Hope for Hepatitis C
Abstracts & Commentary
Sources: McHutchison JG, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic Hepatitis C. N Engl J Med 1998;339(21):1485-1492; Davis GL, et al. Interferon alpha-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339(21):1493-1499.
A consortium of hepatology centers put together several large series of patients treated with interferon with or without ribavirin. The first report was of 912 previously interferon-naïve patients treated with interferon three times weekly plus placebo, or interferon three times weekly, plus 1000-1200 mg of oral ribavirin daily for 24 or 48 weeks. The population studied was the usual for hepatitis C in the United States with an average age in the mid 40s, twice as many males as females, and an average infection period of 19 years. Half of the patients acknowledged drug use as the source of infection, while one-third indicated an unknown source. One-third of patients already had bridging fibrosis on liver biopsies done at the start of therapy. More than 1300 patients had to be screened to find the 900 patients due to exclusion factors such as HIV infection, seizures, serious emotional disorders, azotemia, and ongoing drug or alcohol abuse.
The dropout rate was 9% for the 24-week treatment program and 16% for 48 weeks. Among the symptoms listed for those who dropped out were anxiety (15%), depression (30%), insomnia (30%), and alopecia (30%). Ribavirin was not associated with an increase in depression or psychiatric symptoms but was associated with anemia with a fall in hemoglobin to 10 g/dL or less in 8% of patients. There was also some associated leukopenia and thrombocytopenia.
Of those treated with interferon alone, the virus was shown to be eliminated by PCR in only 6% of those who received 24 weeks of therapy and in 13% of those who received 48 weeks. The addition of ribavirin (compared to placebo) increased the response rates to 31% and 38% for the same intervals. There also seemed to be a comparable response in follow-up liver biopsy results with ribavirin and longer duration of therapy. Poor response was correlated with genotype 1, high initial viral load, and cirrhosis at onset.
The second article examined 354 patients who had relapsed after having had a normal serum alanine aminotransferase after one or two prior courses of interferon therapy. They were randomized to receive interferon three times weekly plus either ribavirin or placebo for 24 weeks. The elimination rate of virus by PCR after an additional 24 weeks was 5% for those who received interferon alone and 49% for those who received interferon with ribavirin. This group also tolerated the medication relatively well.
COMMENT BY Alan D. Tice, MD, FACP
These studies provide some reason for greater optimism for the treatment of hepatitis C, which is thought to infect about 4 million Americans and 100 million people around the world. Prior results of therapy with interferon alone have been disappointing although it has been FDA approved.
The recent national hepatitis C campaigns by the CDC and others have clearly heightened awareness and will continue to do so—especially with the involvement of the blood banks with their "look back" programs. The recent CDC guidelines for the screening of patients for hepatitis C are useful although still somewhat controversial.1
While the addition of ribavirin looks relatively good compared to the standard regimen of interferon alone, it is important to recognize the cost of therapy as well as the side effects. It is clearly a problem trying to treat everyone with hepatitis C when some have liver failure, continue to drink alcohol, or have serious underlying diseases—especially at a cost of about $10,000 per year for interferon alone. The effect on the prison system alone in the United States would be overwhelming if all of the estimated 400,000 inmates with hepatitis C were treated. Not every patient is, however, a good candidate for therapy. With the studies reviewed here, one-third of the patients who were screened were excluded from therapy—usually for good reasons.
On the other hand, there are patients who clearly would benefit from treatment but may not even realize they are infected.
The implications of these studies in regard to the duration of therapy are interesting. It has been hoped that a determination of those who are not going to respond would become apparent by measuring viral load a month or possibly more after therapy is initiated. This did not seem to be possible in the first study as those who were treated for 48 weeks were more likely to respond than if they were treated for 24 weeks with ribavirin or not.
There is also a need to examine the optimal use of interferon with ribavirin. Longer courses of therapy seem to be beneficial. Daily dosing may be more effective and better tolerated. Reducing iron load may be helpful. It may be worth treating relapsers and non-responders again. It is interesting that relapsers had a higher rate of response than those who had not previously received interferon. Further studies on interferon use are ongoing and should be helpful.
In the long term, the search is underway for newer and better agents to treat hepatitis C. There are trials ongoing with a pegylated interferon that can be given once a week. Helicase inhibitors and other new antiviral agents are being studied with the investigations of new drugs spurred on by HIV. Unfortunately, there seems to be no value to the other presently available anti-retrovirals for hepatitis C (as opposed to hepatitis B). In fact, they may be detrimental for people co-infected with hepatitis C and HIV. In terms of alternative medicine therapy for hepatitis C, there has been a nice study of over-the-counter thymic extract reported in the Annals of Internal Medicine, which shows it has no value compared to placebo—despite claims in the media and on the Internet.2
References
1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998;47(No. RR-19):1-40.
2. Raymond RS, Fallon MB, Abrams GA. Ann Intern Med 1998;129(10):797-800.
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