Can We Treat Chronic HCV Infection Without Interferon?

A potent combination of 2 drugs that directly target the hepatitis C virus (HCV) is effective in patients with chronic infection, and doesn’t require interferon therapy, according to an article in the December issue of Gastroenterology.

Patients infected with HCV genotype-1 are usually treated with peginterferon and ribavirin, but approximately 60% do not have a sustained virologic response (SVR, undetectable plasma level of HCV RNA 24 weeks after treatment), and many others cannot tolerate the side effects of peginterferon.

Stefan Zeuzem et al. tested a combination of the HCV polymerase inhibitor BI 207127 and the protease inhibitor BI 201335, each developed by Boehringer Ingelheim, in 31 treatment-naïve patients with chronic HCV, genotype-1 infection. Patients received either 400 mg or 600 mg of BI 207127, 3 times daily, along with 120 mg of BI 201335 and a dose of ribavirin each day for 4 weeks. None of the patients received interferon.

The rate of virologic response (an HCV RNA level below 25 IU/mL) reached 100% by day 22 in the patients given the 600 mg dose of BI 207127, without differences among genotypes—HCV RNA could not even be detected in 71% of the patients by day 29.

One patient in the group given the 400 mg dose of BI 207127 had a virologic breakthrough (a rebound in HCV RNA level) at day 22. The most frequent adverse events were mild gastrointestinal disorders, rash, and photosensitivity, but there were no severe or serious adverse events.

In an editorial that accompanies the article, Prateek Sharma and Anna Lok agree that an interferon-free regimen of direct-acting antiviral agents and ribavirin can suppress HCV for up to 4 weeks. However, they point out that it is not clear if this response, and lack of adverse events, can be maintained for longer time periods.

In a video abstract, Zeuzem states that these findings are a milestone toward different options to achieve viral eradication. “We are looking toward longer treatment exposure with these direct-acting antivirals … with such a safe and tolerable regimen, we hope that 24 weeks may be sufficient to cure patients, without the need for interferon,” he says.

HCV protease inhibitors such as boceprevir and telaprevir are also effective in treating patients chronic HCV genotype-1 infection. However, these drugs must be given with peginterferon and ribavirin, to prevent the development of drug-resistant variants.

The authors propose that the unique structure of BI 207127 precludes the development of resistant viral variants. The drug interferes with a conformational change required for the HCV NS5B polymerase to initiate RNA synthesis; its binding site is an interface between functional domains that restricts sequence polymorphisms. So, BI 207127 seems to have a higher barrier to resistance than other polymerase inhibitors.

Further studies are needed to to determine the exact role of ribavirin in the antiviral activity of this combination. Zeuzem et al. propose that this drug’s weak direct antiviral activity and ability to induce interferon-sensitive genes contribute to its role in the drug combination.

Sharma and Lok conclude that interferon-free regimens are no longer a dream, and that some regimens will also eventually be ribavirin-free. This is good news for patients who cannot take peginteferon or ribavirin because of their interactions with other medications or tolerability issues. However, caution must be taken in selecting which antiviral agents to combine the appropriate dose and duration of therapy for each HCV genotype and subgenotype.

Read the article online. This article has an accompanying podcast and CME activities.
Zeuzem S, Asselah T, Angus P, et al. Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 2011;141:2047–2055.

Read the accompanying editorial.
Sharma P, Lok AS. Interferon-free treatment regimens for hepatitis C: are we there yet? Gastroenterology 2011;141:1963–1967.