The Study
A Boston medical research team has identified an important first step by determining that cachexia, wasting and weight loss associated with a chronic disease, is a prevalent clinical problem in HIV infected men, even when antiretroviral treatment is administered. They found that cachexia is an immunologically driven process rather than the consequence of inadequate food intake.
Cachexia causes lean body mass loss, without loss of weight, at a more accelerated rate than found in wasting. Previous studies have revealed that in rheumatoid arthritis, excess production of catabolic cytokines interleukin and tumor necrosis factor-a by peripheral blood mononuclear cells (PBMC), spurs cachexia and increased resting energy expenditure (REE) and protein catabolism, without weight loss. Since rheumatoid arthritis is a system disease like HIV infection, the research team sought to link HIV infection to this process that causes cachexia.
The authors of the study, “Role of Cytokines and Testosterone in Regulating Lean Body Mass and Resting Energy Expenditure in HIV-Infected Men,” are Ronenn Roubenoff, MD, MHS, Paul R. Skolnik, MD, Eric Tchetgen, BA, Donna Spiegelman, ScD, Tamsin Knox, MD and Sherwood Gorbach, MD, all of the Department of Community Health and Department of Medicine, Tufts University School of Medicine, Boston, MA; Leslie Abad, MS, of the Nutrition, Exercise Physiology and Sarcopenia Laboratory, Jean Mayer USDA Human Nutrition Research Center, Tufts University; and Steven Grinspoon, MD, of the Division of Endocrinology, Massachusetts General Hospital, Boston, MA. Their findings are published in the July 2002 edition of the American Journal of Physiology --Endocrinology and Metabolism. The findings are currently available at “Articles in Press” on the American Physiological Society (APS) website (www.the-aps.org).
Methodology
The study involved:
- One hundred seventy-two participants who contributed 190 observations with a mean study duration of 6.5 months.
- The study population was predominantly white, with a mean age of 41.
- The primary HIV infection risk was injection drug use (15 percent) and homosexual contact (78 percent).
- Sixty-three percent of the population had met the definition of AIDS and 43 percent were taking antiretroviral treatments during the study.
Between May 1995 and August 1998, researchers examined 172 men with adequate venous access to allow significant blood drawing, who donated peripheral blood mononuclear cells for assessment of cytokine production. Sufficient serum production was available for measurement of free testosterone in 166 cases.
Additional tests and measures included: (1) body composition: This was measured at each subject visit by a single frequency, whole body bioelectrical impedence assay (BIA); resting energy expenditure was measured by indirect calorimetry taken after four hours of fasting; (2) cytokine measurements: PBMC were isolated from 20 ml of anticoagulated blood and frozen; (3) free testosterone measurement: serum free testosterone was measured by radioimmunoassay; and (4) other measures: the subjects' dietary intake (three day food records), physical activity, CD4 counts, and plasma HIV were all measured by the researchers during the course of the study.
Absolute changes in weight, lean body mass, and REE over a maximum time interval of eight months were modeled using repeated measures regression methods. Restricted cubic spline regression models tested significant non-linerarity in the independent association dependent variables and the main determinants – cytokines and testosterone.
Results
The primary goal of the study was a longitudinal analysis of change in lean body mass after the date of PBMC culture. Key findings during the observation period included:
- The mean change in weight was a loss of 0.02 kg (range was a loss of 12.2 kg to a gain of 8 kg). Lean body mass had similar results with a mean of 0.02 kg loss and a comparable range.
- The mean change in REE was 6.8 kcal/d.
- Classic wasting (ten percent of weight as found in AIDS patients) was found in only two percent of the patients.
- Both catabolic cytokines tumor necrosis factor and interleukin by peripheral blood mononuclear cells predicted lean body mass. A rise in REE (>200 kcal/d) was found in 17 percent of patients regardless of weight change; PBMC findings predicted the change in REE.
- Serum free testosterone production was inversely associated with cytokine production and not a predictor of lean body mass or change in REE.
Conclusions
This study:
- Finds that loss of lean body mass and rise in REE – indicative of cachexia – persist even with aggressive antiretroviral therapy.
- Reveals that catabolic cytokines tumor necrosis factor and interleukin, interacting with free testosterone, are important determinants of change in LBM and REE.
- concludes that the similarity of findings between an examination of rheumatoid arthritis and HIV infection suggests that the link between PBMC production of cytokines and interleukin may be a primary cause of cachexia in the HIV infected male.
Recommendations The researchers suggest that the continual presence of cachexia, despite antiretroviral treatment, will continue in HIV infected men. They recommend that specific anabolic therapy should be considered for men with severe lean body mass loss as well as a new exercise regimen for these patients.
Source: American Journal of Physiology, Endocrinology and Metabolism, July 2002. (Also now available in Articles in Press.)
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.