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HIV-related diarrhea and cachexia are tremendously serious problems in developing countries where there is little access to antiretroviral medications. They also remain concerns for many AIDS patients in the United States, yet much needs to be proved with regard to treatments. Patients who have these symptoms have a reduced quality of life and can have a shortened life span. One study has shown that 42% of HIV patients taking highly active antiretroviral therapy experienced clinical wasting, according to research presented last October at the American Dietetic Association annual meeting in Denver.
Studies on the incidence of wasting among HIV patients demonstrate that cachexia remains a problem despite antiretroviral treatments, says Alvan Fisher, MD, clinical associate professor of medicine at Brown University in Providence, RI. Fisher says the most effective interventions now available for treating wasting and weight loss in HIV patients and cancer patients are anabolic agents and appetite stimulants.
One study using the appetite stimulant dronabinol (Marinol) vs. a placebo in 94 HIV/AIDS patients showed that patients taking dronabinol had a significant increase in appetite for up to 12 months, according to data presented at the ADA meeting. Another study showed that most patients taking dronabinol had an improvement in symptoms of nausea and vomiting, according to data presented at the Fifth Congress on Drug Therapy in HIV Infection, held in October 2000 in Glasgow, Scotland.
Still, many researchers acknowledge that AIDS patients who have an adequate caloric intake still may suffer from wasting. This is why researchers from a variety of scientific backgrounds are seeking ways to reduce or eliminate this problem in HIV and cancer patients. For example, investigators in the Carolinas and Virginia have studied the use of a glutamine-based oral rehydration solution (ORS) for treating HIV-related diarrhea and wasting.
The work is ongoing, but an interim analysis has demonstrated a favorable trend with respect to stool frequency and stool output, says Nathan M. Thielman, MD, MPH, assistant professor at Duke University Medical Center in Durham, NC. There are two reasons for evaluating glutamine in an ORS, Thielman says. "No. 1, ORS is a time-tested proven means of rehydrating patients with dehydrating diarrheal illnesses," he says. "It takes advantage of elegant physiological mechanisms in which glucose stimulates sodium absorption and hence absorption of fluid in the system, even in cases of cholera." The second reason is that glutamine appears to have some nutritional benefit to the intestines and also is a major source of energy for enterocytes, Thielman adds. The research involved observing patients in an inpatient unit for seven days in which stool samples were obtained.
Thielman also was involved in another study in which the quality of life of HIV patients who suffered from diarrhea and wasting was compared with patients who had diarrhea but no wasting and with patients who had neither diarrhea nor wasting. The quality of life of the patients who had neither diarrhea or wasting was significantly higher than the other two groups of patients, and the quality of life of the patients who had only diarrhea and no wasting was significantly higher than the patients who had both symptoms, Thielman says.
At the University of North Carolina in Chapel Hill, a separate avenue of research is being conducted into developing a better understanding of the mechanisms involved in cachexia. "It was already known that cytokines were involved, and AIDS patients often have elevated cytokines, so cytokines are involved and muscle is involved," says Albert S. Baldwin, Jr., PhD, professor and associate director at the Lineberger Cancer Center at the University of North Carolina in Chapel Hill. "But it wasn’t known what was in between the two." He notes that in addition to HIV-related cachexia, about 50% of late-stage cancer patients suffer from muscle wasting, and cachexia causes nearly one-third of their deaths.
Investigators now have an idea of what is going wrong to cause muscle wasting. Muscle cells normally go through constant loss and repopulation. Animal models suggest that with wasting disease, but the mechanism for replacing lost muscle cells is being blocked.
The first step in the process is to identify the culprit of the process that is downstream of the cytokines and that causes the muscle degeneration. Investigators believe they have found the cause of the block of repopulation, which is called NF-KappaB. Then researchers may identify a drug that could inhibit NF-KappaB and block its ability to cause the muscle degeneration. The next step is to establish animal models for cachexia to determine whether the NF-Kappa B inhibitors will have an effect in these studies. Then it may be another year or longer before human trials can begin.