Hepatitis C Information Central

On May 4 the FDA's Antiviral Drugs Advisory Committee recommended approval of combination treatment with ribavirin plus interferon alpha for Hepatitis C which had not been cured by interferon alone. Ribavirin, a broad-spectrum antiviral long approved for oral use in almost every country of the world except the U.S., is expected to be officially approved and on pharmacy shelves here by this fall. Alpha interferon is already a prescription drug.

As many as 40% of persons with HIV are also infected with Hepatitis C, which causes many deaths, and is more serious for those who are HIV-positive than for the general population. Some HIV physicians are now reporting more of their patients dying from liver cirrhosis caused by this disease, than from AIDS. It is estimated that about four million Americans have Hepatitis C, but only about one million know it.

Patients need to know that Hepatitis C might not be properly diagnosed and treated by physicians, including specialists, who are not experienced in treating chronic viral infections. Until now the only approved U.S. treatment has been alpha interferon alone, usually given for six to 18 months; with this treatment, only about 10% to 20% of patients have been cured, but some of the others appear to have greatly benefited from the drug. ("Cured" means that the Hepatitis C virus becomes undetectable and remains undetectable indefinitely, even after discontinuation of treatment.) Combination treatment with ribavirin appears to at least double the cure rate. But many patients who may need treatment have not been receiving it.

The Hepatitis C clinical trial data so far is from patients who are HIV negative. The first trial for persons with both infections, sponsored by the American Foundation for AIDS Research, is starting now in 17 U.S. cities (see announcement below).

For information on Hepatitis C treatment today we interviewed Douglas T. Dieterich, M.D., Associate Professor of Medicine at New York University School of Medicine. A gastroenterologist, Dr. Dieterich also treats patients at Liberty Medical LLP in New York. He is co-principal investigator of the AmFAR clinical trial.

AIDS Treatment News: In the recent hearing on Hepatitis C, what did the FDA advisory committee recommend for approval?

Dr. Dieterich: The approval recommendation was for re-treatment of patients who had previously failed to be cured by alpha interferon alone. The difference in the response rate was about 4% cure rate in the interferon plus placebo group, and about 48.7% for the interferon plus ribavirin group, for these patients.

ATN: Is the data not available yet for naive patients? From the HIV experience, it would seem that there might be even better results with those who were treatment naive.

DD: Actually in the naive studies, the numbers appear to be about in that 48% range--in the three smaller studies that have been done.

ATN: What is known about the benefits for those who are not cured--with the combination, and also with interferon alone.

DD: We do not have data yet on the combination, but those who were treated with interferon alone seem to have a much lower risk of getting a hepatoma--a primary liver cancer--related to Hepatitis C. Also, progression to cirrhosis is lower, and their Hepatitis C viral load is lower as well, even after the treatment is stopped. So there appears to be a positive effect on the immune system.

ATN: What about the problem of cases being missed by the Hepatitis C antibody test? Which patients should also get a Hepatitis C PCR test (which looks for the virus directly), even if their antibody test is negative?

DD: Those at high risk--for example, a patient who has a history of intravenous drug use, or who has had a sex partner with a history of IV drug use or a history of Hepatitis C.

ATN: How would you test a patient with that history, but who also has only a minor liver enzyme elevation, or even no elevation?

DD: Certainly the Hepatitis C antibody test should be done first. But if that is negative, I think I would go on to do the PCR. You could use either a qualitative or a quantitative PCR; for diagnosis, the qualitative PCR is more than satisfactory. When we are doing studies, we like to do the quantitative test. [A qualitative test only tells whether or not something is present; a quantitative test tells how much.]

Also, until 1990 the blood supply was not tested. So anybody who had a transfusion before 1990 is at risk for Hepatitis C and should be checked. This summer the Surgeon General is going to start a large campaign to look for these people; there may be as many as 400,000 in the U.S.

ATN: Does there seem to be more Hepatitis C now than before--or is it just that we did not know about it before?

DD: The number of new infections today is mostly from IV drug users. But many cases we are seeing are baby boomers who were playing around with injected drugs 20 or 30 years ago, and are now getting diagnosed when they apply for life insurance, etc.

ATN: Which patients are likely to progress rapidly, and which may be OK for years even without treatment?

DD: It is very hard to predict. In general we know that people with HIV progress more rapidly than people without HIV. And people with other immunodeficiencies, like renal failure or transplant patients, also seem to progress more rapidly. But for patients without those risks, it is hard to tell.

ATN: So if somebody does have HIV or other immunodeficiency, that would be an indication to go ahead with treatment, to be more aggressive?

DD: Absolutely. In addition, a way to make some sort of prognosis is to do a liver biopsy. The amount of fibrosis on the liver biopsy shows who is progressing most rapidly toward cirrhosis.

ATN: What patients should not be treated?

DD: That is not yet clear. If people are extremely ill with hepatitis, and have decompensated cirrhosis, the treatment with interferon can certainly make them worse in the beginning. And people who have coronary artery disease should always have a stress test before they take ribavirin, which has a side effect of anemia, which can cause heart problems if somebody becomes very anemic.

And for the most healthy people--those who are HIV negative, and who have normal SGOT and SGPT [liver enzymes which are checked by a blood test]--we have been holding off treating them, for now.

ATN: I understand that the way Hepatitis C progresses is that the virus develops resistance to the body's defenses?

DD: Yes, relapses occur when the virus mutates and produces a different quasispecies, and escapes from lymphocyte control.

ATN: How serious are the side effects of alpha interferon and ribavirin?

DD: Alpha interferon has many side effects. They can include fatigue, fever, flu-like symptoms, aches and pains, depression, thyroid problems, weight loss, maybe wasting, diarrhea, and nausea. With the doses used, people are likely to feel something. Generally it is not terrible; patients can usually control most of the symptoms with over-the-counter medicines.

With ribavirin, aside from the anemia there may a little nausea, similar to the AZT nausea, which usually resolves.

ATN: What are the usual doses for both of the drugs?

DD: The AmFAR study is using 3 million units of alpha interferon three times a week, and 400 mg of ribavirin twice daily.

ATN: Must the ribavirin be taken on a full or empty stomach?

DD: It does not matter.

ATN: What about treatment failures? What is the usually pattern of Hepatitis C treatment not working?

DD: There are two different ways we could look at failures. One is complete non-responders, whose PCR never becomes undetectable . And also there are people who respond and then relapse, either while on therapy or after discontinuing.

ATN: Where are we in the development of new kinds of drugs designed specifically to treat this virus--such as Hepatitis C protease inhibitors, and helicase inhibitors? Are these several years away?

DD: That may be a realistic time. Researchers have only recently figured out the structure of the viral protease. There are no such drugs in trials yet.

ATN: There is now a movement to end the automatic exclusion of persons with HIV from organ transplantation (see AIDS Treatment News #288, February 6, 1998).

How often have liver transplants been used to save the lives of patients with access to them?

DD: Hepatitis C is the number one reason for liver transplants in the U.S. today. It is rapidly running away from the other causes.

ATN: What advice could you give on finding proper specialist care--if somebody is at risk for Hepatitis C infection, or has already been diagnosed?

DD: It is important to seek a physician who understands chronic viral illnesses and their treatment, and the importance of treatment. Many of the classical referrals have been to gastroenterologists, many of whom have little or no experience or interest in treating Hepatitis, particularly in HIV patients.

However, there are some gastroenterologists who are very experienced and knowledgeable--for example, the investigators in our AmFAR trial. I would certainly recommend these people to anyone.

Among other physicians, there are many infectious disease doctors who are quite knowledgeable and capable of treating Hepatitis C--and also HIV specialists who are internists or primary-care docs. These physicians are more likely to understand the importance of treating this infection, and the viral dynamics of the disease. So we should not limit our options to just gastroenterologists.

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Donaghy A, Ross R, Wicks C, and others. Growth hormone therapy in patients with cirrhosis: A pilot study of efficacy and safety. Gastroenterology.1997; volume 113, pages 1617-1622.

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