ALTERNATIVE APPROACHES TO HEPATITIS C

The following memo describes one person's approach to the management of a

chronic hepatitis C infection, using a combination of natural

immunostimulants and other products that can help to keep the liver

healthy. The patient in question is not symptomatic at this stage, and

therefore has decided to defer interferon treatment for the time being in

the hope that better treatments will soon be available.

The following is excerpted from a memo written to seek advice from medical

practitioners. It describes the regime being used, and asks some questions

about it. It then goes on to summarize a number of other products that

could be considered for those looking for alternative or complementary

approaches to interferon treatment.

A number of background papers are attached giving more information about

some of the products described.

It should be stressed that the author of this memo is not a medical

practitioner of any sort, and has simply spent considerable time reading

medical literature in this field. The approach described here is in no way

a substitute for qualified medical advice.

Text of memo follows:

...For a variety of reasons, I have decided against interferon therapy at

this stage. First, the side effects are often highly unpleasant. Second,

the chances of success (meaning sustained response) of standard therapy

against genotype 1a are in the range of 20% or less. Third, some studies

suggest that interferon treatment in patients with normal ALT levels is as

likely to do harm as good, and can sometimes cause a temporary flare up in

the hepatitis.

Fourth, a number of interesting therapies are being researched or are in

trials, and I am inclined to wait for improved therapies. The possible new

treatments include: synthetic hypericin; thymosin alpha 1 (Zadaxin)

combined with interferon; ribavirin combined with interferon; "natural"

interferon produced by human lymphocytes, as opposed to the standard

recombinant interferon currently in general use; amantadine and ofloxacin

alone or in combination with interferon; famcyclovir; and, further off but

of great interest, treatments using anti-viral molecules such as protease

inhibitors, "anti-sense" therapies and therapeutic DNA vaccines.

Set against this, of course, are two considerations. First, there is

evidence that the success rate of interferon treatment declines somewhat

with the length of time the person has the infection. Second, there is an

element of risk with each year the infection continues.

CURRENT REGIME

My reasoning has been that the most important thing to do for the time

being is to strengthen the body's immune defences against the virus. This

can maximise the (small) chance of a spontaneous clearance of the virus,

and in any case can help the body to minimise the replication of the virus.

The evidence available from clinical trials, though scanty, suggests that

immune stimulants tend to reduce serum ALT levels and improve liver

histology in chronic hepatitis. Indeed, I believe that this is one of the

ways that interferon-alpha therapy itself works - not only having direct

anti-viral action, but stimulating the body's own immune system as well.

Among other considerations, I have taken a particular interest in natural

immunostimulants that increase the body's own production of

interferon-alpha. Since interferon-alpha injected has an effect on the

virus and sometimes eliminates it, it may be that inducing interferon-alpha

production in the body could at least help to control the virus, without

the negative side effects of injected interferon.

Whenever possible twice a day, I take moderate doses of the following

supplements. I will briefly summarize here the case for each one, and

include in separate documents more detailed information.

* Thymus

Cow or pig thymus extract is a proven immunostimulant. This is thought to

be because it contains peptide molecules that survive digestion and

stimulate the body's production of T-cells. It has been shown to increase

the percentage of children, and to a lesser extent adults, who clear the

hepatitis B virus. (In the studies on children it was taken twice a day

for a year.) One of the thymic peptides which has been produced

synthetically (thymosin alpha 1) is being tested on adults with hepatitis C

in combination with interferon, with good results. When it was used alone

in a very small trial on ten hepatitis C patients, one out of the ten

cleared the virus. As far as I know it has not yet been tried on children

with hepatitis C, nor have trials on hepatitis C been done with a more

"natural" thymus extract such as thymomodulin containing a broader range

of compounds.

Since it has been speculated that thymus extract works better on children

than on adults with hepatitis B because their immune systems are more open

to immunomodulation, it is not inconceivable that the same might be true

with hepatitis C.

The immunostimulatory action of one of the thymus extracts on the market

has been decribed by researchers as similar to that of interferon-alpha,

and it has been speculated that there is some chemical similarity between

some thymic peptide molecules and interferon-alpha molecules . In vitro

tests have shown that thymic peptides can induce interferon-alpha,

inteferon-gamma and IL-2 production by human immune cells.

A Dr. Carson Burgstiner in Georgia, USA claims to have had good success

with both hepatitis B and C by using a combination of thymic extract and

vitamins.

Since in moderate doses it has no more side effects than any other meat

product, there is nothing to lose, and potentially much to gain, by

including it together with other immunostimulants. I use thymus gland in

tablet form, derived from free-range cattle in the Americas (where there is

no BSE.)

* Shiitake mushroom (Lentinus edodes).

The shiitake is the world's second most popular edible mushroom, and is a

regular part of the Chinese and Japanese diet. There has been extensive

clinical research on it in Japan, and it has been shown to have a

remarkable range of positive effects. It is a proven immunostimulant,

which acts against both infection and cancer, as well as lowering blood

cholesterol and having anti-thrombotic activity. One of its constituent

polysaccharides, lentinan, used as an immunostimulant, is one of the most

heavily used anti-cancer drugs in Japan, and has been shown to improve

survival rates with a number of different cancers (there is evidence that

it can also have an effect against liver tumours.)

One of the most interesting aspects of the shiitake is that it contains at

least three compounds that are strong interferon inducers. This has been

shown in tests in vitro, on animals, and in cancer patients. (I have not

yet checked to find out which variety of interferon is induced.)

Several therapeutic products extracted from the shiitake mushroom have been

used against hepatitis B in Japan, and at least one of them has been shown

to be directly viricidal against the hepatitis B virus.

I have found capsules (brand name Len-Shii) produced by a Californian

company that contain all parts of the shiitake mushroom in powdered form,

and nothing else. Since people have been eating the shiitake with no

ill-effects for thousands of years (it has also been tested for toxicity in

recent years, and found to be entirely safe), there seems once again little

to lose by taking a good dose morning and night.

* Yogurt.

Humble yogurt has been shown to be an immunostimulant and

interferon-inducer. Medical researchers at the University of California

have found that consumption of two cups of yogurt a day leads to a 400%

increase in interferon-gamma levels in the blood. No one has tested for

interferon-alpha, but it has been remarked that the cells producing the

interferon-gamma are also cells that produce interferon-alpha.

Yogurt has also been found to cause natural killer cells to attack invaders

more vigorously, and to boost the body's production of antibodies.

In order to achieve these effects, we need to eat at least two cups of

yogurt a day.

Since eating yogurt can do nothing but good, there seems every reason to

have two cups a day. Danone has a product on the market in some countries

called Actimel, which contains together with the normal yogurt culture the

additional immunostimulant lactobacillus casei.

* Echinacea purpurea.

Echinacea was first used by Native Americans to promote wound healing and

to boost resistance to disease. Just as almost all the research on the

shiitake has been done in Japan, extensive research on echinacea has been

done in recent years in Germany. Medical practitioners there often use it

as an immunostimulant, for example with people prone to influenza and other

respiratory infections.

A number of clinical trials have shown that it reduces the length and

severity of flu symptoms, and reduces the recurrence of Candida infections.

Some of its constituents have been shown in tests in vitro and in vivo to

induce interferon-alpha production. I have spoken to two of the leading

researchers on echinacea in Germany, who say that it is conceivable that

taken orally it could increase the level of interferon-alpha in the body.

Echinacea has been found in tests to have anti-viral activity against

several viruses, and its effects have been described by researchers as

"interferon-like."

Extensive tests have been done to check for adverse side effects. In one

Austrian study, patients were given 600 injections of echinacea juice over

10 years. No negative effects have been found. With high doses there is

very occasionally a temporary temperature rise in the order of 0.5 degrees.

This is believed to result from the body's production of interleukin and

alpha-interferon, and is seen by doctors using it as a positive sign that

the echinacea is stimulating the immune system.

Medical practitioners who use it normally suggest a regime where it is

taken for six weeks followed by a two-week break. This is not because it

has any negative effects, but because there is evidence that the body

adjusts to it over time and its stimulatory effect wears off somewhat with

long-term continuous use. I follow this advice.

* Propolis.

Known as the immune system of the beehive, propolis has been found to have

a number of anti-microbial effects. In one study, a compound contained in

propolis was found to reduce viral DNA synthesis by the herpes simplex 1

virus 32-fold. In another study, compounds contained in propolis were

found to inhibit the infectious activity of the flu virus.

Propolis has also been found to improve liver function in liver-damaged

rats and mice. It has been shown to have an anti-inflammatory effect

comparable to some non-steroidal drugs.

Propolis has been found to activate macrophages, and to help protect

against infections such as colds and flus.

Propolis is widely used, and is available in most health food shops. It

has been tested for adverse side effects. None whatsoever have been found.

* Astragalus membranaceus

Astragalus is one of the most widely used herbs in traditional Chinese

medicine. A number of studies by medical researchers have shown that it is

an effective immunostimulant.

Studies in both humans and laboratory animals have demonstrated its ability

to help protect against infection from the viruses that cause influenza and

the common cold.

At the University of Texas Medical Center in Houston, researchers tested

damaged immune cells from cancer patients, compared against cells from

healthy subjects. Astragalus extracts were able to fully restore the

function of cancer patients' immune cells. In some cases, the compromised

cells were stimulated to greater activity than those from healthy subjects.

Astragalus has been found to be an interferon inducer in humans. The

sketchy information I have gathered so far on this suggests that it

stimulates alpha, beta and gamma interferon. It has been found to induce

other cytokines, such as interleukin-2. It has also been found to

stimulate production of T cells and antibodies.

A Chinese herbal preparation including astragalus with other herbs has been

found to be effective in improving liver function among hepatitis B

patients. Another combination was found to help prevent liver fibrosis in

liver-damaged rats.

I have seen a reference to a study which found that 86% of chronic

hepatitis patients receiving injections of astragalus extract showed

improvement in a randomized, controlled trial, but I have not yet seen the

report on the study itself.

Interestingly, in studies on some other viruses causing cervicitis,

astragalus has been found to be synergic with interferon-alpha therapy.

From what I have read, astragalus does not appear to have any negative side

effects.

* Milk thistle (silybum marianum)

Milk thistle, used in herbal medicine since Roman times, has been the most

extensively studied of the plant substances known to have hepatoprotective

activity. Its most commonly used extract is called silymarin.

Three double blind trials in chronic hepatitis patients in 1977 found

significant histological differences between those treated with silymarin

and those on placebo. A Phase II clinical trial in Italy in 1993 with IdB

1016 (a complex of silybin, one of the components of silymarin) in patients

with viral or alcoholic hepatitis showed a significant positive effect on

liver function tests.

A double blind trial in Italy in 1978 in patients with acute viral

hepatitis found that aminotransferase levels decreased faster after

silymarin treatment than for those in the placebo treated group. A 1992

study in Italy of patients with cirrhosis found that silymarin "seemed safe

and ameliorated the biochemical indices of cytolysis," including in

patients with hepatitis C related cirrhosis.

A 1989 double blind study, reported in The Netherlands, of 170 patients

with cirrhosis found a significant reduction in death rate among those

treated with silymarin compared to the control group. A 1982 study in

Scandinavia of 97 patients with liver disease found significant

improvements in liver function tests and liver histology in the group

treated with silymarin.

Milk thistle has proved remarkably effective in protecting the livers of

people with Amanita mushroom poisoning. Normally about half the people who

have eaten Amanita mushrooms die of liver failure; in a study in a German

hospital where 60 consecutive patients were given intravenous silymarin,

none died.

Among other ways that milk thistle may work, it is thought to be a powerful

antioxidant, to stimulate production of new liver cells and to act as an

anti-inflammatory in the liver. It works in the case of mushroom poisoning

by strengthening the outer membranes of liver cells against Amanita toxins.

It is a source of quercetin (a compound in which some onions are also

rich) which is believed to have anti-viral properties. It is said to

reduce fat deposits in the liver, and may protect liver cells by inhibiting

the formation of leukotreines which can damage liver cells. It is believed

to be an interferon inducer.

Dr. Andrew Weil, in his currently bestselling book "Spontaneous Healing",

says: "I recommend this herb to all patients with chronic hepatitis and

abnormal liver function, and have seen cases of normalization of liver

function in persons who took it every day for several months and also

worked to improve their diets and lifestyles ... You can stay on milk

thistle indefinitely."

The clinical studies generally report no major side effects resulting from

long-term treatment. However, minor side effects are possible at higher

doses - primarily headache, irritability, and minor intestinal upset (eg.

loose stools.) I have seen no sign of these in my son, or in myself, since

I have also been taking it to check for side effects.

* Vitamin E.

Vitamin E is a powerful antioxidant, which combats "free radical" molecules

that damage cell tissues and the "peroxidized fats" that damage not only

the immune system but also the liver. Vitamin E deficiency seems to be

associated with cirrhosis and poor metabolism of fats. It also appears to

be an immune stimulant.

Jeffrey Blumberg has studied the effects of vitamin E at the US Department

of Agriculture's Tufts Nutrition Center. He says: "Researchers noticed some

time ago that vitamin E deficiency was associated with depressed immune

responses. The work that I've done has shown that adequate, and even more

interestingly, above normal levels of vitamin E seem not only to maintain,

but boost immune function."

At the U.S. National Institutes of Health Consensus Development Conference

on Management of Hepatitis C, held in March 1997, Herbert L. Bonkovsky,

M.D. contributed a paper entitled "Other Options for Treatment of Hepatitis

C". His paper is included among the attachments. In it, he makes a brief

reference to Vitamin E:

"...in chronic hepatitis C (as in other liver diseases), oxidative stress

increases and plasma and liver GSH concentrations decrease... Favorable

effects of vitamin E (alpha-tocopherol) on oxidative stress and activation

of the cascade of fibrogenesis were reported recently."

Researchers in the Department of Medicine of the University of California

believe they have found evidence that vitamin E prevents molecular changes

that are associated with the development of cirrhosis, reports the

Hepatitis C Handbook.

Dr. Minhhuyen T. Nguyen in Philadelphia is currently carrying out a study

of the effects of vitamin E in patients with hepatitis C. Dr. Nguyen says:

"Vitamin E is an antioxidant. There is some evidence to suggest that in

addition to direct cytopathic effects, hepatitis virus(es) can cause free

radical injuries as well. The goal of this experiment is to determine

whether Vitamin E is effective in reducing LFTs in Hepatitis C resistent to

alpha-IFN."

A 1996 article in the journal "Free Radical Research" contained the

following report:

"Oxidative stress, with the depletion of antioxidant nutrients, has been

found to occur in patients with liver disease. Previous studies have

demonstrated decreased plasma levels of vitamin E, a crucial fat-soluble

antioxidant, in patients with three diseases that affect the

liver--hemochromatosis, alcoholic liver disease, and Wilson's disease. This

report demonstrates that such decreases also occur in severe cases of viral

hepatitis.

"Plasma vitamin E levels were measured in 48 patients with various types of

viral hepatitis and 32 healthy controls. In patients with highly elevated

serum transaminase levels, vitamin E levels and vitamin E/lipid ratios were

substantially and significantly lower than in controls. In one patient with

acute hepatitis A, vitamin E levels rose progressively as transaminase

levels decreased during recovery. These findings indicate that free

radical-mediated liver injury may play a role in the pathogenesis of viral

hepatitis and suggest that vitamin E might be of value in the treatment of

this disease."

The U.S. Recommended Daily Allowance for vitamin E is 30 IUs daily for an

adult. Vitamin E is considered relatively safe. It has shown no side

effects at intakes up to 300 IUs daily, an amount that is 10 times more

than the U.S. RDA. It is possible that doses higher than that should be

avoided, since some researchers think that, while Vitamin E supplements

boost the immune system, if the intake is too high it may repress the

immune system.

Taken together, these various supplements, combined with a good diet,

plenty of sleep, exercise and laughter (all of which have been shown in

studies to be important for immunity), should help to give the immune

system the best possible chance of successfully controlling the virus.

QUESTIONS ABOUT THIS REGIME

The fact that my son's ALT levels have returned to normal suggests that the

regime he is on may be doing good, as one might expect based on the

information I have summarized. Certainly it shows no signs of doing harm.

I nevertheless have a few questions about it. I would be interested in any

comments you might have.

* Could there be any negative synergistic effects among the herbs and other

supplements that I am using?

I have no reason to think there are, but this seems worth checking,

particularly with a trained herbal practitioner in relation to the three

herbal products: astragalus, echinacea and milk thistle.

* Is there any danger that with these mild doses of immune stimulants, we

might help the virus to develop resistance which will then render

ineffective a stronger treatment later on?

This question has arisen in my mind for several reasons.

Rapid development of resistance is one of the main problems with HIV

therapies. I believe that rapid mutation is a feature HCV has in common

with HIV.

I have noted that in one or two studies researchers have found that

hepatitis C patients who, before interferon treatment, have higher

endogenous levels of interferon-alpha in their blood have a slightly lower

response rate to treatment. This struck me as odd. One explanation might

be that the virus has already developed some resistance to the interferon,

in the presence of low levels which aren't enough to kill the virus off

entirely. If some of our supplements do induce extra interferon production

by the immune cells, this might be a result. There may be quite different

explanations for the research findings, however.

Possibly contradicting these findings, Amarillo Biosciences "has compiled

preliminary data from patients in Canada and Japan indicating that

pretreatment with low dose oral interferon alpha preconditions patients to

respond better to injectable interferon alpha." They have a clinical trial

underway now to test this approach.

I have also noted that Hayashi et. al. in 1991 studied the effects of

treating chronic hepatitis patients with interferon after a short course of

glycyrrhizin (an extract from licorice root which has been found to induce

interferon) and found that the immunomodulation provided by glycyrrhizin

before administration of interferon may be an effective treatment for

patients with chronic hepatitis B. But in both cases, of course,

pre-treatment for a limited period with an interferon inducer or with oral

interferon is a different matter from a long-term regime which raises

endogenous interferon levels.

I have thought about this issue of resistance in relation to thymus

products. One of the most interesting new products now in trials is

Zadaxin, made by SciClone Pharmaceuticals. This is a synthetically

produced version of thymosin alpha-1 (one of the most active

immunostimulant components of thymus extracts.) In combination with

interferon, it is significantly improving response rates to treatment. It

is administered by injection, and being a pure synthetic product it may

have a stronger effect than its naturally derived cousins. It is

attractive as a treatment because it has virtually no side effects.

It is possible that by taking thymus products now, one may help the virus

to develop resistance to any later use of the stronger product. Whereas if

we one day attack the virus without warning and "out of the blue" with

large doses of Zadaxin, it might succumb before it can mutate.

I saw an anecdotal report recently in an internet conference on hepatitis

in which I participate, where a patient had started taking the thymus and

vitamin product developed by Dr. Burgstiner specifically for hepatitis. At

first his ALT levels fell steadily, then they returned to their normal

fluctuations. His doctor speculated that the virus might have developed

resistance.

This concern has led me to refrain for the moment from using thymomodulin,

which is perhaps the most studied thymus extract. It is a somewhat refined

extract, and has been shown in many studies to be a powerful and effective

immune stimulant. What my son is getting is tablets made of thymus itself,

rather than a refined extract. Since thymomodulin, or the injectable

thymosin alpha-1 that is available, are almost certainly more powerful

products, I speculate that they might be more likely to lead to viral

resistance to Zadaxin than the low-powered product I am using now. But

this is complete guesswork.

The same concern has led me to set aside natural hypericin from St. John's

Wort (hypericum perforatum). Hypericin is one of the most promising

products entering trials now, since it seems to be a strong anti-viral

agent against HCV. The product in trials that I know of is a new synthetic

hypericin produced by VIMRx Pharmaceuticals, a pure and potentially

powerful product. There may be another hypericin product being studied in

a collaboration between doctors in Israel and New York, but this too is

likely to be a highly refined product. Various naturally derived hypericin

products are available, but these could conceivably induce resistance to

the more powerful therapy that may be only a year or two away.

* Is it possible that stimulating the immune system could have some

negative effects?

Could immunostimulants, if they fail to clear the virus, have the effect of

increasing inflammation of the liver, or even increase the likelihood of

the autmoimmune complications which sometimes accompany HCV? With regard

to inflammation, there seems to be some reason to believe that the liver

damage resulting from HCV is immune-mediated, perhaps involving T-cells and

other immune responses. (See for example Vento's research, the second to

last item in the attachments labelled "Other herbal products, etc.")

A recent study in Japan with ten chronic hepatitis C patients using

Cyclosporine A, a potent immunosuppressant widely used in organ

transplantation, found that nine of the ten patients saw their ALT levels

improve, though there was no reduction in viral load. (A summary of this

study is included following Vento's.)

Based on what I have seen, my own view is that this is not a serious

concern. Immune stimulants such as interferon-alpha or thymosin alpha-1

have been shown to generally improve liver function during treatment, even

when they don't clear the virus.

(To this might be added the caveat that it is unknown to what extent the

effect of these two products on HCV works through the immune system and to

what extent they may have direct anti-viral effects, which could in theory

compensate for any negative effects of stimulating the immune system.

Particularly in the case of thymosin, though, the immune stimulant effect

is believed to be the most important.)

Interferon-alpha may result in autoimmune side effects in a small

percentage of cases, but I have seen no suggestion that the other immune

stimulants that I am using have any such effects. Indeed, from what I have

read, thymosin alpha-1 or other thymus products have no negative side

effects at all.

* Could milk thistle, while having a beneficial effect on the liver,

repress some immune cells and possibly have a long-term negative impact on

the immune response to HCV?

The studies I have already summarized strongly suggest that milk thistle

has a positive effect on chronic viral hepatitis, and therefore that this

shouldn't be a concern. But it may nonetheless be a question worth asking.

There have been a handful of studies on the effects of milk thistle

compounds on immune cells, which do not all point in the same direction. I

have grouped the abstracts I have at the end of the attached collection of

papers on milk thistle. The 1988 in-vitro study in Milan by Meroni et. al.

suggests that silybin inhibits human T-lymphocyte activation. The 1990

study in Budapest by Kádár et. al. suggests that silibinin (in the product

Legalon-70) enhances the motility of human neutrophils. The 1995 study by

Alarcón de la Lastra et. al. in Seville, studying gastric ulcers in rats,

suggests that silymarin's inhibitory effect on neutrophils may partly

account for its protective effects against ulcers. The 1990 study in

Hungary by Deak et. al. of silymarin's effect in patients with alcoholic

hepatitis suggests that it improves the depressed immunoreactivity of the

patients, including raising the T-cell percentage.

Having no training in immunology, I am unable to assess these reports in

more than a superficial way. At first glance, there seem to be some

contradictions between the results of the different studies (which is no

doubt quite normal in research of this kind.) But I do recall that studies

of the immune response to HCV suggest that the T-cell response is rather

important. Therefore I noted in particular the Meroni study suggesting

that some T-cells may be inhibited by milk thistle.

I also notice in the brief report of a study by Sonnenbichler et. al.,

which I have included, that milk thistle may increase the formation of RNA

in liver cells. This might conceivably be related to milk thistle's

suggested ability to help promote the formation of new liver cells. But is

it imaginable that it could also aid in the replication of RNA viruses, of

which HCV is one? I have no reason whatsoever to think that it does so,

but the question crosses my mind.

The proof of the pudding is in the eating, as we say in English. If milk

thistle improves the condition of hepatitis patients, that's the main

thing. But if you have any thoughts on these questions, I'd be grateful to

hear them.

I also recall seeing on Medline a couple of years ago a report of an in

vitro study which raised questions about possible cell damage caused by

milk thistle, perhaps raising doubts about its long-term use. I didn't

keep a note at the time of where the study was published. I have seen no

other references to this in the literature, however.

* If, as I have read, astragalus also acts as a diuretic, should we be

concerned about possible side effects such as loss of potassium?

If so, we might for example consider potassium supplements. Or eat plenty

of bananas.

* Should I break the regime regularly?

As mentioned above, researchers in Germany told me that doctors there

usually stop echinacea treatment for two weeks every two months or so - not

because of any ill-effects, but because its stimulating effect can wear off

with continuous use. I believe that herbalists will often recommend breaks

in other herbal regimes. Should I be taking a regular break from any other

of the products I am using?

HepC BC