Given the increased response rates to therapy observed with peginterferons, it was natural to test them in combination with ribavirin. At least three large pivotal trials of this therapy have been conducted so far. These studies have many patient inclusion and exclusion criteria in common including raised serum aminotransferases, detectable serum HCV RNA, absence of other liver diseases or coexisting HIV infection.
The results of the first studies were reported by Manns et al in 2001. In this study, 1530 patients with chronic hepatitis C were randomized to one of three treatment groups: standard interferon (3 million units thrice weekly) with ribavirin for 48 weeks (1000-1200 mg daily based on body weight), peginterferon a2b 1.5 µg/kg/week with ribavirin 800 mg daily for 48 weeks or peginterferon a2b 1.5 µg/kg/week for 4 weeks and then 0.5 µg/kg/week for 44 weeks.
The rates of sustained virologic response were greatest in the group receiving higher dose peginterferon a2b with ribavirin (54%), compared to 47% with both the lower dose peginterferon and standard interferon combined with ribavirin. Pretreatment variables influencing the outcome of therapy included HCV genotype, viral load, body weight, age and degree of hepatic fibrosis. Patients infected with HCV genotype 1 and having a high viral load appear to be a particularly difficult group to treat with only 30% experiencing a sustained virologic response, even with optimal therapy.
Because peginterferon dosing is based on weight and because two different doses of ribavirin were evaluated, an extensive post-hoc analysis was conducted to try and evaluate the impact of these variables on treatment outcome. This analysis revealed that the likelihood of SVR increased as the dose of ribavirin increased (expressed as mg/kg of body weight). A threshold value of 10.6 mg/kg could be established, below which rates of SVR decreased significantly.
Also, when the dose of ribavirin was controlled on a mg/kg basis, the estimated effect of the higher dose of peginterferon a2b compared with the lower dose was larger implying that weight-based dosing of both interferon and ribavirin might be appropriate.
A large international trial using peginterferon a2a in combination with ribavirin was completed in 2002. In this trial, patients with chronic hepatitis C were randomized into one of three groups. The first group received standard interferon a2b with ribavirin at standard doses; the second group received peginterferon a2a at a dose of 180 µg/week with daily oral placebo to control for the effect of ribavirin; the third group was treated with peginterferon 180 µg/week with ribavirin 1000-1200 mg based on body weight.
Treatment was for 48 weeks and follow-up for 24 weeks after the end of treat-ment. SVR rates were 45% with standard interferon and ribavirin, 30% with peginterferon alone and 56% with peginterferon in combination with ribavirin. Approximately 7% of patients experienced a relapse of hepatitis C after achieving an end of treatment response in the two groups receiving ribavirin while in the group receiving peginterferon alone, the rate of relapse was substantially higher (29%).
There was a marked difference in rates of SVR in patients with different genotypes. Thus, 46% of those with genotype 1 achieved a sustained response with peginterferon and ribavirin, compared to 76% for those infected with non-1 genotypes (mostly genotypes 2 and 3). Again, the group with both genotype 1 and high viral load proved the most difficult to treat and only 41% of them had an SVR.
The last of the three pivotal trials was designed to assess the effect of duration of therapy and the dose of ribavirin. Thus patients were randomized to receive peginterferon a2a for either 24 or 48 weeks, with either 800 or 1000-1200 mg/day of ribavirin. Within each of these treatment groups, patients were stratified at entry according to HCV genotype (1 or non-1) and viral load (greater than or less than 2 million copies/mL).
SVR was assessed at the end of 24 weeks of follow-up in all groups. In patients infected with HCV genotype 1, the highest rates of response were noted in patients treated for 48 weeks with the higher dose of ribavirin (51%). Interestingly however, rates of SVR were virtually identical in all four treatment groups in patients infected with genotypes 2 and 3 (73-78%).
These data clearly indicate that patients infected with HCV genotype 2 or 3 can successfully be treated with only 24 weeks of therapy and less ribavirin. This represents substantial savings in terms of both cost and side-effects.
RSS Feed
