SEPTEMBER 1998

NUMBER ONE

Freak Fat
"Buffalo humps" and giant breasts aren't fun.

For months, reports have emerged about unusual side effects associated with protease inhibitors, including disfiguring body changes and serious health risks. Now investigators have offered several theories about their cause of this problem, a metabolic disorder called lipodystrophy. At Geneva, researchers reported that an experimental drug, recombinant growth hormone (rGH), seemed to treat the problem in five people, but the therapy is so expensive-$20,000 to $30,000 a year-that it's not likely to benefit most people with HIV.

People with lipodystrophy typically lose weight in their faces, arms, and legs, giving them a gaunt look, but they regain fat in their bellies-dubbed "protease paunch"-and odd fat deposits in the neck and elsewhere termed "buffalo humps." Some women have had extreme increases in body and breast size, from a B to an E cup. While estimates vary greatly, from 10 to 75 percent of people on HAART have developed the condition, usually after about 10 months on combination therapy. Most have been on protease inhibitors but some have used potent non-protease drugs.

Researchers say the therapy impairs the body's ability to break fat down correctly, causing a loss of peripheral fat under the skin and an increase in visceral fat around the abdominal muscles. CAT scans of people with lipodystrophy (see photo) show fat accumulations around the liver and intestines as well.

HIV-related lipodystrophy is characterized by an increase of LDL cholesterol (the bad kind) and a decrease in HDL cholestrol (the good kind), along with increases in triglycerides, plasma insulin, plasma cortisol level, and C-peptide levels, leading to glucose resistance. High lipid levels turn the blood to near-butter and dangerously increase risk of heart attack. Several cases of coronary disorders were reported this year among people on protease regimens, prompting a warning to doctors.

Unfortunately, standard drugs to lower cholesterol and triglycerides seem to have only a partial effect on lowering lipid levels in people with lipodystrophy, as does a low-fat diet. Meanwhile, the increase in glucose levels among those on HAART, as well as reports of diabetes, has prompted the FDA to issue a public health advisory regarding these risks for those on protease inhibitors, especially pregnant women.

Researchers initially thought the cause of lipodystrophy was Cushing's Syndrome, another lipid disorder, but that's been ruled out. Another theory, by Australian researcher Dr. Andrew Carr, proposes that HIV drugs blocking the protease enzyme may also interfere with the function of two other lipid proteins with a similar structure to protease: LRP (low density lipoprotein-receptor-related protein) and CRABP-1, a protein involved in retinoic acid production that uses cytochrome P450.

Dr. Donald Kotler, an expert on nutrition at St. Luke's-Roosevelt Hospital in New York, fingers the stress hormone cortisol as the main culprit. Studies show if you give someone cortisone they develop big bellies, insulin resistance, and hypertension, says Kotler. He thinks lipodystrophy is linked to successful HAART therapy and the subsequent drop in HIV activity, since most people who develop symptoms have below-detectable viral-load levels. Dr. Kotler points out that gaunt faces, big bellies, and skinny legs are common in long-term survivors of HIV with very low viral levels. They're also seen in women who survive cancer, children who survive leukemia, and Vietnam veterans who suffer from a post-traumatic stress disorder characterized by an increase in cortisol (derived from cortisone).

At Geneva, a study of growth hormone (rGH) in five people on HAART found that the drug produced a 25 percent to total resolution in body-fat redistribution but did not improve cholesterol or triglyceride levels, leaving people still vulnerable to a heart attack.

Growth hormone is used to treat HIV wasting and can increase lean body mass and weight. Reported side effects in the lipodystrophy study included two cases of hyperglycemia and one case of increased pancreatic enzyme levels. Other rGH side effects include tissue turgor (swelling of hands and feet), carpal tunnel syndrome, and glucose intolerance with overdosage. That means pregnant women who risk developing diabetes shouldn't use it. Low rGH levels have also been observed in patients with severe liver problems. Since protease inhibitors increase the risk of diabetes and can damage the liver, growth hormone should be used with caution in anyone taking HAART. For now, people with glucose intolerance and liver problems should be closely monitored.

Other strategies, like liposuction, work for "buffalo humps" but don't address the underlying problem, and the fat may grow back. Going off HIV drugs isn't recommended, especially for those with chronic HIV and low T-cells, because of the risk of HIV disease and HIV drug resistance. Dr. Carr has had patients go off their drugs and seen the condition reverse itself in some people but not all. If his theory is right, adopting a non-protease drug regimen or one that doesn't involve p450 inhibitors might help.

In studies of wasting, testosterone plus a combination of resistance training (climbing steps, Stairmaster) and such anabolic 17-alkylated as steroids like Oxandrin have been found to increase lean body mass and weight. At Geneva, a testosterone patch called TMTDS used in women appeared safe and increased weight (in fat). But with lipodystrophy, 17-alkylated steroids like Oxandrin may be risky because they stress the liver, decrease HDL, and increase LDL cholesterol levels as well as the risk of arteriosclerosis and coronary heart disease-the exact risk factors you want to avoid. Doctors also caution against using some lipid-lowering drugs like statins (try Gemfibrozil or Lipitor instead) that may interact with HIV meds. Alternatives to decrease the risk of heart attack are a low-salt or high-potassium diet that can lower blood pressure, or Niacin to lower cholesterol.

"Protease Paunch" Up Close

1. CT scan from an AIDS patient with MAC infection, demonstrating thickening of the intestinal walls and enlarged lymph nodes in the mid-abdomen. There is a fair amount of subcutaneous fat, which is found just beneath the skin, and is represented by a dark band.

2. CT scan from an HIV-infected patent with lipodystrophy. Compared with No. 1, there is much less subcutaneous fat. In addition, the internal structures are surrounded by a larger amount of dark area, representing fat. The CT slice shows that there is excess fat in the intra-abdominal area as well as the retroperitoneum, which is the area behind the abdominal cavity containing the kidneys and adrenal glands, among other structures.

PHOTO COURTESY OF DONALD KOTLER, M.D.