AIDS Treatment News
May 15, 1998

Hepatitis C Important Treatment Advance

Interview with Douglas Dieterich, M.D.

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.

Interview with Dr. Dieterich

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.

Diagnosis and Epidemiology

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.

Who Needs More Aggressive Treatment?

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.

Side Effects of Treatment

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.

Progress Toward Better Drugs

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.

Liver Transplants

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.

Finding Good Care

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.

Bibliography

Lai MY, Kao JH, Yang PM and others. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology. November 1995, volume 111, number 5, pages 1307-1312.

Chemello L, Cavalletto L, Bernardinello E, Guido M, Pontisso P, and Alberti A. The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. Journal of Hepatology 1995; volume 23, supplement 2, pages 8-12.

Reichard O, Norkrans G, Fryden A, and others. Randomized, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Lancet January 10, 1998; volume 351, pages 83-87.

Schalm SW, Brouwer JT, Chemello L, and others. Interferon- ribavirin combination therapy for chronic hepatitis C. Digestive Diseases and Sciences December 1996 supplement; volume 41, number 12, pages 131S-134S.

Sherman KE, Sjogren M, Creager RL, and others. Combination therapy with thymosin alpha-1 and interferon for the treatment of chronic hepatitis C infection: A randomized, placebo-controlled double-blind trial. Hepatology April 1998, volume 27, pages 1128-1135.

Farrell GC, Bacon BR, Goldin RD, and the Clinical Advisory Group for the Hepatitis C Comparative Study. Lymphoblastoid interferon alfa-n1 improves the long-term response to a 6- month course of treatment in chronic hepatitis C compared with recombinant interferon alfa-2b: Results of an international randomized controlled trial. Hepatology April 1998, volume 27, number 4, pages 1121-1127.

Heathcote EJL, Keeffe EB, Lee SS, and others. Re-treatment of chronic hepatitis C with consensus interferon. Hepatology April 1998, volume 27, number 4, pages 1136-1143.

Zeuzem S, Lee JH, Franke A, and others. Quantification of the initial decline of serum hepatitis C virus RNA and response to interferon alfa. Hepatology April 1998, volume 27, number 4, pages 1149-1156.

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.

Hepatitis C and HIV: Ribavirin Plus Interferon Study Recruiting

AmFAR (the American Foundation for AIDS Research) is now beginning the first study of treating hepatitis C in persons who also have HIV. Trial sites are now opening in 14 U.S. cities, and a few others may be added.

Volunteers will be randomly assigned to either interferon alpha-2b plus ribavirin, or to the interferon alone (plus a ribavirin placebo). However, those assigned to monotherapy who have detectable virus at week 12 will be assigned to combination treatment starting at week 16; this assignment will be blinded, so volunteers will not know if their regimen has changed. The drug treatment period will last for 48 weeks, with followup for 28 weeks after that.

Volunteers must be HIV-positive and have hepatitis C disease, be at least 18 years of age, and been on stable FDA-approved treatment for HIV (or on no treatment for HIV) for at least four weeks. This study does not have CD4 count or HIV viral load requirements. However, there are 29 exclusion criteria (mostly for specific medical conditions or medications) -- which may make it difficult to recruit the 200 volunteers being sought.

Also, this trial will only pay for the ribavirin and the hepatitis C viral load tests; volunteers are responsible for the other costs. For those unable to afford the interferon, it is being made available through Schering Plough's patient assistance program. (Schering Plough, which has the rights to distribute ribavirin for hepatitis C in the U.S. and which also markets interferon alpha-2b, is providing partial funding for this study.)

The trial will be conducted at medical centers in the following cities:

East: Baltimore, Hershey, Newark, New York, Philadelphia, Providence;

South: Atlanta, Chapel Hill, Miami;

Midwest: St. Paul, Wichita;

West: Los Angeles, Portland, Sacramento.

AmFAR also hopes to open about three more sites in other cities, including San Francisco.

For more information, call Jeffery Smith at AmFAR, 602-340- 1207, who can discuss the trial in more detail and refer you to one of the sites listed above.

Metabolic Changes: Concerns About Heart, Circulatory Risks

A May 2 research letter in The Lancet, by AIDS, lipid, and cardiology specialists at Regions Hospital in St. Paul and the University of Minnesota Medical School in Minneapolis, highlighted growing concerns that high cholesterol and other metabolic changes being seen in some HIV patients may be increasing the risk of heart and circulatory disease.⁽¹⁾ The letter was prompted by two cases of unusual coronary artery disease in young men being treated with protease inhibitors; there has since been a third case. These incidents led to a chart review of 124 patients on protease inhibitors, which found that 33% of them had high enough lipid (fat) concentrations in their plasma to be referred for treatment, either with diet and exercise or with lipid-lowering drugs.

The Regions Hospital HIV clinic has developed interim recommendations, including getting baseline blood tests before starting protease inhibitors, lifestyle changes such as improved diet and stopping smoking, and treatment when necessary according to the U.S. National Cholesterol Education Program (NCEP) guidelines for lowering cholesterol in patients with heart disease.⁽²⁾

In a phone conversation on May 11, lead author Keith Henry, M.D., explained why this problem may be more important than some have realized:

• Cardiovascular disease usually develops over decades; this is why heart attacks usually happen to people who are older. If this process is accelerated in some HIV patients -- either because of the virus, or because of some the drugs used to treat it -- damage could be happening now which could show up increasingly over the next few years. The Regions Hospital HIV Clinic has not had any deaths from heart problems yet, but Dr. Henry has heard of cases from other physicians.

• High cholesterol levels may be a bigger problem than widely realized, since in many of these patients the triglycerides are also high, which can prevent the cholesterol from being measured accurately. But the plasma from many patients "looks like thick cream." The abnormal fat which may be contributing to cosmetic changes in some patients is carried through the circulation, with unknown effects on parts of the body which are not seen. And a modest total cholesterol elevation can be worse than it looks, because it often consists of a combination of an increase in LDL cholesterol (the "bad" cholesterol) and a decrease in the HDL cholesterol (the "good" cholesterol).

• Lifestyle problems, including smoking, poor diet, and lack of exercise, are likely to increase the risk further. Many patients are not on good diets, since in the past the goal has been just getting calories in.

• There are interim measures which can be taken now. The Regions Hospital clinic obtains a fasting lipid profile before starting patients on protease inhibitors, and then 3-6 months after. Abnormalities are treated according to the NCEP guidelines -- just as the same conditions would be treated in HIV-negative persons with heart disease.

References

1. Henry K, Melroe H, Huebsch J, and others. Severe premature coronary artery disease with protease inhibitors. The Lancet May 2, 1998; volume 351, page 1328.

2. National Institutes of Health. Cholesterol Lowering in the Patient with Coronary Artery Disease: Physician Monograph -- National Cholesterol Education Program. September 1997 (NIH Publication 97-3794). This document is available at: http://www.nhlbi.nih.gov/nhlbi/cardio/chol/prof/chol_low.htm

NTZ: Advisory Committee Votes Against Approval

On May 6 the FDA's Antiviral Drugs Advisory Committee voted 9-1 against approval of NTZ for treatment of cryptosporidiosis, which causes severe diarrhea in persons with AIDS. The one community representative on the panel, Michael Marco of the Treatment Action Group (TAG), cast the vote for approval. A number of treatment activist and patient groups (including AIDS Treatment News) had urged that NTZ be approved, despite disappointment that better data was not available. "Even though the quality of data UNIMED has presented is marginal, undeniably there is a documented clinical response with an excellent safety profile" (quoted from the consensus letter).

A government-sponsored placebo-controlled trial (ACTG 336) was supposed to provide the most important data to support the approval. But this study was closed recently when it proved impossible to enroll. Sixty volunteers were needed, but only 10 had entered in 15 months. The main reason the ACTG trial could not recruit is that peoples' health has greatly improved as a result of the new combination antiretrovirals, reducing the incidence of cryptosporidiosis to a fraction of what it used to be. Also, the trial was unattractive because volunteers had to remain untreated until a positive diagnosis was made, and then risk being assigned to a placebo for the first part of the treatment period.

The FDA acknowledged that it would not be possible to get placebo-controlled data for this drug, and invited the company to submit the results it had. FDA analysts could not find proof of efficacy in the company's data.

NTZ, which "has the broadest spectrum of antiparasitic activity ever achieved with a single drug,"⁽¹⁾ is chemically related to metronidazole (Flagyl), but does not have the severe side effects of the latter. Since NTZ is only partially absorbed from the gut, it is most likely to be useful against pathogens in the intestines. Almost everyone familiar with this drug believes that it does have activity against cryptosporidiosis -- although this parasite is difficult to cure in many cases, possibly because it can get into places where NTZ cannot reach it well. In these cases, treatment may need to be continued. Also, there is still disagreement and confusion about the best strategies for dosing NTZ.

For background on NTZ, see AIDS Treatment News #239 (January 19, 1996), #250 (July 5, 1996), #258 (November 1, 1996), and #288 (December 6, 1997).

Comment

We are concerned about the future of NTZ for several reasons:

• A significant number of people will still need this drug. It is approved in Mexico and available there, but most U.S. patients who need NTZ will not know about it, or be able to obtain it easily.

• NTZ may have major uses aside from cryptosporidiosis. It appears to be effective for microsporidiosis as well, although no trial has been done. It may also be an important contribution against giardia and other parasites which can be difficult to treat in some cases, even though there are approved drugs available.

• Diarrhea caused by parasites is often difficult to diagnose -- especially in cost-constrained public clinics or managed-care settings. Patients and physicians should have the option of trying a broad-spectrum treatment which may be effective against organisms which, for various reasons, could not be identified.

What should be done now? Clearly a controlled trial for cryptosporidiosis is not feasible today -- as the FDA, and most of the members of its advisory committee, apparently recognize. What seems to have gone wrong in this case is that once the classical placebo-trial model was rejected, the development of this drug was on new, unfamiliar ground -- and the company did not get the guidance it needed on how to operate in this new environment in a way that would develop data useful for the regulatory process.

We are preparing a separate article on study designs that would be appropriate for NTZ today -- or for similar situations when they occur in the future.

References

1. Dubreuil L, Houcke I, Mouton Y, and Rossignol JF. In vitro evaluation of activities of nitazoxanide and tizoxanide against anaerobes and aerobic organisms. Antimicrobial Agents and Chemotherapy October 1996; volume 40, number 10, pages 2266-2270.

Update on AIDS Wasting and Lipodystrophy: One-Day Seminar in Geneva, June 28

"Update on Wasting, Metabolism, and Altered Body Shape in HIV/AIDS," a one-day seminar for health professionals co-sponsored by Tufts University School of Medicine and the U.S. National Institute on Drug Abuse, will take place immediately before the 12th World AIDS Conference in Geneva, Switzerland, at the Hotel President Wilson. There is no charge for this program, but preregistration is requested. For those who cannot attend in Geneva, a summary will be posted on the Internet one week after the conference. Funding is provided by unrestricted educational grants from Serono Laboratories, Inc., and Bristol-Myers Squibb.

Topics covered include: hypogonadism, metabolic abnormalities, protease inhibitor associated lipodystrophy (8 a.m. to 10:30 a.m.); dietary considerations, micronutrients, anorexia, and protein-energy undernutrition (10:50 a.m. to 12:00 noon); and nutritional support, testosterone and analogs, resistance exercise, growth hormone, and other therapeutic approaches (1:15 p.m. to 4:00 p.m.). Each of the three sessions consists of several talks by experts, followed by a panel discussion. Speakers include Drs. Donald Kotler, Carl Grunfeld, Marianna Baum, Steven Grinspoon, Morris Schambelan, and Marc Hellerstein.

More information and online registration is available at the HealthCare Communications Group site, http://www.healthcg.com/hiv; the summary will also be available on this site. A registration form can also be faxed to 617-636-0472.

Geneva Conference: Call for Alternative and Traditional Healing Practices Material

The Global AIDS Program of the National Council for International Health (NCIH), in Washington, D.C., is helping to organize a symposium on "Alternative and Traditional Healing Practices" for the 12th World AIDS Conference (Geneva, Switzerland, June 28 to July 3, 1998).

The symposium program will include: Research and Traditional Medicine (What has been documented? Have the findings been distributed? How are the findings put to use?); Traditional and Herbal Medicines (examples of what is being used and requested in selected communities); Collaboration Between Traditional and Modern Medical Practitioners (How have collaborative projects been organized? What are the benefits of these collaborations?); and Life Philosophy (Spiritual practices, self-empowerment, meditation, relaxation, etc.).

If you have materials available for distribution at this symposium, please contact Mr. Mohcine Alami at NCIH, 202-833-5900, fax 202-833-0075, email ncihaids@ncihaids.org, by May 31 if possible.

AIDS Vaccine: Major Report Available

On May 18 the AIDS Vaccine Advocacy Coalition will release 9 Years and Counting, a 53-page agenda for action and report on the status of AIDS vaccine development.

The title refers to a speech one year ago by President Clinton, in which he asked, "Today, let us commit ourselves to developing an AIDS vaccine within the next decade... I am prepared to do all I can to make it happen." But today, "the government's AIDS vaccine research program has continued at the same unhurried pace as before with only nominal achievements and developments, and corporate commitment is at an all-time low" (from AVAC press release accompanying the report).

Every day 16,000 people are infected with HIV, and experts agree that only a vaccine will be able to stop the epidemic. A previous AVAC report found that pharmaceutical and biotech representatives agreed that "sustained political leadership by the President, Vice President and the rest of the administration, and scientific leadership by the NIH" was needed. But "this has not yet happened." The new report includes a 19-point agenda for action, including the U.S. government, private industry, and international organizations.

Copies of the report will be available at http://www.vaccineadvocates.org, http://www.thebody.com, or http://hivinsite.ucsf.edu. Or contact the AIDS Vaccine Advocacy Coalition, P.O. Box 40190, San Francisco, CA 94140-0190, phone 415-643-3534, fax 415-821-9131, email avacscott@aol.com.

ISSN # 1052-4207

Copyright 1998 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.