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Metabolic Disturbances in HIV Infection Find Friend Not Foe in Protease Inhibitor Regimens

Refeeding paradox

On May 20-21 the Office of AIDS Research (OAR) sponsored a conference, the first of its kind on AIDS wasting syndrome. Alongside Michael Marco and TAG’s wasting maven Tim Horn, Mark Harrington was in attendance. He prepared this report.

The specific causes of AIDS wasting remain unknown. Triglyceride levels, cholesterol synthesis and total energy expenditure rise. Body fat is preserved even while protein is depleted. And profound metabolic abnormalities develop, such as hypogonadism (reductions in testosterone levels).

Protein Lost is Replaced by Fat

For reasons we don’t yet understand, metabolic dysfunctions in HIV infection result in a refeeding paradox which drives energy from protein to fat. Weight is lost in the form of lean body mass, but when it is replenished (e.g., with total parenteral nutrition (TPN), appetite stimulants such as megesterol acetate (Megace), or dronabinol (THC)), it is regained as fat. With Megace, for example, 70-100% of the weight gained back is fat. (Megace also decreases testosterone levels, helping to explain its ability to induce production of fat.) Anecdotal reports implicate some of the protease inhibitors (particularly indinavir) in exacerbating this metabolic dysfunction, but further study is needed in order to make any definitive conclusions.

In one small study (31 patients, of whom 4 were women) presented at the meeting by Sherwood Gorbach of Tufts University, most protease inhibitor-induced weight gain was found to be predominantly in the form of fat — as opposed to lean body mass. Four months after starting protease inhibitor-containing treatment regimens, study participants’ weight had risen to levels not seen since enrollment into the study (8 1/2 months prior). When lean body mass was assessed by bio-electric impedance analysis in a subset of twenty patients, it was found that the proportion of total body weight represented by lean body mass had fallen from 83% before protease to 81% after.

Repeating the analysis with the more discriminating “anthropometric” method, the Tufts team reported a change from 81% lean body mass before protease therapy to 78% after. Both differences were statistically significant. Since the amount of absolute lean body mass among the study participants had not changed throughout the course of the study, Dr. Gorbach explained, all weight gained must have been in the form of fat. This may mean that people on protease inhibitors will need additional interventions to correct metabolic abnormalities, such as exercise, growth hormones or anabolic steroids, in order to restore lean body mass.

Possible role for weight training

In a second paper from Tufts, Ronenn Roubenoff presented a study of progressive resistance training in seven HIV-infected individuals (median CD4 cell count= 200). The training consisted of three 45 minute weight training workouts per week, with the amount of weight being increased every two weeks. Over the eight-week study period, participants experienced a 50% increase in strength. Weight rose by 3.8% (or 6.2 lbs). Of the weight gained, 79% was lean body mass and only 21% was fat (p<0.03).

Hypogonadism — and nandrolone

Whereas uninfected males have a median of 450-700 ng/dl of free testosterone in their blood, HIV-infected men have 200-450 ng/dl. One hypothesis is that weight loss leads to hypogonadism, which leads to “nutritional partitioning.” Is this borderline hypogonadism clinically significant? And will HIV-infected hypogonadic persons respond to androgen replacement therapy? One anabolic steroid, nandrolone, given at 200 mg two times weekly, increased nitrogen balance (indicating protein production) about as much as does growth hormone, and led to increased muscle mass. In a 12-week study, individuals gained 11-13 lbs, with 7-8 lbs (67%) in the form of lean body mass. Nandrolone is also said to decrease fat production.

Energy expenditure, total vs. resting, and protein turnover

Derek Macallan and colleagues of the University of California at Berkeley discussed energy expenditure and protein metabolism in AIDS. In their cohort studies, total energy expenditure was not particularly elevated in HIV infection (which contradicts some earlier reports). And, in what at first seems another paradox in AIDS wasting, HIV-infected individuals with the lowest total energy expenditure lost the most weight. This is probably because the low total energy expenditure resulted from immobilizing opportunistic infections and reduced in-take of food. During the course of such infections, individuals have heightened resting energy expenditure but reduced total energy expenditure. And as CD4 cell count decline, resting energy expenditure increases while total energy expenditure declines. In-take drives wasting.

Another useful metabolic measurement in HIV infection is called whole body protein turnover: the rate at which lean body mass is destroyed and replaced within the body. In HIV-infected individuals, whole body protein turnover is elevated by about 16-18%; in people with AIDS the percentage rises to 25%, although the number varies according to the nature of the inflammatory condition. A common theme observed and commented on in several of the meeting’s presentations appears to be what researchers in this area refer to as an “anabolic block” wherein new nutritional in-take is converted into fat — and not into the lean body mass which was depleted during the acute infection. Considerations for people with AIDS include: 1) maintaining energy in-take, 2) consideration of anabolic steroids (in concert with resistance training where possible) when in-take is inadequate, or to direct use of nutritional supplements, 3) consideration of anti-inflammatory agents, and 4) monitoring of outcomes.

At lunch, Tim Horn, Michael Marco and I met with Judith Fradkin of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD), Fulvia Veronese and Ellen Cooper of the Office of AIDS Research (OAR) and Beverly Alston of NIAID’s Division of AIDS to discuss implementing the recommendations of TAG’s Wasting Report by increasing the amount of funding for basic research, natural history and therapeutic intervention studies for AIDS-related wasting, cachexia, and metabolic disorders. Follow-up is on-going.

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