burden. With the development of numerous investigational directly-acting antivirals (DAAs), treatment of HCV without either interferon or ribavirin will soon be possible. Everson et al [1] reported an interim analysis of an all oral DAA regimen consisting of daclatasvir (DCV), a potent NS5A inhibitor, asunaprevir, a 2nd generation HCV protease inhibitor and one of two doses (75 or 150 mg bid) of BMS 791325, a non-nucleoside NS5B inhibitor given for either 12 or 24 weeks. Sixty-six treatment-naive, HCV mono-infected genotype 1 patients were randomized into the four treatment arms. Three-quarters had genotype 1a. SVR12 was achieved in 89-94% with no apparent differences between the two doses of 791325 or the two durations of treatment. Only two viral breakthroughs and one relapse occurred. There were no grade 3/4 laboratory abnormalities and no patient discontinued for adverse effects.

One of the most promising interferon-free regimens is the two drug combination of the nucleotide NS5B polymerase inhibitor sofosbuvir (SOF) and DCV. In small, preliminary trials, this regimen produced high rates of SVR for all genotypes studied. Sulkowski et al. [2] reported their experience using this regimen in one of the most difficult-to-treat patient groups, genotype 1 patients who failed triple therapy with ribavirin, peginterferon and a first generation HCV protease inhibitor, either telaprevir or boceprevir. The 41 enrolled in the trial were a mixture of non-responder, relapser and breakthrough patients. Cirrhotics and those who failed prior therapy due to adverse events were not included. Eighty percent were genotype 1a and almost all had IL28B T alleles, factors that result in lower responses to many HCV regimens. All received SOF and DCV for 24 weeks. Additionally, participants were randomized to add or omit open label ribavirin. There were no discontinuations for adverse events and no virologic breakthroughs. One participant had missing data at post-treatment week 12. All others achieved SVR12. No grade 3/4 AST/ALT elevations and only 2 grade 3/4 adverse events of any kind were recorded. This very powerful regimen produced very high cure rates in difficult-to-treat patients with prior HCV protease failure and unfavorable HCV and IL28B genotypes. The addition of ribavirin did not appear to be necessary. Unfortunately, as it stands now, this combination will not be studied in large scale clinical trials. Instead, SOF will be studied with another NS5A inhibitor and DCV will be studied with other DAAs.

These studies show that very high rates of HCV cure are possible with combinations of 2 or 3 DAAs given for 12 to 24 weeks, even for hard to treat patients with genotype 1a or prior treatment failure. Interferon and ribavirin are not required and their elimination enhances safety and tolerability. Future clinical use of these very promising experimental regimens should greatly improve treatment and health outcomes in HCV-infected individuals.

1. Everson GT, Sims KD, Rodriguez-Torres M, et al. Interim Analysis of an Interferon (IFN)- And Ribavirin (RBV)-Free Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 In Treatment-Naive, Hepatitis C Virus Genotype 1-Infected Patients. ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1828.
2. Sulkowski M, Gardiner D, Rodriguez-Torres M, et al. Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) In Chronic HCV Genotype (GT) 1-Infected Patients Who Previously Failed Telaprevir (TVR) or Boceprevir (BOC). ID Week 2013, San Francisco, CA, October 2-6, 2013, abstract 1357.

Source: Reporting from San Francisco for PRN News: Davis H Shepp, MD