A new form of alpha interferon clears hepatitis C infection more effectively than the form currently in use, according to reports from two large international studies published today in the New England Journal of Medicine.
Pegylated alpha interferon is removed more slowly from the circulation due to the attachment of polyetheylene glycol to alpha interferon. Pegylation results in a ten to one hundred fold reduction in the clearance of alpha interferon. This allows the compound to be administered once weekly instead of three times weekly (the standard dose for alpha interferon), and also improves the efficacy of alpha interferon.
A formulation of pegylated alpha interferon known as Pegasys, manufactured by Roche, was compared with three times weekly dosing of interferon-alpha in 531 individuals with chronic hepatitis C. Two doses were compared with standard dosing of alpha interferon in a more advanced group of patients, 271 individuals with chronic hepatitis C and cirrhosis. Both studies lasted 48 weeks, followed by 24 weeks follow-up after treatment was stopped. All patients were HIV-negative.
In the first study patients received either 180ug of subcutaneous peginterferon-alpha 2a once a week for 48 weeks, or 6 million units of interferon alpha three times weekly for 12 weeks, followed by 3 million units three times weekly for a further 36 weeks. Nineteen individuals discontinued peginterferon due to adverse events compared with 27 discontinuations for adverse events in the alpha interferon group, whilst discontinuations due to lack of treatment responses were 13 in the PIA arm compared to 53 in the interferon group. By intent to treat analysis, 69% of the PIA group had undetectable HCV RNA at week 72, compared with 19% of the interferon group. The PIA group was also significantly more likely to experience a decline in liver enzyme levels, and to experience improvements in liver tissue inflammation.
Dose modification due to neutropenia was required in 11% of the PIA group and 7% of the alpha interferon group.
The investigators commented that responses in the Pegasys group were similar to those seen in the studies of alpha interferon plus ribavirin in comparable populations and with comparable follow-up periods.
In the second study patients were randomised to receive either 90ug or 180ug of pegylated alpha interferon once a week or 3 million units of alpha interferon three times a week. Participants had already been diagnosed with liver cirrhosis or bridging fibrosis by liver biopsy. Of the 271 patients enrolled, 8% of the alpha interferon group, 15% of the 90ug peginterferon group and 30% of the 180ug peginterferon group (p=0.001) had undetectable HCV RNA at week 72 by intent to treat analysis. Liver enzyme levels were normalised in 15% of the alpha interferon group, 20% of the 90ug PIA group and 34% of the 180ug PIA group (p=0.004). Improvements in liver inflammation were also significantly more common in the higher dose peginterferon group (54% vs 44% and 31%, p=0.02) among 184 individuals who received a follow-up liver biopsy at week 72.
Bone marrow toxicities have been observed frequently in the past in patients with hepatitis C and cirrhosis, but in this study there were no discontinuations due to neutropenia, and only two due to thrombocytopenia (in peginterferon 180ug recipients). The peginterferon 180ug group had the highest rate of discontinuations due to adverse events (13%), and these were largely the flu-like symptoms commonly seen with alpha interferon treatment.
In both groups, mixed patterns of responses were observed, with histologic improvements seen in some patients who still maintained detectable HCV RNA at week 72, suggesting that alpha interferon may still have benefit to the liver even if it cannot control viremia. Although it has been assumed that undetectable HCV RNA after a 48 weeks course of therapy signals the complete clearance of the virus, an accompanying editorial in the New England Journal of Medicine urges caution in describing undetectable plasma viremia as a "cure" for HCV. The authors also note that whilst the results of these studies are promising, they may hold out less promise to individuals infected with the more common HCV genotype 1, since these patients were less likely to have a sustained response compared to those with other genotypes.
References
Heathcote EJ et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. New England Journal of Medicine 343 (23): 1673-1680, 2000.
Zeuzem S et al. Peginterferon alfa-2a in patients with chronic hepatitis C. New England Journal of Medicine 343 (23): 1666-1672, 2000.