April 1997
NEW YORK – While interferon-alfa is currently the most effective treatment for the three chronic hepatitis viruses — (hepatitis B (HBV), hepatitis C (HCV) and hepatitis D (HDV)— research suggests that other antiviral drugs used either alone, or in combination with interferon-alfa, may be more effective in inhibiting long-term viral replication and decreasing patient relapses, according to Jay H. Hoofnagle, MD, and Adrian M. Di Bisceglie, MD, in a report that appeared in The New England Journal of Medicine.
The research reinforces the contention that the best treatment for chronic hepatitis is therapy that manages it as a long-term viral disease, rather than as a symptomatic liver disease, said Hillel Tobias, senior hepatologist and associate professor of medicine at New York University Medical Center.
According to Tobias, early detection of asymptomatic patients and subsequent antiviral treatment are crucial to preventing the development of fatal chronic illness. By identifying chronic viral hepatitis before its clinical manifestations, it can be treated when there is less virus present. This gives the clinician an increased chance of curing the disease and preventing fatal complications, such as cirrhosis and hepatocellular carcinoma, he said.
"It's important to do testing on anybody who is either in a high-risk group or who has had possible exposure to hepatitis C, in particular, and D as well, so that you can determine if they have any evidence of viremia; if so, then you can treat them with available anti-viral drugs to try to prevent them from developing symptomatic liver disease."
While HBV, HCV and HDV are similar in their symptoms and characteristics, they vary in their response to interferon-alfa therapy and have shown promise with different antiviral drugs.
According to the article, interferon-alfa administered for HBV at the recommended dose of either 5 million units daily or 10 million units three times a week, for four to six months, induces a long-term remission in 25% to 40% of patients. Researchers hoping to improve these response rates and provide an option for retreatment, in which interferon-alfa is unsuccessful, have found noteworthy results in treating HBV with several new nucleoside analogues, particularly famciclovir (Famvir, SmithKline Beecham) and lamivudine (Epivir, Glaxo Wellcome).
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Preliminary findings of ongoing research on long-term therapy and combination therapy indicate that prolonged treatment with these drugs is well tolerated and can promote the sustained disappearance of HBV DNA from serum and improvements in serum aminotransferase concentrations and liver histology, the article reported.
Given these findings, Hoofnagle and Di Bisceglie predicted that the nucleoside analogues have the potential to change the treatment approach to chronic hepatitis B from current interferon-alfa therapy, which is aimed at clearing viral markers from serum and inducing remission, to long-term suppressive therapy, based on one or more antiviral drugs intended to impede viral replication.
For treatment of HDV, studies have indicated that therapy requires relatively high doses of interferon-alfa in a regimen of 5 million units daily or 9 to 10 million units three times a week for periods of up to 12 months. Administering the drug in these doses for prolonged periods leads to long-term improvement in 15% to 25% of patients tested, according to the article.
While the current interferon-alfa regimen for hepatitis C is 3 million units, three times a week for six months, recent reports have indicated that longer courses result in higher rates of sustained response, with an increase from approximately 15% with a six-month course to more than 25% with a 12- 18- or 24-month course, the article reported.
Tobias also advocates the use of high-dose interferon therapy for HCV. His regimen includes treatment with 6 million units, three times a week for 16 weeks. If there is no response, he uses a 16-week regimen of 8 million units and, if necessary, progresses to 16 weeks of 10 million units. "We find that there's a significant number of people that respond to the increased dose. We have had quite a few people who have responded to 10 million units that did not clear the virus on 3, 4, 5 or 6 million units," he said.
The most promising new approach to hepatitis C therapy is ribavirin (Virazole, ICN), a broad-spectrum oral antiviral drug, which has been most effective in combination with interferon-alfa. The article cited results from four pilot studies in which a six-month course of the combination was associated with a 40% to 77% rate of long-term response, significantly higher than the response for interferon-alfa alone (0 to 23%). While ribavirin did not increase the interferon-alfa response rate, it was effective in decreasing the relapse rate post-therapy, proposing that the combination might be most helpful in patients who have an initial response to interferon-alfa and later relapse, according to the article's authors. Further investigation using a large multinational trial to compare the combination of interferon-alfa and ribavirin against interferon-alfa alone is in progress.
The treatment of hepatitis C has also benefited from the availability of tests using polymerase chain reaction to determine levels of HCV RNA. This information regarding the viral load supports physicians in their tracking and management of hepatitis C as a viral disease, Tobias said. "Because the interferon frequently reduces the inflammation, the enzymes will go down, but 'Did you clear the viral load?' — because if you didn't clear the viral load, then you're not sure what you've really done for the patient. If you stop the interferon, then everything blossoms out again."
The potential for further advances in hepatitis therapy is promising, according to Tobias. "I think that, ultimately, there will be a group that responds to [high dose] interferon and a group that responds to two or three drug combinations. I think that the future for antiviral therapy is very good."
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