Ray C. Wunderlich, Jr., M.D.

According to the Centers for Disease Control (CDC), approximately 4 million Americans are infected with the hepatitis C virus. The CDC has estimated that 20 to 50% of infected hepatitis C patients will develop liver cirrhosis, and 20 to 30% of those will go on to develop liver cancer or liver failure requiring a liver transplant. Hepatitis C infection contributes to the deaths of 8000 to 10,000 Americans every year. This toll is expected to triple by the year 2010 and exceed the number of annual deaths due to AIDS, according to the CDC. There are also other nonliver diseases associated with hepatitis C viral infection.

Infection with the hepatitis C virus occurs from blood transfusions, needle sharing, working in a medical environment, and sexual contact. Often, the infected individual does not know how he or she acquired this potentially lethal virus that has a high affinity for liver cells.

Hepatitis C used to be called non-A/non-B hepatitis and was not considered a significant health risk. The growing awareness of this new viral epidemic has resulted in more research being conducted on hepatitis C than on any other cause of liver disease.

Diagnosis

People are diagnosed with hepatitis C when a blood test reveals a positive reading for the hepatitis C antibody. While the hepatitis C antibody test can diagnose whether one may have the disease, the blood test that identifies and measures the overall viral load is the polymerase chain reaction test (PCR). Standard tests to measure hepatitis C activity include the liver function tests SGOT, SGPT, GGTP, and alkaline phosphatase. Hepatitis C antibody tests can accurately diagnose hepatitis C infection, but they are not always precise in evaluating the success of treatments.

How Hepatitis C Damages The Liver

The hepatitis C virus does most of its damage by latching onto molecules of iron and delivering massive free-radical damage to liver cells. These free radicals can mutate cellular DNA to cause hepatocellular carcinoma, and they can kill large numbers of liver cells. Liver dysfunction wreaks havoc throughout the body. Successful eradication of the hepatitis C virus from the body requires that iron levels in the liver and blood be at very low levels, and thus it can be said that high stores of iron in the liver preclude successful therapy against the hepatitis C virus. It is mandatory to reduce iron levels in the body before initiating treatment with interferon-ribavirin combination therapy.

Hepatitis viruses have been shown to induce liver inflammation, cirrhosis, and primary liver cancer via free-radical attacks on liver cells. The ensuing liver dysfunction causes havoc throughout the body. Antioxidant supplements, in addition to antiviral therapies, are used by innovative physicians to protect against the liver-destroying free radicals generated by the hepatitis C virus.

In areas of China with high rates of hepatitis B and primary liver cancer, epidemiological surveys demonstrated that high levels of dietary selenium reduce liver-cancer incidence and hepatitis B infection. Animal studies showed that selenium supplementation reduced hepatitis B infection by 77.2% and precancerous liver lesions by 75.8%. In a 4-year trial on 130,471 Chinese, those who were given a selenium-spiked table salt showed a 35.1% reduction in primary liver cancer, compared with the group given salt without selenium added. A clinical study of 226 hepatitis B-positive people showed that one 200-mcg tablet a day of selenium reduced primary liver-cancer incidences down to zero. Upon cessation of selenium supplementation, primary liver cancer incidences began to rise, indicating that viral hepatitis patients should take selenium on a continuous basis. Selenium also appears to be effective in suppressing the hepatitis C virus.

In patients with hepatitis C, particularly those who are HIV-positive, a systemic depletion of glutathione is present, especially in the liver. This depletion may be a factor underlying the resistance to interferon therapy. This finding represents a biological basis for N-acetyl cysteine (NAC) and glutathione supplements as adjuvant (assisting) therapies. Hepatitis C patients should also consider taking 30 to 60 grams a day of whey protein isolate concentrate to boost liver glutathione levels to help protect liver cells against hepatitis C-induced free radical liver damage. High-quality whey-protein supplements can also help to boost immune function. The fact that hepatitis C often becomes active in the body after age 40 indicates that age-associated immune decline plays an important role in the progression of the disease.

Conventional Therapy

The FDA-approved therapy to treat hepatitis is a 6-month regimen of injectable alpha-interferon. The standard treatment consists of 3 million IU injected subcutaneously 3 times a week for 6 months, always prescribed and supervised by an infectious-disease specialist. Even in patients who do not respond to interferon therapy by itself, inasmuch as there still is viral activity in the liver, there is a significant reduction in primary liver cancer. Many hepatitis C patients have refused interferon therapy because of its toxic side effects and low rate of response (20%), but the fact that a recent study showed that interferon therapy confers a 75% reduction in the risk of lethal primary liver cancer in hepatitis C patients warrants consideration of a 6-month therapy with interferon (combined with ribavirin).

About half of patients with chronic hepatitis C treated with interferon will not have a biochemical or virological response. In an attempt to improve that statistic, one study showed that the removal of a pint of blood every 2 weeks until iron deficiency was produced led to an improvement of 15% in the interferon treatment. Furthermore, elevation of storage iron in chronic hepatitis C has been associated with a poor response to interferon. Currently, however, the overall evidence shows that iron removal (via phlebotomy) lowers the transaminase blood tests but may not substantially improve responsiveness to alpha-interferon treatment. Nevertheless, iron reduction could delay the progression of liver injury to fibrosis and cirrhosis. Therefore, phlebotomy is usually recommended for even mildly iron-loaded patients with hepatitis C virus infection. (The production of anemia, whether by ribavirin or by phlebotomies, always must be considered a potential risk to patients struggling to obtain health.) Forty to fifty percent have an initial response to alpha-interferon treatment, but most relapse. Only 15 to 20% of patients with chronic hepatitis C have a sustained response to interferon therapy.

The Rationale For Using Ribavirin with Interferon

Hepatitis C patients exhibit, at best, only a 20% response to treatment with alpha-interferon. (Initially, 40 to 50% may have a response, but most relapse). When the antiviral drug ribavirin is combined with interferon, the response rate improves two- to tenfold. The standard regimen consists of 800 to 1200 mg a day of orally administered ribavirin taken in 3 divided doses for 6 months (200 to 400 mg, 3 times a day). At this time, however, the FDA says that ribavirin can be used only after a patient has already failed a 6-month regimen of alpha-interferon therapy. The FDA's concern about ribavirin stems from the appearance of anemia seen in 10% of treated patients. (The anemia disappears after cessation of ribavirin therapy but could have a deleterious effect upon already sick individuals.)

Ribavirin can be bought over-the-counter in many countries and has been safely used by millions of people for more than 10 years. The FDA insists, however, that ribavirin is a dangerous drug. The experience of the Life Extension Foundation indicates otherwise. Ribavirin is a broad- spectrum, antiviral drug that Foundation members have used safely since 1983 to suppress acute and chronic viral infections. There has been no report of the toxicity that the FDA warns about. Perhaps it is the simultaneous use of folic acid, vitamin B12, and melatonin (along with the other nutrients) that have protected these individuals against anemia. Published studies show that folic acid and vitamin B12 are especially effective in treating anemia and that the hormone melatonin can protect against chemotherapy-induced anemia. It might be a good idea for those taking ribavirin to also take at least 500 mcg of melatonin at night in addition to the daily intake of folic acid (800-1600 mcg a day) and vitamin B12 (1000-3000 mcg a day).

There are numerous studies showing ribavirin to be a relatively safe agent. Both the FDA and Life Extension Foundation agree that all who take ribavirin should have blood testing done first and repeatedly thereafter at 2-week intervals while on the drug in order to detect anemia at an early stage (and to either treat it successfully or to withdraw the medication). Those who use ribavirin for less than 14 days to treat acute influenza (or just plain flu) have little reason to be concerned about anemia.

The published research shows that 10% of hepatitis patients taking ribavirin for 6 months will develop anemia. Anemia can pose a serious risk for those with coronary artery disease, pulmonary disease, or pre-existing blood disease. The FDA, however, mandates that hepatitis C patients first fail the brutal 6-month regimen of alpha-interferon therapy before being allowed to try ribavirin, even though interferon appears to be the more toxic agent. The brutal side effects of interferon treatment include aches, pains, malaise, gastrointestinal symptoms, and depression, which has led to suicidal behavior and actual suicides. These and other adverse reactions are contained in the standard warnings for the use of the drug.

Based upon the review of published studies about ribavirin toxicity, it is the Life Extension Foundation's position that the FDA exaggerates the potential adverse effects of ribavirin and denies this drug to hepatitis C patients for reasons that are not scientifically based. One example of ribavirin's lack of toxicity can be read in the conclusions of a study by French investigators who stated, "long-term administration of ribavirin is well tolerated and may be beneficial in controlling the progression of chronic hepatitis C." (Zoulin et al. in the J. Viral Hepat. [England], May 1998, 5 [3]:193-98).

If anemia is already present, ribavirin should not be used. Ribavirin use must also be avoided in a pregnant or lactating woman, as well as in a woman seeking to become pregnant and in a man seeking to impregnate a woman. Individuals with coronary artery disease, severe pulmonary disease, and kidney disorders should be closely monitored for ribavirin-induced anemia and kidney toxicity.

Using Interferon and Ribaviron Together

At the University of Florida, Gainesville, the effectiveness of interferon alone versus interferon and oral ribavirin was studied in patients with relapses of chronic hepatitis C (after standard interferon treatment). There were 172 patients who received interferon and placebo, while 173 patients received interferon and oral ribavirin, 1000 to 1200 mg a day (depending on body weight) for 6 months. At the end of the study, 82% of those treated with interferon and ribavirin had no detectable hepatitis C virus in their serum, compared to only 47% in the interferon-placebo group. The investigators concluded that in patients with chronic hepatitis C who relapse after treatment with interferon, therapy with interferon and oral ribavirin results in higher rates of sustained virological, biochemical, and histological response than treatment with interferon alone. The researchers' comments on the "toxicity" of ribavirin further support the view of the Life Extension Foundation: "Combined therapy caused a predictable fall in hemoglobin concentrations but otherwise had a safety profile similar to that of interferon alone." In other words, no toxicity except the known anemia effect of ribavirin was encountered. One strongly suspects that these medically managed patients, too, failed to receive the folic acid, vitamin B12, and melatonin that, for the most part, has characterized those Foundation members who have used oral ribavirin to treat a variety of viral disorders since 1983 without a single report of the toxicity about which the FDA warns.

When interferon and ribavirin were used together for initial treatment of chronic hepatitis C, investigators, using similar criteria of response and similar doses to the previous study, found a 38% response rate with interferon and ribavirin versus a 13% response with interferon alone. The best response rate was obtained with 48 weeks (rather than 24 weeks) treatment duration.

The hepatitis C virus inflicts massive damage to liver cells, which often leads to cirrhosis and primary liver cancer. It is crucial for those infected with the hepatitis C virus to eliminate the virus from their bodies before it causes irreversible liver damage. Since interferon therapy by itself is only effective in 20% of cases, the FDA's ban on using combination interferon-ribavirin therapy sentences 80% of hepatitis C patients to treatment failure and severe liver damage.

The scientific literature supports the use of ribavirin and interferon as the primary treatment for most hepatitis C infections, yet the FDA chooses to ignore the science, thus condemning tens of thousands of hepatitis C patients to liver degeneration and death.

The Life Extension Foundation believes that the FDA's suppression of ribavirin provides a commonsense example of just how incompetent this agency is at evaluating scientific data. The Foundation has spent hundreds of thousands of dollars exposing the FDA's failure to approve of ribavirin because this issue provides blatant evidence of FDA fraud and incompetence.

Additional Ribavirin Studies

In a double-blind study published in the Lancet (1998, 351 [9096]:83-87), 100 patients were randomly assigned to treatment with interferon in combination with ribavirin or placebo for 24 weeks. The primary endpoint to the study was eradication of the hepatitis C virus. The findings of this study showed that 36% of patients in the interferon-and-ribavirin group experienced elimination of the virus from the blood compared with 18% of patients in the interferon-and-placebo group. The scientists concluded that the patients with high levels of the hepatitis C virus in their blood should be treated with interferon and ribavirin.

The Lancet study showed that the addition of ribavirin to interferon therapy doubled the number of hepatitis C patients who experienced eradication of the virus from their blood. This new Lancet report confirms previous studies showing a consistent 50% improvement in hepatitis C therapy when ribavirin is added to standard interferon therapy.

While the FDA has not approved ribavirin as the primary therapy to treat hepatitis C, your doctor can legally prescribe it to you. You probably won't get insurance reimbursement, however, since the FDA doesn't approve of ribavirin until after interferon therapy fails. The brand name for the FDA-approved ribavirin drug is Rebetol.

Most people use ribavirin by itself for short periods (2 to 10 days, 600 to 1200 mg a day) to knock out common flu viruses, or to treat lethal infections such as viral cardiomyopathy, Hanta virus, viral encephalitis, or influenza. There are over 2000 published studies that discuss ribavirin, and only 261 of these studies mention toxicity problems. Here are summaries of some of the published literature concerning ribavirin and toxicity:

Long-term therapy in humans using combination ribavirin and interferon to treat hepatitis C enhances the therapeutic efficacy two-to threefold without increasing the toxicity (Scandinavian Journal of Gastroenterology, Supplement [Norway], 1997, 32 [223]:46-49).

Treatment of measles patients with ribavirin resulted in shorter and less severe disease, as well as fewer complications, compared with patients in the placebo group. Ribavirin was well tolerated. There were no side effects or changes in laboratory values that could be associated with drug-related toxicity (Clinical Therapeutics [USA], 1981, 3 [5]:389-96).

Ribavirin enhances the efficacy, but not the adverse effects, of interferon in chronic hepatitis C. A meta- analysis of individual patient data from European centers shows that the sustained response rate was significantly higher for the interferon-ribavirin combination therapy than for interferon or ribavirin mono-therapy. No serious adverse events were observed. The efficacy of interferon-ribavirin therapy appears to be enhanced two- to threefold over interferon mono-therapy in all major subgroups of chronic hepatitis C patients tested. In view of its acceptable toxicity profile, interferon-ribavirin combination therapy is a candidate for the new standard therapy for chronic hepatitis C (Journal of Hepatology [Denmark], 1997, 26 [5]:961-66).

The FDA wants hepatitis C patients to first fail interferon therapy before being allowed to use ribavirin and interferon, despite the above three studies showing little or no toxicity.

The efficacy and toxicity of ribavirin (and of another antiviral drug called ddl) given for 6 weeks were investigated in the murine acquired immunodeficiency syndrome model. The results showed a significant protection against splenomegaly, lymph-adenopathy, and hypergammaglobulinemia in mice treated with ribavirin by itself at the human equivalent dose of 1800 mg a day. Ribavirin (and the other antiviral drug) protected against the loss of T cells in spleen and restored the capacity of splenocytes to proliferate after activation with a mitogenic agent. Moreover, the drug combination resulted in a protection of the spleen and cervical lymph node architectures and a regression of germinal centers. Toxicity to the blood appeared at a human equivalent dose of 9000 mg a day of ribavirin (Journal of Pharmacology and Experimental Therapeutics [USA], 1996, 279 [2]:1009-17).

This study shows that 7 to 14 times more ribavirin than what is administered to humans produces blood cell toxicity. Humans usually take 600 to 1200 mg a day of ribavirin.

Ribavirin protects mice against the effects of retrovirus infection at doses of less than or equal to the human equivalent dose of 3,600 mg a day, but induces severe blood cell toxicity at doses less than or equal to the human equivalent dose of 7,200 mg a day (Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology [USA], 1996, 12 [5]:451-61).

The effects of testicular toxicity of ribavirin and its reversibility in mice were evaluated. At the human equivalent dose of 2,520 mg a day, there was mild testicular damage after six months. At the human equivalent dose of 5,400 to 10,800 mg a day there was significant testicular damage after six months. Upon cessation of treatment, essentially total recovery from ribavirin?induced testicular toxicity was apparent within one to two spermatogenesis cycles, which was consistent with negligible effects (Toxic Substances Journal [USA], 1994, 13 [3]:171-86).

The FDA uses this study to support its position that most hepatitis C patients should not receive 1200 mg a day of ribavirin.

To evaluate the efficacy of oral ribavirin, 24 patients with chronic active hepatitis B were put on a course of treatment with 800 to 1000 mg a day ribavirin and/or interferon. Ribavirin, alone and in combination with interferon-beta, decreased hepatitis B virus levels in most patients to approximately half of baseline levels. Interferon alone exerted the most inhibitory effect on hepatitis B virus activity. Ribavirin was well tolerated, but the dose was transiently reduced in two cases because of mild anemia, although all patients completed the treatment schedule. The combination of interferon and ribavirin did not appear to result in greater toxicity. These results indicate that ribavirin suppresses hepatitis B virus replication, although its effect is less than that of interferon, and that it may be useful as adjunctive therapy for chronic hepatitis B (Hepatology [USA], 1993, 18 [2]:258-63).

When developmental toxicity of ribavirin was examined, few if any developmental malformations were present that could be related with confidence to the drug. Several malformed fetuses were present in the highest dose level tested in rats (only 720 mg a day human equivalent) from days 6 through 15 of pregnancy. When evaluated for effects on reproduction and postnatal survival in rats, ribavirin at human equivalent doses of 4,320 to 6,480 mg a day produced statistically significant and/or clearly dose?related increased incidences of fetal resorptions, abnormalities, and reduced postnatal survival. Most significantly, pregnant baboons (most similar to humans) given ribavirin orally at human equivalency levels of 4,320 mg to 8,640 mg a day during critical periods of differentiation and organogenesis were reported to have produced no adverse effects on in utero development (Journal of the American College of Toxicology [USA], 1990, 9 [5]: 551-61).

CAUTION: Nevertheless, based on contradicting studies, pregnant women should avoid antiviral drugs.

The FDA says that ribavirin has produced embryonic damage in all "adequate" studies, but clearly there are studies showing that ribavirin does not always produce teratogenic effects.

Ribavirin was tested to determine its effects on the offspring of male rats. Human equivalent doses of 3,600 to 14,400 mg a day were administered for five days. Ribavirin was regarded as being devoid of any mutagenic potential demonstrable by a rat- dominant lethal assay (Mutation Research [Netherlands], 1987, 188 [1]:29-34).

CAUTION: Despite this positive study, humans involved in reproduction should avoid antiviral drugs such as ribavirin.

To assess safety, tolerance, and the clinical and laboratory effects of oral ribavirin in patients with AIDS, the AIDS and the AIDS-related complex (tests) were performed. Nine of ten patients with AIDS had a CD4 count of less than 100, and all patients with the AIDS-related complex had a CD4 count of less than 200. Oral ribavirin was administered in the high dose of 1200 mg twice daily for 3 days followed by 600 mg a day for up to one year. Ribavirin treatment was well tolerated, with anemia requiring transfusion in one of the ten patients with AIDS [who was] receiving the drug for 8 weeks; no other significant toxicity occurred. Six of nine patients initially positive for HIV-1 in blood became negative during ribavirin treatment. Six of nine patients with AIDS had a twofold improvement in lympho-proliferative response with ribavirin treatment. The conclusions were that 600 mg a day of ribavirin was well tolerated and safe in the patients with severe AIDS and the AIDS-related complex (Annals Internal Medicine [USA], 1987, 107 [5]:664-74).

HIV infection can itself induce anemia, so it is not surprising that 10% of patients required a transfusion. To reiterate, there are now more effective drugs than ribavirin approved by the FDA to treat HIV.

Based on a review of the published studies about ribavirin toxicity, it is clear that the FDA is grossly exaggerating the potential side effects of ribavirin and is denying this drug to hepatitis C victims for reasons that are not scientifically based.

Summary
Complementary Therapies

The Life Extension Foundation's protocol for hepatitis C includes

1. The standard dose of alpha-interferon (3 million IU injected subcutaneously 3 times a week for 6 months) prescribed by an infectiousdisease physician. Interferon is the FDA- approved therapy for treatment of hepatitis C. However, it works only in a minority of patients when used without ribavirin.

2. 1000 to 1200 mg a day of ribavirin (taken in 3 doses) for 6 months. Ribavirin increases the effectiveness of interferon therapy by up to tenfold.

3. The standard doses of Life Extension Mix and Life Extension Herbal Mix. Please note that some hepatitis C patients encounter liver enzyme elevations in response to the moderate doses of vitamin A, niacin, and beta-carotene in Life Extension Mix. If your liver-enzyme levels elevate after starting Life Extension Mix, discontinue it and take separately the other nutrients contained in Life Extension Mix. Beta-carotene possesses unique immune- enhancing benefits that could help suppress the hepatitis C virus, but some hepatitis C patients cannot tolerate it.

4. High doses of green tea polyphenols (300 to 900 mg/day and garlic (2000 to 4000 mg/day of a high-allicin garlic supplement) to reduce serum and liver iron levels to a minimum. Iron promotes hepatitis virus-induced liver injury and precludes successful treatment with interferon. Verify that liver iron levels have been reduced before starting interferon therapy. Some people must donate blood before going on interferon-ribavirin therapy in order to sufficiently reduce iron levels.

5. Liver-protecting nutrients and immune-boosting therapies such as 200 mg of milk thistle extract, twice a day; 500 mg of licorice extract, 3 times a day (monitor blood pressure to make sure licorice does not elevate it); 800 mcg a day of selenium; 1200 mg a day of N-acetylcysteine; and vitamin C ranging from 4000 to 10,000 mg a day.

6. S-adenosylmethionine (SAMe) for the purpose of protecting and restoring liver cell function destroyed by the hepatitis C virus. SAMe is in clinical trials in the United States for treating liver cirrhosis, and published research shows a significant benefit. The high cost of SAMe may preclude some hepatitis C patients from being able to afford it. The suggested dose of SAMe is 200 mg, 3 times a day to be taken with the methylation-enhancing agents trimethylglycine (TMG), in a dose of 1000 mg, twice a day; folic acid in the dose of 800 mcg, 3 times a day; and methyl cobalamine (a form of vitamin B12) in the dose of 5 mg, twice a day (taken by sublingual administration).

7. Alpha-lipoic acid, 250 mg 2 times a day to boost glutathione levels in liver cells.

8. L-glutathione, 500 mg, 3 times a day.

9. Whey protein concentrate/isolate powder, 30 to 60 grams a day (to boost immune function and liver cell glutathione levels).

10. Grape-seed extract (85 to 95% proanthocyanidin) 100 mg, 2 to 3 times a day (to protect against free radicals in the liver).

11. Make sure serum iron levels are at the lowest possible tolerable levels (ideally below 60 mcg/ dL of blood). As long as anemic symptoms do not appear, lower iron as much as possible, under physician's supervision (refer to Hemochromatosis protocol for iron-lowering suggestions).

12. Melatonin, 500 mcg to 6 mg at bedtime.

(See the Life Extension Immune Enhancement protocol for additional suggestions.)

For more information. Contact the American Liver Foundation, (800) 223-0179.

Product availability: Life Extension Mix, Herbal Mix, silymarin (milk thistle), licorice, garlic capsules , selenium, alpha lipoic acid , glutathione , whey powder , N-acetyl cysteine, vitamin C , Green tea capsules (regular and decaffeinated), SAMe, . Order by calling 1(800) 544-4440 or Online. Ribavirin can be obtained from Mexican pharmacies and imported for personal use. A directory of offshore companies that ship ribavirin to Americans for personal use may be obtained by writing the International Society for Free Choice, 9 Dubnoc Street, 64368, Tel Aviv, Israel.