Seminar Summary June 20, 2002, 6:30-7:30 pm

Topic: Preventing and Treating Side Effects of HIV Therapy
Presenter: George M. Carter
Notes by: Brian Varner, George M. Carter
Location: Knox County Health Department, Knoxville, TN
For: Tennessee AIDS Support Services, Inc. (TASSI)

Speaker's Bio
George M. Carter has been an activist since he joined ACT UP/New York in 1989. ACT UP is the AIDS Coalition to Unleash Power, a direct action, in-your-face political action group. He's been working on a variety of issues since that time but spent a lot of his time working on treatment issues. This has included studying how HIV causes disease in people to try to figure out other ways of managing the disease. He has written articles for a great number of AIDS newsletters and magazines, attended many conferences and given many presentations over the years. He was the director for Treatment Information Development for DAAIR, a not-for-profit buyers' club for so-called alternative treatments. Recently, in his frustration over the inadequate amount of data for these kinds of treatments, he and others, including folks from Columbia University, started the Foundation for Integrative AIDS Research (
http://aidsinfonyc.org/fiar/index.html). They hope to do clinical studies both in the United States and abroad, where drug treatment is not readily available. (Also known as FIAR as in "Fight fire with FIAR")

Summary

It's important to first give definitions of "Complementary Medicine" versus "Alternative Medicine". Complementary Medicine is an approach designed to enhance a person's existing therapy. In the United States, most physicians treating HIV disease, use traditional western medicine to treat HIV and the range of opportunistic infections that can be associated with HIV infection.

Alternative medicine is a term to describe a non-standard approach compared to traditional western medicine. Alternative medicine may include use of vitamins and supplements, a change in dietary content and/or a change in daily routines, such as exercise and meditation and other stress reduction techniques.

It is important to note that in both traditional and non-traditional treatment systems, individual needs call for individual approaches and that people may meet their needs using a variety of treatment systems.

Mr. Carter, for example, currently uses a non-traditional "alternative" approach to treat his condition, which happens to be a Hepatitis C (HCV) infection. Speaking openly about his yeas as an IV drug user, George told our group about being addicted to heroin and how he contracted HCV by sharing needles with other users. His particular infection is of the HCV genotype 1 A variety which does not respond well to current traditional methods of treatment. (The best so far for this genotype appears to be Pegasys, a pegylated form of alpha interferon, plus ribavirin--but even at the best, it's only a 50-50 shot.) Thus, he chooses to employ the use of supplements such as an iron-free multi-vitamin, B-complex, extra vitamin C, Milk Thistle and a combination of herbs (an alternative approach) until better treatments come along.

George hopes that one day, using an "Integrative" approach to treatment, the differences that exist between traditional western medicine and complementary or alternative medicine will "dissolve" so we can talk about "Treatment" for all diseases without such distinctions.

Allopathic Medicine vs.? Integrative Medicine

Currently, western medicine (sometimes referred to as allopathic) is "reductionist." This means that you break down the problem into little pieces and figure out what is causing the problem and attack it. The traditional approach to treating HIV infection has been to determine T-cell and Viral Load counts first, then to prescribe a drug regimen designed to increase and decrease these counts respectively.

This approach can potentially overlook problems with the pancreas or the nervous system, problems with cholesterol and many other indicators of a person's overall health.

There are other systems of medicine that evaluate the whole person (holistic). These systems look at where you are such as Chinese medicine, traditional systems of Africa, the Caribbean and India. In India, there are several major systems, including Ayurvedic, Unani, Siddha and Tibetan medicine.

Each system uses various methods for diagnosing peoples' ills. However, it may be better to say that they diagnose imbalances that the physician then employs various means to correct and bring a person back into balance.

A variety of diagnostic approaches are utilized. Pulse taking is used in most traditions, much like western medicine, but in a more sophisticated way. While in the West, we use the rate of the pulse and the pressure, more experienced physicians in ancient system identify a variety of other attributes. In Chinese medicine, for example, the pulse may be identified as slippery, weak or deficient, wiry and so forth. In addition, practitioners look at your tongue, nose, eyes, urine; they may palpate (thump) on various parts of the body. Again, there are many ways that similar observational techniques as well as history taking are utilized in allopathic medicine as well.

Other aspects of eastern traditional medicinal systems may sound odd to our ears. You may have too much yin or yang, be too cold or too damp, etc. The Spleen or other organs may be described in different ways. These descriptions sometimes correspond with medical terms we're more familiar with. For example, Inflammation parallels the concept of Heat in Chinese medicine. The overall diagnostic picture from these perspectives then leads to prescriptions that include modifying diet, exercise, meditation/relaxation or other spiritual practices, and often times herbs, minerals, animal products or other interventions, designed specifically to restore balance.

These observations are taken to help design a course of treatment that helps you get yourself back into "balance" rather than the approach Western medicine often takes, which is often more limited to "here's a bug, here's a drug."

This is not to discount some very important drugs used in Western medicine like penicillin for example, which is very good a killing a variety of bacterial infections. However, over time we began to see that penicillin wasn't effective against other infections, such as viral infections. We also began to see problems with toxicity (development of allergies) in some people and that certain strains of bacteria were resistant to penicillin. No system is perfect--each has their strengths and weaknesses.

From our perspective as patients, George thinks we will be the ones to build the bridges that creates new synergies between different systems of medicine. Basically, we're only interested in what works.

There are other approaches that talk about the body being out of balance, where treatment is not reduced to "take this pill and be done." Rather, our whole way of living is taken into consideration, how we move or exercise. For example, Yoga as brought to us from India is part of the complete system of treating these imbalances.

Making Choices

There are many things we can do in our treatment that are free. Another aspect of alternative treatment is meditation. Just the simple act of breathing and focusing on the breath--not being distracted but merely observant of the thoughts and feelings that arise and try to take our concentration off the breath--can be enormously helpful. Simple calisthenics (like push ups and sit ups), walking and running are all free. Weight lifting can be done even by simply filling a sock with sand or rocks.

Here, George warned our group to beware of fundamentalism, which in light of recent events, can lead people to do very weird things. However, "a tradition that helps you [if that includes prayer] can't be denied." George also noted that some studies have shown that people who don't deny their disease, tend to do better overall.

Meditation through breathing is a way of letting our thoughts happen, but not letting them distract us. Concentrating on the simple "in breath, out breath" can help direct us to a quiet, serene place we can go. Meditation can help us "settle the silt and mud out of our life." Meditation can help us see how we can choose how we deal with things in life.

Meditation can help us feel our emotions fully and completely and let them go--or at least not let them dictate our behavior and responses to the world.

There are many techniques used in other treatment systems that we may not fully understand. There is a technique called "Moxibustion," which involves burning a cone composed of herbs on a meridian. What does it accomplish? We don't really know. (George readily admits that when he says "we" don't know, he means himself and western medicine which has not clinically evaluated this approach, as far as he knows. It is not to imply either that it is a useful or worthless approach. Knowing the ways we are ignorant is also important!)

Another medical system people talk about is homeopathy. This approach is based on the idea that "like cures like" and may involve outright poisonous substances. However, they are repeatedly diluted, with the compound being shaken between dilutions, to a degree where little of the original substance is almost completely gone. Studies on homeopathic remedies have borne out mixed results. Some show good effect for some indications, while other interventions failed. Why this should ever work at all is not yet clear. It's enough to know that some systems can work, not necessarily exactly how they work. [Note to the side, though--there have not been any homeopathic remedies that have been found to be useful for HIV disease.]

What's the rationale for using any of these systems in the context of HIV? There are more reasons that one might think.

In George's work with ACT UP/New York, he wrote an extensive table that listed treatments against HIV as well as opportunistic infections. These tables included information on pharmaceutical drugs as well as alternative and complementary treatments that were being tried. Concurrently, he worked in the Pathogenesis Working Group of ACT UP's Treatment & Data Committee. Pathogenesis is the big word used to describe the processes that occur that allow disease to develop. Patterns of pathogenesis began to emerge that helped to shape the structure of these tables. Indeed, where the first versions of the table started with antivirals like AZT and ddI, it eventually evolved to include nutritional interventions as the first place to start with treatment.

Pathogenesis and Therapeutic Implications

How does HIV cause AIDS? That is, what is the pathogenesis?

George referred to the standard model of how the HIV virus infects a T-cell (via the CD-4 receptor and co-receptors), how HIV uses its reverse transcriptase enzyme to transform the HIV RNA (genetic material) into DNA and then integrates the new HIV DNA into the host cell's genome. He noted how HIV protease cuts up the major proteins produced by the DNA so that new virus can form and bud off through the surface of the T-cell. The standard model of infection is only part of the truth: there are a lot of other things going on that we don't hear much about. For example, lots of T-cells die that aren't infected.

One can start by asking, where is all this activity with HIV going on? Most of the body's T-cells are located in gut associated lymphoid tissues (GALT). The intestines are lined with tiny hair-like processes called "villi" where both T cells and HIV-attacking T cells are located. All this immune system and viral activity can stunt the growth of villi and limit their ability to absorb nutrients in the gut. This partly explains why the levels are reduced of many vitamins and minerals such as selenium, zinc, B-vitamins and retinoids.

Other clinical data tend to support these observations. For example, Hogg and his group from Canada have observed that people with HIV need to take in more calories than their HIV-negative counterparts. However, what they didn't talk about so much was the need to identify the best source for those calories. Eating the wide range of colorful fruits and vegetables will provide many of the important antioxidants that can help to fight HIV disease--or at least slow it down. Taking in more whole grains is excellent for the digestive tract. Avoiding soft drinks, fried, greasy food and other "empty calorie" junk food is also just common sense. Many of these so-called foods make it harder for the body to work trying to digest them and they provide none of the nutrition the body needs. With antiretroviral drugs, hepatitis and other problems adding burdens to an already stressed liver, why not utilize food as your first tool in fighting disease?

Indeed, a critical aspect of his presentation was the fact that what we put into our face is one of our first levels of choice. Much of what we do in life may be guided by choices we make unconsciously. But HIV forces us to be more aware of the preciousness of life. All along the way, we can make choices about whether to have a cigarette or not, eat something or not--and choose what we eat. The power is in our hands!

The effects of those choices accumulate. Healthier choices will help the body to be stronger. It's not rocket science--it's biology!

But is food enough? Some data suggest it isn't. An early epidemiological study showed that people who took a simple multi-vitamin had a 30% reduction in the rate of progression. While not a cure, it is certainly an inexpensive intervention that may help millions--and could be provided to nearly every HIV-infected individual on the planet at very little cost. Subsequent studies in Africa of B-complex and other interventions also tend to support these findings.

So there is but one example of how understanding how the disease develops leads us to a therapeutic implication. Inflammatory activity in the gut reduces the levels of micronutrients--and taking a multivitamin can help to offset this and indeed even reduce the rate of HIV disease progression to AIDS dramatically.

There are other aspects of pathogenesis that can help guide our treatment choices. One can look at cells such as macrophages, which can also be infected. When David Ho developed the "tap-and-drain" model, we didn't know about resting cells. But Ho knew that the macrophage was infected, as can other cells that have a CD4 receptor. Nonetheless, Ho developed a model of "hit hard, hit early" on the theory that starting as soon as possible might help to rid the body of all HIV. This seemed a little too hopeful (while also being a pharmaceutical company's wet dream) even at the time. Macrophages aren't as susceptible to treatment by antiretrovirals. They may go on to continue causing damage because HIV causes them to lose a co-receptor that can fully activate T cells. (This might be one of the reasons that some uninfected T cells die as well.)

We now know that "hit hard, hit early" doesn't really help everyone. The wrong theory or model of HIV pathogenesis led to too many people getting too much treatment or treatment too early. Now, the NIH is saying to wait to begin therapy because the drugs are very toxic for long-term use, resistance to the drugs eventually develops, and there aren't really any clinical data to support the notion of starting treatment with a higher T-cell count. (The one exception is if a person can be capture IMMEDIATELY after being infected--even before the body produces the antibodies to HIV; sadly, few people are captured that quickly.) Latest recommendations suggest that one wait until the T cell count hits 350 and then, based on many issues including how fast (or slowly) T cells are falling, consider treatment between 200-350. Below 200 it's a pretty good idea to get started on antiretrovirals! This is because when immunity is impaired that much, the risk of opportunistic infections increases dramatically.

One can also look at how HIV damages other systems beside the immune system. HIV attacks the nervous system, specifically, the glial cells resulting in inflammation and an elevated production of interleukins that can kill neurons. This can result in neuropathy and/or dementia. One of the causes of this is a condition called oxidative stress. A study is being conducted of a substance known as acetylcarnitine to evaluate its effects in managing neuropathy.

The endocrine system that controls the flux and flow of hormones is also affected. Both men and women eventually see declines in testosterone with disease progression. The therapeutic implication is even recognized by most mainstream physicians: testosterone replacement. In addition, other interventions may help. Megace (progesterone) is a women's hormone used to treat wasting in men but only added fat weight. Might it be helpful for women? Also, the hormone dehydroepiandrosterone (DHEA) becomes depleted in many individuals, often resulting in an increase in cortisol. Supplementing may be helpful for some folks, as well to offset fatigue related to the decline in DHEA.

AIDS can now be better described as Acquired Immune Dysregulation Syndrome. For example, while loss of T cells is clearly the "Deficiency" part of the definition, excessive production of inflammatory cytokines, B-cell hyperactivation and other aspects are representative of the problems arising from increased--but not healthful--immune activity.

Oxidative Stress

Each cell carries out a tightly knit balance of redox reactions (short for reduction-oxidation). Free radicals are "hungry" for electrons and will grab them from anywhere, even the surfaces of cells. This can cause damage to cell membranes, proteins, DNA and other structures that cells need to function properly. A good example is a burn caused by the sun that causes free radical tissue damage via ultraviolet radiation in the epidermal tissues of the skin.

In HIV, the increased oxidative stress can lead to a depletion of glutathione (GSH). GSH is found in virtually every cell in the body in high concentrations. It is one of the mops the body uses to help stop the free radicals that are generated when the immune system is busy fighting HIV. When glutathione levels decrease, the rate of progression increases.

GSH is made up of three amino acids (the building blocks of proteins) which include cysteine, glutamine and glycine. The body has plenty of glycine and usually there is a enough glutamine (or glutamic acid). So often what the body needs in a state of severe oxidative stress is the amino acid cysteine: it's the "rate-limiting" step of refreshing the pool of glutathione. Cysteine itself can be toxic, so the supplement people have studied in HIV is NAC (N-acetyl-cysteine).

NAC is relatively inexpensive and it's something for which PWA's can advocate to have added to the TennCare formulary. This is being considered in many states by grassroots organizations. The problem now is that the voracious greed of the pharmaceutical industry has resulted in ADAP and other programs in many states being destabilized and resulting in waiting lists just to receive antivirals.

Antiretroviral Drug Side Effects

There are a wide array of side effects that are caused by antiretrovirals. A variety of different publications from Houston Buyer's Club and DAAIR (www.daair.org). At the DAAIR site, click on the button "Countering Toxicities" found at the left. You can download a complete and comprehensive document as a pdf file. In addition, these clubs (listed at the end) often provide supplements at much lower cost than local retailers.

Mr. Carter's time was limited so he focused the issue of lipodystrophy. Lipodystrophy is a catch-all term for many different types of side effects such as hypercholesterolemia, hypertriglyceridemia central adiposity or buffalo hump, peripheral lipoatrophy (loss of fat in arms, legs and face) and insulin resistance/diabetes. There are probably several distinct mechanisms that cause it

One mechanism that may describe some aspects of lipodystrophy is mitochondrial toxicity. Usually there are lots of mitochondria running around in cells. They serve to produce energy for the cell in the form of ATP (adenosine triphosphate). This occurs when an electron transport chain of proteins embedded in the membranes of the mitochondria undertake a series of reactions that have, as by-products, the production of free radicals like hydroxyls and so forth. The mitochondria has defense mechanisms in the form of antioxidants like glutathione, catalase and superoxide dismutase to take care of that damage.

Nucleoside analog drugs (like AZT, d4T, ddI) can damage the DNA found inside mitochondria, resulting in fewer mitochonria inside cells. The cell's whole oxidative need becomes compromised. Mitochondria require a type of enzyme (a protein that speeds up reactions) called polymerase gamma to build their own DNA. This polymerase is very similar to the polymerase(s) HIV uses to make it's own proteins and viral RNA, thus, antiretroviral drugs can (and do) interfere with the mitochondrial ability to replicate.

Coenzyme Q10, B vitamins (especially thiamine and riboflavin) and carnitine can be helpful in treating mitochondrial toxicity. (Part of the evidence for this comes from hereditary diseases like "MELAS" which is treated with these supplements.)

Carnitine is available as a prescription called "Carnitor." Carnitor is indicated for the treatment of primary deficiency of carnitine as evaluated by serum, red cell and/or low tissue carnitine levels. It has also been used to treat high triglycerides and, to a lesser extent, elevated LDL cholesterol. This drug helps to bring fatty acids into the cell's mitochondria. The amino acid, carnitine, can be found through buyer's clubs and some health food stores but it is very expensive unfortunately, which is why it may make more sense to get it prescribed.

Another form of carnitine is acetyl-L-carnitine which crosses the blood brain barrier. It is also very expensive but it may help to alleviate peripheral neuropathy. Currently, a clinical study is underway.

In lipodystrophy, especially the loss of fat to face, limbs and butt, and its treatment with supplemental systems, we won't see sudden changes overnight. Patience is needed as we address the use of supplements and changes in diet. So far, there are no data that suggest that peripheral atrophy will be treated by supplements. However, some of the antioxidant and mitochondrial protecting activities may help to prevent it or slow its development. This idea remains to be clinically evaluated.

Conezyme Q10 (CoQ-10) is a protein found embedded in the membrane of the mitochondria. It too has been used to treat mitochondrial diseases and a disease that causes damage to the heart (cardiomyopathy) caused by many things, including chemotherapeutic drugs like adriamycin. The best dose is uncertain but perhaps 60 mg/day to start (however it is very expensive). It can also help to manage bleeding gums.

One botanical that can be very helpful is Milk Thistle (latin name, Silybum marianum) as it is very good in treating toxic liver. An NIH study by Steve Piscitelli, PhD. and reported by NATAP (reporting on the first conference on HIV Pathogenesis in Buenos Aires, Venezuela in 2001) noted that use of milk thistle did not have a deleterious effect on protease inhibitors. In fact, if anything, it somewhat increased the plasma level of some PIs. Look for milk thistle standardized to 80% Silymarin, and consider using 100-150 mg 3 x day. It may also help to replenish depleted glutathione stores. As with most supplements, it's probably best to start with a low dose and work up. Milk Thistle has been shown in many studies to help normalize or reduce elevated liver enzymes.

There are a lot of options for statins in cholesterol management. Statins are very costly and can be toxic. Due to interactions with antiretroviral drugs, only a select few can be used. Other interventions that may help to reduce the "bad" LDL and increase the good "HDL" include niacin, guggul lipids, carnitine, hawthorn and garlic. It may be best to avoid excessive garlic intake if taking saquinavir because one study showed it can reduce saquinavir levels significantly. FIAR hopes to conduct a study to evaluate some of these alternatives in the near future.

Bitter melon (Momordica charantia) has been studied for its effects as an anti-HIV intervention. Alone it has some benefit. It may also help to address problems with increased blood sugar that may arise due to drug side effects. It may reduce the dosage needed for insulin. Consider this option with your healthcare providers.

Indeed, on a separate note, Mr. Carter pointed out that a variety of botanicals have been studied for their anti-HIV properties. Individually, they show some modest benefit in delaying progression overall. But AZT doesn't do much better when taken on its own. He hopes that FIAR will be able to do some clinical studies of combinations of botanicals to see if progression can be slowed or treatment interruptions can be prolonged.

Clearly, there are many other side effects and far more interventions that can be investigated. For more information or specific questions, don't hesitate to contact him at gmc0@ix.netcom.com.

Political Action and Starting a FIAR

Some of the interventions I've discussed above cost money. Some, like coenzyme Q10 and acetylcarnitine can be very expensive! And around the world, most people with HIV don't have access to antiretrovirals at all. Can some combinations of botanicals help to slow progression. Do these supplements really work?

Clearly, the data show that some do and some don't. But there are a great number of questions that remain to be evaluated. This is why Mr. Carter, along with others, formed FIAR. They hope that the community of people living with HIV around the world will begin to identify the things they think are the most important to be studied. Results of such studies can help to guide treatment decisions.

If the study shows no benefit--well, that's easy. Don't expect that treatment to work for whatever the study was evaluating.

But if it DOES work--this can be political and fiscal ammunition. Treatments like these while costly out-of-pocket, are often much cheaper from a public policy standpoint. If side effects can be reduced, progression delayed, symptoms alleviated using simpler, less expensive and often less toxic interventions, there is a good rationale for the state medical programs to cover these types of interventions. Thus, there can be greater assurance that those who are not able to pay for some of these costlier interventions will still be able to access them. So activism is a critical part of this--for survival!

By contrast, it isn't really controversial to advocate for people to use a potent multivitamin and a B-complex from the moment HIV infection is identified. The problem is that these aren't readily available to many people in the world. Some programs, such as OMNI (a USAID program based in Arlington, VA), provide vitamin A, iron and iodine. Activists have been trying to convince them to provide that multi and B complex to people with HIV. Of course, even before that, many folks first simply need enough food.

HIV has shown a spotlight on many of our failings as a culture, a country, a world. There is much we can do to help alleviate suffering. The interface between politics, policy, business and science need not merely be one of greed that grinds others into the grave. With a good spirit and a raised voice, change can and does happen. The first step is knowing that you can make the choices.

Buyers' Clubs

(See the LINKS page.)