PROGRESSIVE MANAGEMENT OF AIDS WASTING: 2000, Part one

By Donna Tinnerello MS, RD, CDN, and Sharon Ann Meyer, AS, AA, DTR

The number of people learning about the benefits of maintaining optimal nutritional status increases every year. The New York City group Nutritionists in AIDS Care (NIAC) held an all day conference earlier this year and discussed optimizing nutritional status, preventing malnutrition, and maintaining lean body mass. This article highlights information from five speakers: Donald Kotler, MD, Lawrence Fontana, MD, John Babish PhD, Johannes Koch, MD, and Charlie Smigelski, RD. A complete set of audiotapes with speaker handouts is available from NIAC Chair Alan Lee, RD, at <> or at .

AIDS Wasting: Past, Present, and Future

Donald Kotler, MD

The keynote speaker was Donald Kotler, MD, a gastroenterologist at St Lukes Roosevelt Hospital <http://www.wehealny.org/studies/index2.html#hiv>. He is a New York Citybased gastroenterologist and researcher and one of the first investigators to study the nutritional issues of people living with HIV (PLWHIV) and AIDS.

Past

Knowledge about HIV and nutrition has gone through a remarkable evolution over the past 20 years. Dr. Kotler called the initial epidemic years a period of patient "carnage": there was a very high death rate and there was nothing anyone could do about it. What we are seeing now is another scenario that is not quite so direa phenomenon called lipodystrophy (altered fat deposition). Today, we need to focus attention on metabolic abnormalities: hyperlipidemia, insulin resistancenot wasting, not obesitybut rather atherosclerosis (coronary artery disease).

Survival was about three months for hospitalized patients early in the epidemic, and to be a hospital-based HIV specialist meant a focus on critical care and nutrition support. In the late 1980s, Kotler revolutionized nutrition-assessment techniques when he started investigating body composition technology using resources at St Lukes Roosevelt Hospital. Body composition continues to be his passion and the foundation of his work in the area of nutrition.

Kotler used a compartment model to describe the body.¹ His early studies showed that AIDS patients had a disproportionate loss of body cell mass (BCM) that led to disability and death.² The metabolically active lean body mass is life sustaining and does all the bodys metabolic activity. It is separate from bone, fat, and extracellular water.

Dr. Kotler spoke about the adaptation response to an HIV-related infection. Initially, it is life-saving and not so different from how the body responds in other acute instances such as burns or pancreatitis. The acute-phase response is the mobilization of skeletal amino acids to produce "acute-phase" proteins needed during stress. Kotlers colleague, Dr. Carl Grunfeld, found that in a 70 kg (154 pound) person

we could expect to have a protein breakdown of 75 grams after a 24 hour fast. With food, protein turnover is decreased so muscle is preserved. When the person becomes ill, food is withheld, and the protein in skeletal muscle is used to make acute-phase proteins. Acute-phase proteins are responsible for clearing the damage and replacing dead tissue, thus preventing oxidation and the generation of free radicals that are self-perpetuating and can lead to complete multi-system organ failure. Insulin shifts glucose away from the cells toward the liver so that the liver will have the energy to make these acute-phase proteins.

Hypogonadism or low testosterone is one of the most common disorders in AIDS. It is also part of the acute-phase response and correlates with disease progression. According to Dr. Kotler, the body adapts by using nitrogen to stay alive instead of making muscle. In the acute phase, the proper role for muscle is to waste, and hypogonadism decreases skeletal muscle synthesis. Exogenous synthetic gonadal hormones are harmful during the acute phase.

There are a number of other reasons why people with AIDS waste, including problems with chewing and swallowing, anorexia secondary to systemic infections, altered gastrointestinal emptying, and cytokines that cause fever. Even people with malabsorption have an element of anorexia in which poorly absorbed materials, once they are in the lower intestine, increase anorexia. Most importantly, people waste because of the metabolic change that results in increased resting energy expenditure (REE). According to Kotler, 70% of the energy used in these situations is REE, and even though voluntary energy expenditure falls, it cannot fall enough to make up for the increase in REE. Unlike with starvation, where protein is spared, there is protein breakdown. It is this protein breakdown that is designed to be protectiveit is not a metabolic derangement; it is a metabolic adaptation. Kotler contends that if the adaptation does not occur, people will die; if it does occur, they will live but they will waste.

Over the short term, the acute-phase response is beneficial, but over the long term, a sustained acute-phase response can be fatal. Kotler talked about malnutrition and the timing of death; he plotted the actual loss of BCM as one nears death. A 54% loss of BCM and a 66% total weight loss caused death in AIDS patients that he studied.2 Just giving food or TPN does not cause anabolism or reverse wasting. According to Kotler, in this instance, the only way to increase skeletal muscle mass is to treat the underlying disease. Kotler is in favor of cautiously trying anabolic agents, growth hormone, and anti-cytokine therapies. He is currently involved in a study using growth hormone and thalidomide (anti-cytokine) in AIDS patients with acute infections. The goal is to slow the wasting process. Kotler says he has to warn himself that the bodys compensations are important; if we interfere with them, we might do more harm than good. He noted a European study that used growth hormone in non-HIV intensive-care-unit (ICU) patients where mortality was doubled.

Present and Future

In 1997, HIV therapy became much more effective with the widespread use of protease inhibitor (PI) drugs, and death rates decreasedin some centers by as much as 90%. The need for nutrition therapies plummeted because the prevalence of wasting and malnutrition decreased. What has changed dramatically is body composition; treatment today is all about fat (lipodystrophy). He described visceral fat accumulation in the belly; dorsocervical fat buffalo humps and lipomas anywhere at all on the body, often placed asymmetrically; and enlarged breasts in women. Fat thinning in the extremities and face occurs as well. Metabolic abnormalities include high triglycerides and high cholesterol, with low high-density lipoprotein cholesterol (HDL, "good" cholesterol) and very high low-density lipoprotein cholesterol (LDL, "bad" cholesterol) plus insulin resistance. Kotler stated, "We are concerned because this visceral fat coupled with the hyperlipidemia and insulin resistance looks for all the world like another metabolic disorder called Syndrome X."

Kotler went on to describe what are now thought to be two different kinds of syndromes. The type related to PIs is that of fat accumulation, e.g., visceral abdominal obesity and buffalo hump along with hyperlipidemia and insulin resistance. The other type is fat atrophy with weight loss, lactic acidosis, and frequently liver disease. This latter component is related to the nucleosides (the AZT-type drugs) that are thought to block the DNA in the mitochondria, more often seen in women. The question is still what causes altered fat deposition syndrome? According to Kotler the causes are probably mutifactorial, including both classes of drugs as well as HIV-disease itself.

Treatment should be individualized; each patient is slightly different. When PIs were thought to be the cause, many patients opted for protease-sparing treatment. Blood sugars and lipids improved but the visceral fat did not go away. Statins work for hyperlipidemia, but drugdrug interactions can limit their use. For insulin resistance, Glucophage (metformin) is safe to use and seems to work to improve insulin sensitivity and to cause a decrease in visceral fat. This lends credence to the belief that the visceral fat might be a complication of insulin resistance.

Kotler ended his talk by stating that because there is less emotion connected with lipodystrophy than with death from wasting, people are a little less interested in taking antivirals than they used to be. This tends to be

problematic since drug therapy is the reason that people are not wasting and dying. We do not have all the answers yet, but what is needed is to find ways to prevent other longer term complications such heart attacks and strokes ten years down the road.

Micronutrient Deficiencies in AIDS Wasting

John Babish, PhD

John Babish, PhD, is a molecular biologist formerly with Cornell University <http:// www.cce.cornell.edu/food/resources.html> as a tenured associate professor of pharmacy and toxicology. He has authored over 100 peer-reviewed publications and is currently chairman for BIOnexus, (visit <http://www.bionxs.com>).

Babish opened his session by building on Dr. Kotlers remarks about the acute-phase response to infection. He discussed the ravages of HIV and AIDS at the cellular level and the synergistic effect of multiple micronutrients and medications in the management of HIV.

We were reminded that disease presentation changes during the life of the individual living with HIV, for the disease is present in every organ and tissue of the body. Within 24 hours of infection, HIV makes itself very much at home in the gut-associated lymphoid tissue (GALT), a large pool of CD4 T-cells in the stomach. One of the first changes seen with HIV infection is a decrease in stomach acidity. Essentially, the naturally acidic environment of the stomach protects against the invasion of foreign pathogens such as molds and bacteria. Decreased acidity sets the stage for proteolytic enzymes that activate other digestive enzymes and facilitates the activation of intrinsic factor, which is crucial for the absorption of vitamin B12. The lack of complete digestion can set the patient up for diarrhea. The integrity of the villi in the small intestine depends on the rapid turnover of gastrointestinal (GI) cells. The virus itself can cause a block in the cell cycle and thus dramatically reduce the GI surface area and absorption Because our patients are all different, some exhibit changes at the level of the gut to a greater extent than others.

Although Babish was able to highlight valuable micronutrient data, his theme throughout the talk was that there is no single nutrient or magic bullet for any disease state, including HIV. The B vitaminsmost importantly, the methyl donor group: vitamin B12, folate, and B6are protectors of the DNA. DNA is what differentiates each cell. Babish discussed a retrospective study done at John Hopkins University of vitamin B12, HIV disease progression, and death.³ Over 3.5 years, HIV-positive people with a low vitamin B12 level were 2.2 times more likely to die than those with normal serum levels. Babish also talked about low serum selenium levels and HIV progression; he noted that there are tremendous amounts of research on selenium in cancer, HIV, and other virus-associated wasting diseases. Babish recommends about 200 µg of selenium per day for PLWHIV.

Babish spoke on the use of mixed carotenoids and discussed a Finnish study where researchers learned a very important lesson in the lung-cancer intervention trial⁴: intervention with beta-carotene was only harmful, even though in vitro it demonstrates very good activity against cancer cells. Overload with only a single carotenoid creates a chemical imbalance and thus puts people at risk for tumor progression. The beta-caroteneintervention finding demonstrated that we really cant take a reductionist viewpoint when it comes to dietary intervention in cancer or AIDS. The best approach is to provide a mixture of carotenoids that includes lutein and lycopene among others.

Nacetyl cysteine (NAC) is FDA-approved for the treatment of acetaminophen overdose. It is a source of exogenous glutathione (a biological tri-peptide of nonprotein origin, which may reduce wasting and boost T-cell function)⁵ and is one of the most important and abundant antioxidants in the body. Numerous studies have been published on NAC and HIV that show that decreasing glutathione levels in CD4 T-cells is a very good predictor of CD4 T-cell death. It is also a good predictor of survival; when glutathione levels are low, survival in both cancer and AIDS patients is poor. In addition, NAC has been demonstrated to inhibit the HIV reverse transcriptase enzyme the same enzyme, that AZT and other nucleoside drugs in this class work on to inhibit HIV replication.

L-carnitine appears to be deficient in 25% of HIV-infected patients. Babish talked briefly about the current thinking that reverse transcriptase inhibitors can damage the mitochondrial DNA.⁶ Supplementation with L-carnitine can protect the mitochondria from oxidative damage and death. Lower carnitine levels mean that the mitochondria are more susceptible to damage. In HIV, this damage can occur in various body tissues such as liver cells, muscle cells, etc. One manifestations in HIV is AZT-induced myopathy.

To help us understand the role of carnitine, Babish discussed carnitine deficiency in kidney disease and hemo- dialysis patients. In these patients, the deficiency can be extreme, because carnitine is synthesized in the kidney and the liver. In kidney disease a carnitine deficiency leads to hypertriglyceridemia and hypercholesterolemia⁷ and thus supports the use of L-carnitine for hyperlipidemia in HIV disease.

Dr Babish closed his talk as he had opened it, by stressing that we cannot overload with a single nutrient. We need balanced micronutrients for good health. He also cautioned the PLWHIV in the audience to not rely solely on nutritional supplements for antiviral protection, but to use them judiciously in combination with a healthy diet and antiretorivrals.

Information on the session given by Charlie Smigelski, RD is noted in this issue's dietician column in the Alliances section. In our next issue we will review the presentations given by Lawrence Fontana, MD, and Johannes Koch, MD.

Donna Tinnerello, MS, RD, CDN is an HIV specialist living in New York City. She works at Cabrini Medical Center and is a private consultant and is the Nutrition Editor at Always Your Choice <http://www.alwaysyourchoice. com/nutritional.html>. Contact Donna at <>.

Sharon Ann Meyer, AS, AA, DTR, Certified HIV Counselor, is the President of HIV ReSources, Inc., and Editor-in-Chief of the HIV ReSource Review <http://www. hivresources.com/NewsInfo.htm>. Contact her at <>.