October 23, 2001
It is estimated that 170 million people worldwide are infected with the hepatitis C virus. In the United States, 3.9 million test positive for anti-HCV, and 2.7 million are viremic. These numbers exclude institutionalized individuals such as prisoners and the mentally ill, and does not include the veteran population. Thus, it is likely that the actual number of Americans infected with hepatitis C is much larger than previously estimated.
Interferons provide the backbone of treatment for chronic hepatitis C infection. According to Dr. Bacon, initial therapy with interferon alone resulted in disappointing sustained response rates of <10% and has been largely abandoned. Most recently, combination therapy with interferon and ribavirin markedly increased the sustained response rates. Approximately 40% to 45% of people treated with interferon alfa-2a and ribavirin for 12 months achieve a sustained viral response. Results are less favorable in patients infected with genotype 1; only about 28% are able to achieve a sustained response. In contrast, close to 70% of those infected with genotype 2 or 3 may clear the virus permanently after therapy with interferon and ribavirin.
One of the most important advances in the treatment of hepatitis C has been the development of pegylated interferons. Pegylation is the process by which a molecule of polyethylene glycol (PEG) is attached to a molecule of interferon. The resulting "pegylated" compound has a longer half-life and duration of action. As a result, the pegylated interferon preparation only has to be injected once a week, and since it provides continued therapeutic levels of interferon in blood, it has a more potent antiviral action.
Dr. Bacon explained that pegylation is not a new process. Scientists have successfully pegylated other medications that are currently in use, thus the process is safe and free of side effects. There are several ways of pegylating the interferon molecules and changes in the size and shape of the PEG molecule used, as well as the site of attachment to the interferon, may affect the efficacy, safety and side effect profile of the final product. For example, the larger the PEG molecule, the longer the half-life of the product and the lower the antiviral activity. Thus, a balance between longer half-life and antiviral activity must be reached to produce a successful product.
According to Dr. Bacon, there are currently two pegylated interferon products in development. PEG-interferon alfa-2b (PEG-Intron) is manufactured by Schering-Plough Pharmaceuticals and consists of a small 12 kilodalton linear PEG molecule attached to a molecule of interferon alfa-2b. PEG-interferon alfa-2b was approved by the FDA for use in January 2001 and is currently available by prescription. The second pegylated product in development is PEG-interferon alfa-2a (Pegasys), manufactured by Roche Pharmaceuticals. Pegasys consists of a larger 40 kilodalton branched PEG molecule attached to the interferon alfa-2a molecule. This product has not yet received FDA approval for general use, but approval is expected in the near future.
PEG-interferons have several advantages:
Thus, patient acceptance of the pegylated interferons is usually better than regular interferons.
Dr. Bacon discussed that PEG-Intron is dosed in a per-weight basis: when used in combination with ribavirin, the optimal dose of PEG-Intron is 1.5 micorgrams per kilogram of weight per week. In contrast, Pegasys has a fixed weekly dose for all patients of 180 micrograms per week. Both products are injected subcutaneously.
The pegylated interferons have a stronger antiviral activity compared with regular interferons. Approximately 20% to 35% of patients treated with PEG-interferon monotherapy achieve a sustained response, compared with only 10% to 20% of those treated with standard interferon. The efficacy of pegylated interferons however is lower than the efficacy of regular interferons used in combination with ribavirin (Rebetron), thus, pegylated interferons should be used in combination with ribavirin to maximize the chances of viral clearance. According to Dr. Bacon, PEG-interferon monotherapy is only indicated for those patients who cannot tolerate ribavirin, or those who are on long-term maintenance therapy with interferon.
The efficacy of PEG-interferon alfa-2b (PEG-Intron) and ribavirin was compared to standard interferon plus ribavirin in a trial enrolling 1,530 patients. Sixty-eight percent of the patients were infected with genotype 1. The results indicated a clear advantage to using the 1.5 microgram per kilogram dose compared to the lower dose. Among all the patients treated, 54% of those receiving 1.5µg/kg PEG-interferon + ribavirin achieved a sustained viral response. In contrast, only 47% of those using the 0.5µg/kg PEG-interferon + ribavirin achieved a sustained response. By comparison, 47% of those treated with standard interferon + ribavirin (Rebetron) cleared the virus. These results indicate that to maximize response to treatment, PEG-interferon alfa-2b should be dosed at 1.5µg/kg/week.
The use of PEG-interferon alfa-2b in combination with ribavirin was also beneficial for patients infected with genotype 1. When treated with 1.5µg/kg of PEG-interferon alfa-2b and ribavirin, 42% of those infected with genotype 1 cleared the virus, compared with only 33% treated with Rebetron. The advantage for genotype 2 patients was not as clear; 82% of them achieved a sustained response with PEG-interferon alfa-2b compared with 79% treated with Rebetron.
Dr. Bacon emphasized that recent trials have stressed the importance of using a weight-adjusted dose of ribavirin as well. When the results were analyzed in a retrospective fashion, it was noted that of all patients treated, 54% achieved a sustained response. In contrast, those who received the equivalent of >13mg/kg of ribavirin per day, 61% were able to achieve a sustained viral response. These results need to be validated in a prospective fashion, but suggest that ribavirin should be dose based on weight rather than on a fixed dose schedule.
Dr. Bacon also discussed the clinical trials using interferon alfa-2a (Pegasys). PEG-interferon alfa-2a monotherapy is definitely more effective than interferon afla-2a monotherapy; up to 30% of patients achieve a sustained response when treated with 180µg/week of Pegasys. Pegasys in combination with ribavirin is clearly more effective than Rebetron therapy. In a study of approximately 1,200 patients treated with interferon alfa-2a alone (Pegasys), interferon alfa-2b + ribavirin (Rebetron) or Pegasys + ribavirin, the sustained response rates were 30%, 45% and 56% respectively. Among genotype 1 patients, 21%, 37% and 46% achieved a sustained response in response to Pegasys monotherapy, Rebetron or Pegasys + ribavirin respectively. The corresponding sustained response rates for genotypes 2 and 3 were 45%, 61% and 76%. Results presented by Dr. Fried at the recent Digestive Disease Week meeting also indicate that the use of Pegasys with ribavirin may be associated with fewer side effects than Rebetron, increasing quality of life during treatment. These results, while preliminary, raise hope of decreasing the side effect profile of current antiviral therapy for hepatitis C.
Dr. Bacon discussed that current results indicate that both PEG-interferon alfa-2a and PEG-interferon alfa-2b are more active than regular interferon and when used in combination with ribavirin have become the standard of care for patients with recently diagnosed hepatitis C infection.
The role of pegylated interferon therapy in patients who previously failed Rebetron therapy is currently being explored according to Dr. Bacon. It is clear that a subset of patients who were not able to clear the virus with Rebetron may do so after treatment with PEG-interferon and ribavirin. Current studies in progress are showing that approximately 35% to 40% of previous non-responders to Rebetron are becoming virus negative during treatment. It is not known however, how many of these patients will become long-term non-responders once treatment is completed.
It is likely that those patients who responded and then relapsed after Rebetron therapy will be the ideal candidates for treatment with PEG-interferon and ribavirin. Another subset of patients who may respond are those who had a substantial (>2 log) decrease in viral load while on Rebetron, but were unable to clear the virus. Those who demonstrated no appreciable response to Rebetron were the least likely to achieve a sustained response when retreated with PEG-interferon and ribavirin.
Dr. Bacon emphasized the importance of having patients adhere to treatment and minimize dose reduction during therapy. He showed results of a retrospective analysis of clinical trials showing a sustained viral response of 72% of patients that were able to take >80% of the prescribed dose for >80% of the time compared with a sustained response of 54% among all treated patients.
Dr. Bacon summarized the current treatment with PEG-interferon and ribavirin as a significant positive step toward achieving viral clearance in hepatitis C and stated that currently this should be the treatment of choice for patients with chronic hepatitis C infection.
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