12th World AIDS Conference
Combating HIV with good nutrition
Leading HIV nutrition researchers gathered in Geneva in June and July for the 12th World Conference on AIDS and a daylong symposium, entitled "Update on Wasting, Metabolism and Altered Body Shape in HIV/AIDS," held prior to the international conference. AIDS Project Los Angeles nutrition advocate Marcy Fenton, M.S. R.D., attended both conferences and wrote the following report on information presented in Geneva.
Recent acknowledgment of metabolic abnormalities and body composition changes among people with HIV infection have forced mainstream HIV researchers and clinicians to pay attention to nutritional considerations. Why are these problems occurring and what can be done?
In reviewing my notes from the 12th World AIDS Conference in Geneva, the problems become a wee bit clearer. Still, much more remains to be understood why these changes are occurring and to identify helpful treatment options.
Maintaining body mass
Early HIV nutrition studies determined that severe weight and protein loss would lead to death, despite high CD4-cell counts.
Because water gain can mask loss of body cell mass (cells found in muscle and organs), while weight stays the same, researchers learned that body weight is not an adequate way to monitor these changes. This led to the greater use of bio-electric impedance analysis (BIA) and other techniques of monitoring body cell mass.
Early studies found that body cell mass loss often occurs in the asymptomatic stage of HIV disease and that men and women lose body cell mass at different rates. This difference is likely due to the basic hormonal differences of how and where men and women store fat and muscle. In early stages of wasting, women seem to lose fat and not lean body mass, while in late wasting both fat and lean body mass is lost. Men seem to lose lean body mass earlier and subsequently in the disease.
Determining how many calories are needed by people with HIV disease has been very important. Researchers have used the measurements of "resting energy expenditure" and "total energy expenditure." Resting energy expenditure is the amount of energy used when the body is at rest and necessary to breathe and support the basic body functions. It does not include the energy needed for play, work and digestion. Total energy expenditure includes all these components.
In early studies, researchers also found an association with malnutrition and opportunistic infections. Other direct relationships between nutritional alterations and HIV infection include:
With the increased use of protease inhibitors and other potent antiretroviral drugs, a decrease in the numbers of cases and severity of malnutrition has been seen. Yet numerous posters presented in Geneva at the conference and the pre-conference update showed that wasting still occurs and adequate routine screening and intervention still must be provided.
Sherwood Gorbach, M.D., of Tufts University in Boston called for re-examination of the AIDS wasting definition. He pointed out that weight loss can occur without chronic fever or diarrhea, as the current definition states, and how recent research has found that as little as 5 percent weight loss over four months was associated with increased opportunistic complications and a decreased survival. While a study at the U.S. Centers for Disease Control and Prevention found the occurrence of AIDS wasting at 18 percent, nutrition centers estimate malnutrition at 50 percent.
Simple starvation -- plain inadequacy of intake -- is the main reason for weight and lean body mass losses. This could reflect many reasons, including anorexia, fatigue, lack of money, social isolation, depression, malabsorption, nausea, fevers or difficulty eating or chewing. At the update, Derek Macallan, M.D., a respected researcher from England, stressed that inadequate intake is the major factor in weight loss.
In studies published in the New England Journal of Medicine and Journal of Clinical Endocrinology and Metabolism, intake has been repeatedly assessed to be 40 percent below meeting dietary needs at time of severe weight loss. Macallan showed that weight loss occurs when people actually have a lower total energy expenditure. They are using less than normal amounts of energy for activity and digestion. This often is coinciding with an acute infection and the major factor is that intake is poorer.
Macallan's work underscores that it is important to maintain intake in order to maintain weight and lean body mass. It also reminds us of the need for aggressive attention and nutrition feeding in order to maintain weight and lean body mass during periods of inadequate intake. Intake is not the only factor, but a vital one.
Building body mass
How fat (lipid) and protein metabolic changes affect weight and energy balance has not been resolved.
Abnormal lipid metabolism with elevated triglyceride levels has long been recognized. This problem, possibly caused by an effect of cytokines (interferon-alpha, tumor necrosis factor, interleukin-1), has been associated with an increase in synthesis of fat and a decreased clearance of triglycerides.
Daily breakdown and building (or "synthesis") of body protein is often referred to as "protein turnover." Usually breakdown and synthesis are equal and fairly constant. There is an increase in usual protein turnover seen in body building, in wasting, and in recovery from an illness or trauma.
An increase in protein metabolism doesn't automatically translate into increases in lean body mass. While S. Bruce Williams et al (Abstract 42339) found that high protein intake assists in maintaining or increasing body cell mass in HIV-positive men independently of muscle-building activity, providing adequate calories, proteins and nutrients is not enough.
To best utilize nutrients and build lean body mass, individuals must be more physically active, free of systemic illness and metabolic abnormalities. In recovery from catastrophic events, initial weight gain is primarily in fat. Over time, with increased strength, function and desire, activity increases to tone muscles. Muscle, however, may never be regained to reach original baseline level. It is important to evaluate therapies over time and consider all these components.
Researchers, clinicians and patients search for ways to maintain and/or increase lean body mass.
Appearance of a very troubling syndrome has coincided with the success of potent antiretroviral therapy.
While the syndrome lacks an official name, it is now being called "lipodystrophy" or "peripheral lipodystrophy syndrome," and just last year it was known as "Crix belly" or "protease paunch." The medical dictionary defines lipodystrophy as a disturbance of fat metabolism, and there are different kinds of it.
The two major components of lipodystrophy include: (1) changes in body shape, with an increase in fat located in the middle of the body, and a reduction in fat from the arms, legs, face and buttocks (peripheral fat wasting) and (2) changes in the way nutrients are metabolized, causing high levels of triglycerides, cholesterol, blood glucose and other abnormalities. (See list on this page for other metabolic abnormalities.) You may see the term body "habitus" used in abstracts or clinical journals. Habitus is just another way of saying body physique or body shape.
The rate of incidence of lipodystrophy is not known. As with other syndromes and early in exploration of most new phenomena, numerous symptoms are suspected to be a part of this syndrome. Many nutrition researchers suspect that all symptoms do not have to be present.
Following the 5th Conference on Retroviruses and Opportunistic Infections, the reports of lipodystrophy occurrence ranged from 5 percent to 64 percent. In reports from the 12th World AIDS Conference, the incidence of lipodystrophy among HIV-infected people on HAART were more often in the range of 12 percent to 26 percent (Abstracts 12299, 12373 and 12391). Changes seem to be occurring between three months to three years after initiation of therapy. Bottom line: no clear definition and no clear numbers.
Your body is your castle
Body shape changes can include an increase in belly fat or width, sometimes to the point where the individual, man or woman, appears to look pregnant.
This belly fat is primarily an increase in "visceral fat" or "visceral adipose tissue" (VAT), a hard type of fat that surrounds and protects the abdominal organs. It is not the flubby, soft fat usually seen, which is fat that is deposited under the skin. This second type of fat is called "subcutaneous fat" or "subcutaneous adipose tissue" (SAT).
Losses in subcutaneous fat often occur as losses in the extremities of the body, that is, the face, arms, legs and even the buttocks. A few studies reported that there was a greater amount of visceral fat as compared to subcutaneous fat in patients treated with protease inhibitors than those not taking protease inhibitors. Doctors David A. Cooper, M.D. and Andrew Carr, M.D. from Sydney, Australia found that the VAT/SAT ratio was greater in those who complained of gastrointestinal symptoms and had an enlarged abdomen than without complaints.
Another body shape change is the "buffalo hump." The anatomical term for this is the "dorsocervical fat pad," located just below the back of the neck. The buffalo hump has been found to occur in people on combination therapies with and without protease inhibitors. It has also been associated with greater truncal fat and the other abnormalities, though it is not yet clear if it is caused by a separate mechanism.
Cooper and Carr have been closely monitoring this syndrome and had much to share at the update and the conference. Effects and side-effects noted have been:
In a report in the June 20 edition of The Lancet, Cooper and Carr hypothesize that lipodystrophy occurs because HIV-1 protease inhibitors have a high attraction for the active site of the HIV-1 protease, which may be similar enough in structure to some human proteins and affecting their function.
Two proteins that may be affected are low-density lipoprotein-receptor-related protein (LRP) and cytoplasmic retinoic-acid binding protein type-1 (CRABP-1). They described the metabolic pathways in which these proteins are involved, how they lead to insulin resistance, hyperlipidemia and complication with retinoic acid analogues. Their hypothesis requires better analysis and more decisive studies.
In a possible variation to the previous hypothesis, Donald Kotler, M.D., of St. Lukes Roosevelt Hospital in New York City suggests that the appearance of these body shape alterations were seen prior to the era of protease inhibitors. According to Kotler, fat redistribution and metabolic abnormalities are a response to life-threatening illness and due to changes in a hormone called cortisol.
Blood cortisol levels change throughout the day and night. A 24-hour urine collection and testing for "free cortisol" may better reveal any irregularities over a single blood sample.
In a study presented at the World AIDS Conference, body shape changes were seen in 16 percent of 118 women after initiation of successful antiretroviral therapy with a protease inhibitor (Abstract 12373). Women more often experienced increase in breast size (71 percent) and abdominal belly size (71 percent). About half experienced total weight gain (47 percent) and the same percentage, but not necessarily the same women, experienced peripheral wasting. Fewer women experienced loss of fat from the buttocks (29 percent) and buffalo humps (23 percent).
HyperglycemiaMore cases of insulin resistance have been reported in people taking protease inhibitors (Abstract 32172).
High levels of blood glucose, also called blood sugar, indicate problems with usage of insulin or amount of insulin in the body. Insulin resistance is when there is a problem with the use of insulin. Unlike antiretroviral drug resistance, which occurs when HIV is no longer responding to the drug, insulin resistance may require diet, exercise and meds to help in transporting of the insulin or help in making the cells more receptive to the insulin.
Insulin resistance may be difficult to detect. Accurate tests to measure insulin resistance are not widely available, and insulin resistance may exist without apparent changes in blood glucose. The normal fasting blood glucose value is 80 to 110 mg per decaliter "Impaired fasting glucose" is the term used when someone's fasting blood glucose is higher than 110 but below 126 mg/dl. Diabetes is diagnosed when two fasting blood glucose values are more than 126 mg/dl.
How protease inhibitors alter glucose metabolism is not understood. Is there some defect at the cellular level, low insulin secretion (Abstract 32172), an increase in fat accumulation, an accelerated insulin clearance (Abstract 32276) or do protease inhibitors cause an inhibition of the protease that converts proinsulin to insulin (Abstract 12387)?
One abstract from Stanford University reported hyperglycemia in about 11 percent of the 215 patients receiving at least one protease inhibitor. Median serum glucose was 86.5 mg/dl prior to beginning protease inhibitor therapy and rose to 138.6 mg/dl after therapy began. Prevalence of hyperglycemia associated with indinavir (Crixivan) was 11.6 percent; saquinavir (Invirase), 4.3 percent; nelfinavir mesylate (Viracept), 8.2 percent; and ritonavir (Norvir)/saquinavir combination, 6.3 percent. One study found 15.1 percent of 45 patients developed hyperglycemia (greater than 120 mg/dl blood glucose). Another study, however, reported 2 percent incidence of hyperglycemia or diabetes, which is no greater than the 2 percent to 6 percent seen in the general population (Abstract 60148).
All people taking protease inhibitors should have their blood sugar checked every three to six months. If you have a history of diabetes in your family, make sure your doctor is aware of it. The primary treatment for hyperglycemia is diet and exercise. Oral hypoglycemic medications or injectable insulin are options to add if and when diet and exercise aren't enough.
The American Diabetes Association recommends that people with diabetes receive their treatment and care from a physician-coordinated team, which should include at least a physician, nurse, dietitian and mental health professional with expertise and interest in diabetes.The American Diabetes Association recommends that a "registered dietitian knowledgeable and skilled in implementing current principles and recommendations for diabetes, be a member of the treatment team."
The Health Care Financing Administration, the federal agency that regulates and monitors Medicare, recently issued instructions on Medicare coverage of physician-prescribed diabetes, outpatient self-management training services and home blood glucose monitors and test strips for all people with diabetes. Coverage took effect July 1, 1998.
A blood glucose meter can cost $60 or less, and may be obtained without cost. Ask your pharmacist for information. The cost of monitoring strips varies widely. Medicare, Medi-Cal and some insurance providers wil cover them. Non-physician services, such as medical nutrition therapy from a registered dietitian, must be part of a physician's professional service.
Heart disease and hyperlipidemias
Low high-density lipoprotein levels and high triglycerides have been seen in people with HIV disease for a long time, but the number of people experiencing these abnormal values is increasing, along with the abnormal values themselves.
Lipoproteins are molecules that have proteins and lipids packaged together. When the lipoprotein package has more protein than fat, it is called a high-density lipoprotein, or HDL. When the lipoprotein package has more fat than protein is called a low-density liprotein (LDL) and when there is much more fat than protein, it is called very low-density lipoprotein (VLDL). Factors that increase the possibilities of heart disease are blood values high in cholesterol, high in LDL, low in HDL, excessively high in triglycerides, high in blood glucose and insulin resistance.
The major concern with excessive triglycerides is pancreatitis, where 5 percent of all patients are at risk. With protease inhibitors, especially ritonavir, triglyceride, LDL and cholesterol levels have dramatically increased. Insulin resistance may make triglyceride levels worse. All these changes make reducing risk factors for heart disease a very real concern.
Prescriptive use of gemfibrozil (Lopid) and atorvastatin, lipid-lowering agents, have been reported to have some benefit in reducing lipid levels. There was discussion at the conference that the lipid-lowering drugs known as statins, should not be used with protease inhibitors.
Leading researchers at both the conference and the preceding update suggested following the National Cholesterol Education Program (NCEP), which aims to reduce cholesterol, high serum triglyceride levels by body weight control, limiting consumption of saturated fat and cholesterol, regular exercise, stopping smoking and restricting use of alcohol.
Specific dietary recommendations regarding saturated, monunsaturated and polyunsaturated fatty acids, cholesterol, sodium, complex carbohydrates and alcohol, as well as an exercise program, should be fully explored by your physician, registered dietitian and rest of your medical team.
While some success at treating buffalo hump through liposuction has been reported, one poster presented at the conference reported on improvement in the condition using recombinant human growth hormone (Serostim) (Abstract 32164).
Growth hormone promotes the breakdown of fat, building of lean tissue and depositing of triglyceride from the blood into the cells. The report was based on two individuals experiencing buffalo humps along with associated symptoms of central adiposity, peripheral muscle wasting, fatigue and hyperlipidemia. Other studies looking at lipodystrophy and the use of growth hormone are under way, and more are needed.
For the most part, reports used computerized tomography (CT), dual X-ray absorptiometry (DEXA) or magnetic resonance imaging (MRI) to precisely measure fat in the arms, legs, face and trunk. BIA, while good at identifying trends in fat and body cell mass, is not able to distinguish visceral and subcutaneous fat changes. Regardless, BIA was and still is used in identifying changes in monitoring body composition and nutritional health.
Some claim that the reduction in death and opportunistic infections attributed to protease inhibitors and potent antiretroviral medications outweigh "cosmetic" problems with body shape. Others say that these body-shape changes are not merely "cosmetic."
While there were some reports of switching antiretroviral medications in an effort to decrease symptoms of the syndrome, the overriding belief among clinicians is to continue using anti-HIV drugs. One grave concern expressed in Geneva is that increased amount of visceral fat coupled with other developments, insulin resistance, and changes in lipid profile to low HDL-cholesterol and high LDL-cholesterol, is a formula for atherosclerosis and heart disease. Indeed, there have been reports of blockage in the arteries to the heart (myocardial infarctions) and deaths.
Other concerns are that body changes are psychologically devastating, make confidentiality more difficult to maintain, and can be physically uncomfortable. Added medical, dietary and behavior changes necessary to treat hyperlipidemias or hyperglycemias can be confusing and burdensome.
Replacing one protease inhibitor with another has been reported to be only somewhat helpful. Switching from indinavir (Crixivan) to nelfinavir mesylate (Viracept), for example, was reported to often coincide with some reduction in triglycerides, visual signs of peripheral lipodystrophy syndrome and hyperglycemia, but not cholesterol (Abstracts 12287, 32172).
Other studies reported at the conference showed that a patient's self-report of body shape changes matched actual changes. Hopefully, the days are over when doctors will tell their patients that perceived body changes are "all in your head."
Progressive resistance therapy
Using exercise, testosterone and anabolic agents as a way to interrupt wasting and to build lean body mass was discussed at the update and a topic of a satellite symposium at the conference.
Continued successful use of progressive resistance training (PRT) to build lean body mass is one of the key results presented in the area of wasting. Ronenn Roubenoff, M.D., of Tufts University in Boston and part of the Nutrition for Life Study there, shared results of his study which demonstrated that PRT could be safe and effective in HIV infection.
The benefits of PRT has been well recognized in the elderly, and people with rheumatoid arthritis, congestive heart failure, coronary artery disease and chronic renal insufficiency. One of the concerns in HIV disease has been that excessive exercise increases IL-1 and TNF levels that could stimulate HIV replication and make clinical condition worse.
At the update preceding the conference, Roubenoff presented results of a study that found no harmful effects on viral load following muscle stimulation. In the study, which involved 25 men and women, a small decrease in viral load was seen at two and six hours after exercise.
At the update, Roubenoff presented results from a study involving 15 HIV-infected males and four HIV-infected females participating in a short-term, high-intensity progressive resistance training program (Abstract 42357). For eight weeks, participants used compressed air resistance equipment three times a week at 80 percent of 1-repetition maximum, performing three sets of eight repetitions per machine. Roubenoff stressed training on the large muscle groups rather than small, and participants were trained to perform on machines to do leg extensions, leg presses, chest presses and lateral pulls.
Results of this study showed a significant increase in muscle strength, generally an increase in total body weight that was actually exceeded by the increase in lean body mass, and a decrease in body fat. A subgroup of people who had wasting before the study gained both fat and lean weight and a greater overall weight gain than the non-wasted participants.
Positive changes were also found eight weeks after the training period ended. Roubenoff is in the process of developing a PRT protocol that can be easily followed and more widely distributed into the HIV community.
Studies on hypogonadism, which is a reduced activity of the sexual glands, were also presented in Geneva.
Hypogonadism correlates with negative sexual (androgenic) and body composition (anabolic) effects. This means sexual function, psychological status, mood, energy, appetite and bone density can be affected. Changes in nutritional status due to hypogonadism can occur before the appearance of sexual dysfunction. Hypogonadism can occur even when there is adequate sexual function.
The normal range for total testosterone is wide, and a definition of hypogonadism is not clear. Both free and serum total testosterone are often low in HIV-infected men and women, though the estimated range of 30 percent to 50 percent for men, may be less in the era of protease inhibitors than before (Abstract 32174).
At the update preceding the conference, Adrian Dobs, M.D., suggested screening for hypogonadism in men be done using total testosterone, as the costs are lower and results can be categorized as absolutely low (less than 300 nanogram per milliliter), indeterminate (300-500 ng/ml), and normal (greater than 500 ng/ml).
According to Dobs, individuals with indeterminate results should receive serum-free testosterone tests, which are more sensitive and expensive. Gonadal hormones should be checked regularly, especially in symptomatic men. Low testosterone in HIV is usually related to a response to chronic disease. Other possible causes are malnutrition, megestrol acetate (Megace) therapy or advancing age.
Dobs reported on a double-blind, placebo-controlled trial in which men with low free but normal total testosterone were administered 5 mg testosterone scrotal patches (transdermal) daily. While free testosterone increased, there were no changes in body composition, likely to be the inadequate amount of testosterone administered.
Dobs compared this study to the one by Bhasin, where 600 mg testosterone per week was given with and without exercise. Even without exercising, subjects experienced an increase in lean body mass and strength. With exercise, the results were greater.
Researchers agreed, however, that this very high dose of testosterone has too many detrimental side effects for therapeutic use.
At the update, Steven Grinspoon, M.D., suggested that a deficiency of free testosterone depletes muscle mass. In a six-month, placebo-controlled intervention study, 300 mg of testosterone enanthate was injected intramuscularly every three weeks to people with hypogonadism and 10 percent weight loss. Fat-free mass, lean body mass and muscle mass were all significantly improved with testosterone.
In another testosterone study discussed at the update, women who were mostly androgen deficient and who had a 10-percent weight loss received 150 ug of testosterone patch each day. An improvement in free testosterone to normal levels, a 1.9-percent increase in fat mass, and significantly improved quality of life scores were seen. Study participants who received a placebo or a double-dose patch did not gain weight.
One poster at the conference contradicted fairly widespread views on the relationship of testosterone and wasting (Abstract 32174). Reviewing charts of HIV-infected men after initiation of protease inhibitor therapy and some who were on anabolic agents over a two-year period found that hypogonadism did not correlate with CD4 count or viral load and was not significantly associated with wasting. Seventy-five percent of those patients who were wasting were not hypogonadal and hypogonadism did not significantly predict the occurrence of wasting.
Review of growth hormone
Treating HIV wasting with growth hormone, which has been shown to spur nitrogen retention, was reviewed at the update by Kathleen Mulligan, Ph.D., from the University of California at San Francisco.
Nitrogen retention results when body protein (mainly muscle and organ tissue) is no longer being broken down and lost. HIV-infected people who either had lost more than 10 percent of their usual weight or were less than 90 percent of their ideal weight were given either 0.1 mg/kg of growth hormone per day or placebo over 12 weeks.
Patients receiving growth hormone generally experienced a significant increase in lean body mass greater than the increase in total body weight. They also experienced a loss of fat mass and a significant increase in treadmill work outputs. The weight of those in the placebo group did not change significantly. Side effects were mild, and included swelling or puffiness, athralgia or myalgia (diffuse muscle pain), or diarrhea.
An increase in resting energy expenditure with an increase in the breakdown of fat and decrease in the breakdown of protein was also reported. Growth hormone does not seem to change HIV progression or viral load. A subset of the participants in the study kept written records of their "self-selected dietary intake" before beginning treatment and at the end. There was little difference in dietary intakes between the group that received growth hormone and the placebo. Adequate dietary intake, however is important and should be stressed when taking growth hormone in order to assure energy for weight gain and continued lean body mass growth.
According to Mulligan, optimal dosing, impact on disease progression and survival, timing of intervention and interaction with other therapies and exercise are all areas of growth hormone that still need to be addressed.
Research reported at the update and at the conference by Marc Hellerstein, M.D., Ph.D., showed the benefits of testosterone injections and progressive resistance training (Strawford, 42335). In this eight-week trial, 24 HIV-infected men with greater than 5-percent weight loss were given 100 mg of testosterone injections per week to establish similar androgen levels, and progressive resistance training. Subjects were randomized and given either oxandrolone at 20 mg per day or placebo.
At the end of eight weeks, both placebo and oxandrolone groups were in positive nitrogen balance, all gained lean body mass (8.8 pounds and 15.4 pounds, respectively), and both groups gained muscle strength, though in each category significantly more in the oxandrolone group. No adverse effects or significant changes in viral load were reported.
At the satellite symposium during the conference, sponsored by the maker of oxandrolone, Carl Grunfeld, M.D., revealed the first reports of a trial comparing 20 mg, 40 mg and 80 mg doses of oxandrolone. Elevated liver function tests, AST (SGOT) and ALT (SGPT), an increase in LDL and drop in HDL were seen in the 40 mg and 80 mg groups, with the most severe adverse effects seen in the 80 mg group.
High levels in liver enzymes, which may indicate liver cell injury, should be taken very seriously. Liver disease, injuries, tumors or certain medications all may result in high liver enzyme levels. Both Grunfeld and Hellerstein cautioned against taking the higher doses of oxandrolone, or using it as a prophylaxis, and both agreed that oxandrolone was indicated for those who were exhibiting signs of weight loss or wasting. Using the approved dose of 20 mg per day with a progressive resistance exercise routine seems to be safe and beneficial.
At the symposium, Linda Heller, M.S., R.D., C.S.P., of Children's Hospital of Los Angeles, presented data on the first study looking at the effects of anabolic agents on children. Ten malnourished children between the ages of 4 and 14 used oxandrolone at .1 mg/kg for three months and then monitored for an additional three months off drug.
Total weight gain, increased muscle and loss of fat weight were seen in this study. The prescriptive period was followed by a reduction in weight, muscle and fat, though not significant. Laboratory values reflecting sexual development were normal. Remarkably, Heller's skinfold thickness measurements on these children were closely matched to computerized tomography measurements, the techniques used to test body composition.
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.