For patients with the most common and difficult-to-treat form of hepatitis C, a new oral, direct-acting, experimental drug combination is safe and well tolerated, and shows promising antiviral activity. Importantly, in some patients with no response to interferon-based standard therapy, the virus was undetectable after just 13 days of taking the combined treatment. The authors suggest that 8-12 weeks of this regimen could be sufficient to cure many patients with hepatitis C, as long as resistance does not develop. These are the findings of an Article published Online First in The Lancet.
Worldwide, more than 170 million individuals are infected with the hepatitis C virus (HCV), and it is a growing public health problem. Standard therapy is a combination of the antiviral drugs interferon and ribavirin. However, this treatment is long (48 weeks), has significant side-effects, and moreover, only cures about half of patients. Thus, there is an urgent need for the development of a treatment regimen of direct–acting antiviral drugs with different mechanisms of stopping the virus and a higher barrier to resistance, which can improve cure rates and shorten treatment time.
The INFORM-1 trial was designed to assess the safety, tolerability, and antiviral activity of an oral combination treatment with two experimental drugs, RG7128 (a polymerase inhibitor that blocks elongation of the new HCV RNA chain) and danoprevir (a protease inhibitor that blocks an enzyme the virus needs to replicate itself) in patients with chronic HCV.
88 patients with the most common form (gentotype 1) of the virus were recruited into one of seven treatment groups and randomised to receive various doses and schedules of the combined treatment (74) or placebo (14) for up to 13 days. Some patients had never been treated before, while others had failed interferon-based standard therapy. Change in HCV RNA concentration (the amount of virus in the blood) was measured at the start of the study and at regular intervals during treatment up to day 14.
Patients who had never been treated before who received the highest doses of the two drugs (1000 mg RG7128 and 900 mg danoprevir twice daily) had a median HCV RNA reduction after 14 days of 5•1 log10 IU/ml, compared with a reduction of 4.9 log10 IU/ml in patients who had shown no response to previous standard treatment, and an increase of 0.079 log10 IU/ml in patients taking placebo.
The combined treatment of RG7128 and danoprevir was generally well tolerated with no treatment-related severe side-effects, and no safety-related treatment discontinuations.
Additionally, there was no evidence of treatment resistance, unlike the rapid development of resistance shown by some classes of direct-acting antiviral drugs when given as monotherapy.
The authors conclude: "The combination of RG7128 and danoprevir should be further developed and might be a viable interferon-free all-oral regimen for patients with chronic HCV infection."
In a Comment, David Thomas from Johns Hopkins School of Medicine, Baltimore, MD, USA points out that even a 100% effective treatment will not cure many of those infected because, "only a small fraction of the estimated 170 million individuals with chronic hepatitis C infection know they are infected; far fewer ever start treatment."
But he adds: "On the other hand, if interferon-sparing treatment is safer, more effective, and simple to administer, such an approach could markedly expand testing, treatment uptake, and treatment efficacy, similar to how the development of highly active antiretroviral therapy led to expanded testing and treatment of HIV."
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Journal
The Lancet