INTRON A (INTERFERON ALPHA 2B, RECOMBINANT)
Interferon is a genetically engineered product originally licensed in 1986 to treat hairy cell leukemia. It is a copy of a protein found naturally in low levels in the human body. It was OK'd by (US) FDA Feb. 25, 1991, to treat hepatitis C. The product, alpha interferon, is the first effective treatment against this form of hepatitis, which affects an estimated 150,000 Americans each year.

According to the manufacturer's (Schering-Plough) literature for using Interferon in the treatment of Hepatitis C: 3 million units per dose 3 times a week Interferon has an effective cure rate of about 25% .

Besides hairy cell leukemia and hepatitis C, alpha interferon is licensed for treatment of AIDS-related Kaposi's sarcoma and genital warts. Schering-Plough Corporation of Kenilworth, N.J., which markets a version of the product under the trade name Intron-A, received approval for the product's use for hepatitis.

Treatment: Interferon has been approved for chronic HCV. Patients are selected for therapy on the basis of persistently abnormal liver function (blood) tests, rather than on the presence or absence of symptoms. It's not known what should be done for patients with mild chronic HCV infection; since some patients with mild disease can go on to develop cirrhosis, a trial of therapy with interferon is usually recommended. It's recommended that such patients be referred to specialists with knowledge in liver disease (gastroenterologist/hepatologists). -- "Prevention, Diagnosis, and Management of Viral Hepatitis", AMA

About half of patients treated with interferon respond, with better blood tests and better liver biopsies. Half the patients who respond relapse once the interferon is stopped. -- "Prevention, Diagnosis, and Management of Viral Hepatitis", AMA

Alpha interferon seems to work better the sooner it is used after infection. However, in many cases of hepatitis C the symptoms get worse again when the treatment is stopped. In one study, half of the chronic hepatitis C sufferers who had responded to alpha interferon had a relapse within six months after treatment stopped. Thus only 25 percent of HCV patients respond favorably without relapsing.

The average six months of injections three times a week are expensive ($75 a week). Many patients also suffer side effects, such as flulike symptoms, a reduction in the number of disease fighting white blood cells, and a decreased number of platelets in the blood. (Platelets are needed for blood clotting.)

Factors most closely associated with response to interferon are:

1. absence of fibrosis or cirrhosis in the pretreatment liver biopsy;
2. HCV genotype other than 1;
3. lower RNA levels in the blood (e.g., less than 2 million/ml); and
4. shorter duration of infection (which often isn't known).

INTERFERON "BREAKTHROUGH" AND "NON-RESPONSE"
Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the eatment, in spite of a complete initial response breakthrough). Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients. - "Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection: prevalence, etiology, and management." - Hepatology Vol. 21 no. 3 pp. 645-9 1995 Mar

A report in the Archive of Virology 1997 ;142(3):535-544 suggests that an inapparent coinfection of the hepatitis B virus (HBV) along with the hepatitis C virus may be implicated in cases of resistance to interferon treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by interferon treatment.

IRON REDUCTION THERAPY
A new study published in the fall issue of American Journal of Gastroenterology, Vol 89, No. 7, suggests that using "Iron Reduction Therapy" along with interferon can result in an effective cure rate in the area of 75-80% and that adding cytokines and antivirals such as ribavirin can improve effectiveness even further. The theory behind this is that viruses need iron to replicate, and by reducing the hepatic iron in the liver you prevent them from replicating. It should be noted that this new procedure is not yet FDA approved and is still in the early trial stages.

Iron is an element required for replication of virtually all virulent microorganisms. Reducing the amount of iron helps to limit the replication of the hepatitis C virus. The role of iron influencing the natural history of viral hepatitis was reported in a study more than 15 years ago ( Blumberg BS, Lustbader ED, Whitford PL. "Changes in serum iron levels due to infection with hepatitis B virus." Proc Natl Acad Sci USA 1981;78:3222-4 ). In this study it was observed that patients with hepatitis B viral infection with higher serum iron or ferritin levels had greater likelihood of development of chronic infections than those with lower levels, who more often resolved their infections spontaneously.

Increases in levels of serum ferritin, iron, and transferrin saturation also have been noted with high frequencies in patients with chronic hepatitis C, and the higher levels have, in general, been associated with lesser likelihood of response to interferon therapy.

Complete responders to interferon have, on average, lower hepatic iron concentrations than do noncomplete responders.

In a report by Hayashi and colleagues ("Improvement of serum aminotransferase levels after phlebotomy in patients with chronic active hepatitis C and excess hepatic iron." Am J Gastroenterol 1994;89:986-8 ) it was reported that iron reduction alone, by repeated venesection (bloodletting), led to significant improvement in serum alanine aminotransferase (ALT) levels in chronic hepatitis C.

RIBAVIRIN
Many hepatitis C patients show a clear-cut biochemical response to ribavirin, with a lowering of liver enzyme levels. However, the ribavirin does not clear circulating hepatitis C virus RNA and relapses occur after they discontinue taking the drug.

INTERFERON AND RIBAVIRIN COMBINED (REBETRON)
Recently the U.S. Food and Drug Administration approved the Rebetron combination therapy (interferon-alpha2b plus ribavirin) for the treatment of chronic hepatitis C patients who have relapsed following alpha interferon therapy. At six months post treatment, 45.7% who received the combination therapy had undetectable virus levels, compared to the 25% response rate to interferon alone.

The recommended dosage for this combination therapy is 3MIU of interferon-alpha2b (Schering-Plough brand name Intron A) injected subcutaneously three times per week and 1000 - 1200mg of ribarivin (Schering-Plough brand name Rebetol) capsules administered orally in a divided daily dose for a duration of 24 weeks. This combination therapy is packaged as Rebetron by the drug company Schering-Plough, with the interferon and ribavirin bundled together in one package. A six-month treatment with Rebetron is estimated to cost between $6,400 and $8,600 depending upon dosage.

The most common side effects associated with the combination therapy are: Flu-like symptoms, such as headache, fatigue, muscle pain, fever, and the destruction of red blood cells which may be severe enough to result in anemia.

Psychiatric disorders have also been reported. Depression is a fairly common side effect, and in some cases it may become severe. Rare cases of suicidal thoughts and suicidal attempts have been reported.

The combination therapy is associated with a significant risk of abnormal fetal development, and women of childbearing potential should not begin combination therapy until a report of a negative pregnancy test has been obtained.

At the present time, the FDA has approved Rebetron combination therapy only for HCV patients who have previously undergone alpha interferon therapy and who have relapsed. It has not yet been approved for "naive" patients (meaning those who have not yet taken interferon alone), but FDA approval for this use is expected shortly. However, physicians can prescribe drugs for individuals for whom they think it will be helpful. Therefore, physicians can prescribe combination therapy for naive patients prior to FDA approval for that specific use.

LOW DOSE ORAL INTERFERON AND HIGH DOSE INJECTABLE INTERFERON - COMBINED
According to a news release from Amarillo Biosciences, Inc, dated May 12, 1997, a study is commencing to test low dose oral interferon alpha as a combination treatment with high dose injectable interferon alpha in hepatitis C patients in Canada and Mexico. The company has compiled preliminary data indicating that pretreatment with low dose oral interferon alpha preconditions patients to respond better to injectable interferon alpha. A clinical trial will be conducted with Dr. Elliott Alpert of Montreal as the principal investigator and another hepatitis expert located in Mexico as co-investigator. The study is expected to eventually enroll 180 patients and could take 2-3 years to complete.

CONSENSUS INTERFERON (INFERGEN)
Consensus interferon, or CIFN, is a synthetic form of one type of interferon. Created by Amgen scientists, the drug has undergone extensive clinical testing for treating hepatitis C, cirrhosis and a form of cancer.

According to the NIH Consensus Development Conference on Management of Hepatitis C 1997:

Consensus interferon at a dose of 9 ug administered tiw for 24 weeks is safe and effective for the treatment of chronic HCV infection in interferon-naive patients and results in a sustained HCV RNA response rate of 12 percent.

When compared to with MU (15 ug) IFN alfa-2b, 9 ug CIFN may result in higher sustained HCV RNA response rates in patients with genotype 1 and in patients with high pretreatment viral loads.

In patients failing prior CIFN or IFN alfa-2b therapy, retreatment with a higher dose of CIFN (15 ug) for 24 weeks results in sustained HCV RNA response rates in 8 percent of nonresponders and 32 percent of relapsers and is well tolerated.

NATURAL SOURCE INTERFERON ALPHA-N3 - HUMAN LEUKOCYTE-DERIVED (ALFERON)
Alferon, produced by Interferon Sciences Inc., is an injectable, natural-source, multispecies alpha interferon produced from human peripheral blood leukocytes which is currently in clinical trials for the treatment of hepatitis C. The preliminary results of the trials are encouraging and further studies are planned. It is thought that the chance of "breakthrough" is less when using natural source interferon, than with the standard interferon alpha 2b preparation. If the results at the end of clinical trials are favorable, the company intends to seek FDA approval of Alferon N Injection for the treatment of hepatitis C by the end of the third quarter 1998.

ROFERON (INTERFERON ALPHA 2A, RECOMBINANT)

LYMPHOBLASTOID INTERFERON (WELFERON, OMNIFERON)

PEGYLATED INTERFERON (PEG-INTRON A)
PEG-Intron A is a modified form of Schering-Plough's Intron A (interferon alfa-2b, recombinant), developed by Enzon, Inc. to have longer-acting properties. Currently in Phase III clinical trials, PEG-Intron A is administered once a week, compared to the normal dosage of 3 times a week for Intron A.

INTERFERON AND GM-CSF - COMBINED
Effects of granulocyte/monocyte colony stimulating factor (GM-CSF) have generally been disappointing: it is expensive, poorly tolerated, and without beneficial effect except perhaps in a rare patient who develops severe neutropenia due to interferon, in whom GM-CSF may permit continuation of higher doses of interferon.

An open label trial of GM-CSF plus high-dose interferon (IFN) alpha 2b was performed in 16 patients with chronic hepatitis C, who either failed to clear virus with 6 months of daily high-dose IFN (5 MU daily) therapy (n = 22) or were considered untreatable because of advanced disease and leukopenia (n = 2). The dose of GM-CSF used was 500 mu g subcutaneously twice weekly, The dose of IFN used was 5 MU daily, Both agents were administered for 4 months. Five of the 16 hepatitis C virus patients responded to combined therapy having previously failed IFN therapy alone. No such differences for responders and non-responders were seen with the hepatitis C virus patients, These data suggest that the combination of GM-CSF and IFN may be more effective at achieving viral clearance than IFN alone. - "A Preliminary Experience with GM-CSF Plus Interferon in Patients with HBV and HCV Resistant to Interferon Therapy," Journal of Viral Hepatitis 1997 ;4:101-106

BETA INTERFERON, RECOMBINANT
According to a report in the Journal of Interferon and Cytokine Research 1997 Jan; 17(1):27-30, the intramuscular administration of interferon-beta (IFN-beta) at a dosage of 6 million units three times per week for 6 months was evaluated in 90 patients included in a multicenter, randomized, controlled trial for the treatment of chronic at the dosage used has little efficacy in the treatment of chronic hepatitis C.

While the efficacy of beta-intereron has been proven to be ineffective when administered intramuscularly, a study reported at the 1996 Annual AASLD conference (" Therapy of Chronic Hepatitis C Non-Responders to Alfa-Interferon: A Preliminary Report of Intravenous Natural Beta-Interferon" ) reports that beta-interferon has been proven to be efficacious when administered by intravenous infusion, and that intravenous beta-interferon can be a well tolerated effective treatment for patients with chronic hepatitis C non-responders to [alpha]-IFN.

Another study reported at the 1996 Annual AASLD conference ("Analysis of Amino Acid Residues 2209 to 2248 of NS5A of HCV-1b in Relation to the Response to Interferon Beta Therapy"), suggests that some HCV patients with genotype 1b who have a mutant type of the NS5A2209-2248 gene are sensitive to interferon beta therapy regardless of lower doses and shorter treatment periods compared to interferon alpha. HCV-1b patients with the intermediate or the wild type of the NS5A2209-2248 gene are resistant to interferon beta therapy.

URSODEOXYCHOLIC ACID (ACTIGALL)
Ursodeoxycholic acid (UDCA) has been used in chronic liver diseaes and can limit hepatocyte injury. The various mechanisms of action of this hydrophilic bile acid include direct cytoprotection, detergent action on dysfunctional microtubules, immunomodulation and induction of hypercholeresis. It has recently been used in the management of chronic hepatitis, cirrhosis, post liver transplant rejection, graft -versus-host disease and acute viral hepatitis, where it not only relieves symptoms of cholestasis but also arrests ongoing hepatocyte necrosis.

According to a study reported at the American Gastroenterology Association Digestive Disease Week meeting in Washington in May 1997 (Treatment of chronic hepatitis C with interferon with or without ursodeoxycholic acid: a randomized prospective trial), combination therapy with UDCA plus interferon was no more effective than interferon monotherapy in inducing a biochemical response in previously untreated patients with chronic hepatitis C. UDCA was, however, useful in prolonging the sustained biochemical response of IFN therapy in this small pilot study

HYPERICIN (VIMRx, HIFRITZEN)
THYMOSIN
Thymosin alpha 1 is a protein produced by the human body, the cow and others which is supposed to enhance the immune system. It is associated with the thymus gland, which shrinks as we get older - yet has important role in immunity. There are over the counter products which take raw cow thymus - dry - defat - and process the gland in tablet form which some claim when taken causes the human body to increase natural production of "thymosin alpha 1". Dr. Burgstiner in Savannha, Georgia, believes he cured himself of hepatitis B by using this formula (telephone 912-355-5755). That preparation is called "Thymic Fractions" and is produced by a company in California called Bio-Naturals at 800-991-7990. The reference to Dr. Burgstiner can be found in Naomi Judd's book " Love Can Build A Bridge" paperback edition - Pages (480-482) Dr. Burgstiner believes that this preparation must be taken with vitamins to act as coenzymes in order to be effective.

There is also a synthetic "thymosin alpha 1" being produced by a company called SciClone Pharmaceuticals - Telephone - 415-358-1446 available only in trials - It is given intravenously and has been - and is currently being studied for use in treating hepatitis B and C - in hepatitis B the results have been promising - and it is now being studied in combination with interferon.

THYMOSIN AND INTERFERON COMBINATION In November 1996, SciClone Pharmaceuticals, Inc. commented on results from a randomized, placebo-controlled, double-blind phase III study in chronic hepatitis C patients receiving a combination therapy of thymosin alpha 1 and interferon alpha-2B. A life-table analysis showed almost 50% of the 65 patients had complete normalization of ALT in the thymosin combination treated group and in less than 20% of the interferon-only treated group. The study showed a statistically significant reduction in ALT levels in the combination group and significant complete normalization of ALT levels, as compared to the interferon only and placebo groups. Also observed were significant early virologic response in patients treated with combination therapy when compared to the interferon arm."

PROTEASE INHIBITORS
HCV protease is one of the proteins that catalyze critical steps in the viral life cycle of hepatitis C. Recent efforts have focused on the molecular mechanism of hepatitis C replication as this has proven to be a successful approach in the treatment of HIV. The combination of HIV protease inhibitors and nucleoside analogs have been the first major breakthrough in the treatment of AIDS. There are similarities between the HIV and hepatitis C viruses as they are both RNA viruses which have a tendency to mutate. The HIV protease inhibitors are aspartate proteinases whereas the HCV protease is serine-based. This makes it unlikely that any of the current drugs being used for HIV would be effective in patients with hepatitis C.

Particular attention is being focused on the NS3 protease domain of the hepatitis C virus as this is an enzyme considered essential for replication of the hepatitis C virus. Recently the crystal structure of the hepatitis C virus NS3 protease domain was reported by two separate groups in the journal, Cell. This will no doubt lead to rapid development of protease inhibitor drugs by a number of biotechnology and pharmaceutical companies who are racing to accomplish this. Other logical targets for inhibition are the NS3 helicase and the NS5b polymerase enzymes as these are also essential for viral replication. It is likely that a number of inhibitor drugs will reach clinical testing phase in the next 18 to 36 months. (As of yet there are no protease inhibitors in clinical trials.) - "Emerging Therapies for HCV," - Scripps Clinic and Research Foundation, Liver Disease Study Group

Shering-Plough has signed an agreement with Corvas International to collaborate on research to seek orally bioavailable inhibitors of a key protease necessary for hepatitis C virus replication.

RIBOZYME GENE THERAPY

ANTISENSE BASED THERAPIES
Antisense drugs are large, highly charged molecules which form DNA-RNA or RNA -RNA hybrids with the target RNA receptor. In the case of hepatitis C this hybrid would form with the hepatitis C RNA which is the viral replicative material. This occurs by simple Watson-Crick base pairing. Once an anti-sense DNA hybrid has been formed it inactivates the viral plication process. - "Emerging Therapies for HCV," - Scripps Clinic and Research Foundation, Liver Disease Study Group

AMANTADINE
Amantadine (trade name Symmetrel) is a drug commonly used in the treatment of Parkinson's disease, and for the prophylaxis and treatment of illness caused by the influenza A virus. It is thought to prevent viral uncoating and thus viral multiplication. Amantidine was recently tested in patients with HCV, and clinical trials will be beginning soon.

(From the 96th annual meeting of the American Gastroenterological Association, Digestive Disease Week , San Francisco, CA, May 21, 1996)

Dr. J.P. Smith presented the results of a recent trial of the antiviral agent, amantadine hydrochloride, in patients with chronic hepatitis C infection who had previously failed to respond to interferon alpha-2b. Twenty-two patients were treated with orally administered amantadine HCl, 100 mg twice a day, for 6 months. These same patients served as their own controls during two intervals of no treatment (24 months before and 12 months after previous treatment with interferon) and during interferon therapy. Twenty of the 22 patients completed the 6-month study of amantadine.

Thirty percent of those patients completing the study demonstrated a complete response to therapy as demonstrated by the normalization of serum alanine aminotransferase (ALT) levels. Forty percent of the patients achieved a partial response (defined as a reduction in ALT of greater than 50%), and 30% failed to respond to amantadine therapy. Responders and partial responders maintained therapeutic benefits 6 months after treatment was stopped.

Two patients were discontinued from the study as a precaution due to cardiac-related side effects. Two patients reported difficulty concentrating, two patients reported constipation, and one experienced insomnia, but none of these patients discontinued the study. There was no observed decrease in WBC levels, nor was there any detrimental effect on the bone marrow attributable to treatment with amantadine.

Dr. Smith noted that the comparative costs of therapy at the Hershey Medical Center were $120 for 6 months of therapy with amantadine HCl vs $3,000 for interferon.

As shown by this study in 20 patients, amantadine HCl (which has the additional benefit of being taken orally vs by subcutaneous injection for interferon) may prove to be a useful alternative to interferon in treating patients with chronic hepatitis C. - "Treatment of Chronic Hepatitis C with Amantadine", J. P. Smith, The M. S. Hershey Medical Center, Pennsylvania State University Hershey, PA

OFLOXACIN
CYCLOSPORINE THERAPY

TRANSPLANT
When does a liver transplant need to be done? This is a very complex issue and must be answered on a case by case basis. Anyone with hepatitis C should be followed by a physician regularly. If signs of progressive disease appear, the person needs to be referred to a gastroenterologist (specialist in digestive diseases and liver diseases). Since hepatitis C is known to progress very slowly, it is not necessary to have a liver transplant until the disease has reached "end stage". Factors to be assessed include the rate of progression of the disease, whether or not complications of liver failure have occurred and laboratory value including albumin, bilirubin, and prothrombin time.

What are my chances with a liver transplant? The survival rate after liver transplant overall is approximately 80% at one year, and 70% at five years. The odds for hepatitis C are approximately the same as for the average liver transplant for another reason.

How long will a new liver last? No one knows how long a transplanted liver can last. The longest reported survivor is 25 years. Ten year survival is commonplace. Hopefully improvements in techniques and medications that are continually occurring will allow most patients receiving liver transplants today to have long productive lives.

Will the hepatitis C be cured by a liver transplant? No. Hepatitis C can live in cells other than in the liver. Once the old liver is removed and the new one is connected the hepatitis spreads back into the liver within the first weeks to months after the transplant. This is the bad news: at present we have no way to make the hepatitis C go away completely. The good news is that overall results with hepatitis C after liver transplantation is good. Although the disease comes back it does not seem to greatly damage the liver in the majority of cases. It is possible for the hepatitis to return so severely that the new liver fails, but this is uncommon. Long term results (ten years) are difficult to interpret since we have only been able to diagnose hepatitis C since 1990. Many people that were transplanted in the 1980's may have gotten hepatitis C at the time of transplant, since the blood supply was contaminated then. These people may have different chances compared to those that had transplant because of hepatitis C. Realistically it is likely that hepatitis C will be a long term problem in liver transplant recipients that harbor the virus. We do not yet know how bad a problem this will be.

What can be done for hepatitis C that comes back in a transplanted liver? No treatment has been shown to change the course of the disease. Interferon alpha is being tried in experimental settings without much success.

I have hepatitis B and hepatitis C. Can a transplant still be done? Yes, some transplant centers are currently doing liver transplants for this indication.

Where do donated livers come from? Livers are donated, with the consent of the next of kin, from individuals who have brain death, usually as the result of a head injury or brain hemorrhage.

How can I donate my organs? If you wish to be an organ donor, carry an organ donor card and place an organ donor sticker on your medical identification card.

Statistics to date:

• There are 6,684 on waiting list for livers
• There were 3,922 done in 1995
• 804 died waiting

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