Combination of Investigational Drugs Helps Alleviate Hepatitis C Symptoms
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The results from a small study of patients with hepatitis C virus (HCV) genotype 1 infection showed that a combination of 2 investigational drugs suppressed the virus for patients who previously had no response to treatment. The findings are significant because the only current treatment for hepatitis C is a combination of the antiviral medication ribavirin and peginterferon alfa—a drug that has high rates of adverse events and is not well tolerated by patients [N Engl J Med. 2012;366(3):216-224].
Hepatitis C affects 180 million people globally, including 4.1 million Americans. It is the most common cause of chronic liver disease in the United States and a leading cause of cirrhosis and liver cancer. Hepatitis C genotype 1 is the most difficult to treat.
In the open-label, proof-of-concept, phase 2a study, the researchers sought to determine if patients with hepatitis C who have not responded to therapy with peginterferon and ribavirin would benefit from the addition of multiple direct-acting antiviral agents to their treatment regimen. The investigational drugs studied were daclatasvir and asunaprevir. Daclatasvir is a first-class, highly selective HCV NS5A replication complex inhibitor with picomolar potency in vitro. Asunaprevir is a highly active HCV NS3 protease inhibitor. The study included an exploratory cohort of 21 patients with chronic HCV genotype 1 infection who had not responded to previous therapy (had not had ≥2 log10 decline in HCV RNA after ≥12 weeks of treatment with peginterferon and ribavirin). Eligible patients were enrolled at 7 centers in the United States from December 2009 through February 2010. Eligible patients were men and women, 18 to 70 years of age, who had chronic HCV genotype 1 infection, HCV RNA levels ≥105 IU/mL, and no evidence of cirrhosis.
Patients were randomly assigned in a 1:1 ratio to receive daclatasvir and asunaprevir for 24 weeks (group A=11) or to receive daclatasvir, asunaprevir, peginterferon alfa-2a, and ribavirin for 24 weeks (group B=10). Daclatasvir was administered orally at 60 mg once daily and asunaprevir at 600 mg twice daily. Peginterferon alfa-2a was administered subcutaneously at 180 mcg/week, and ribavirin was administered orally twice daily with doses determined by body weight. The primary end point was the percentage of patients with a sustained virologic response 12 weeks after the end of the treatment period.
The findings showed that 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 and 24 weeks after treatment. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases. In group B, all 10 patients had sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment.
Most adverse events were mild to moderate. The most common adverse events among group A and group B patients were diarrhea (8 vs 7, respectively), fatigue (6 vs 7, respectively), headache (5 for both groups), and nausea (2 vs 5, respectively). Six patients (group A=4 and group B=2) had transient elevations of alanine aminotransferase levels to >3 times the upper limit of normal range.
“Therapy with daclatasvir, asunaprevir, peginterferon alfa-2a, and ribavirin for 24 weeks provided a high rate of sustained virologic response in patients with HCV genotype 1 infection who had not had a response to previous therapy with peginterferon and ribavirin,” concluded the researchers. “The response in some patients to the combination of daclatasvir and asunaprevir alone showed proof-of-concept that a sustained virologic response can be achieved without peginterferon and ribavirin therapy.”