Fat Disorders: A Growing Threat
Health Risks include Heart disease.
by Ed Sussman

Over the past few months, a disturbing drug side effect that was first dismissed as unusual has taken center stage, threatening to reverse the gains we've made using new combination therapies. At the recent Third International Conference on Nutrition and HIV in Cannes, France, Dr. David Zucman of Hopital Foch in Suresnes, France, reported that 51 heart-attack cases including 10 deaths, had been recorded as of March 30 by French health authorities in people taking HIV combination therapies, an alarming finding. Some doctors worry that these cases could be linked to a syndrome known as lipodystrophy. For now, this link is speculative, since heart attacks are known to occur in people with HIV.

Lipodystrophy refers to a perplexing fat distribution and metabolic disorder that causes some people on HIV combination therapy to lose fat in their arms, legs, and face, but gain it in their abdomen, chest, and in women, in their breasts, and on the back of their neck, where the fat lumps are called "buffalo humps." People typically develop dangerously high cholesterol and triglyceride levels, which increase their risk of a heart attack and pancreatitis, respectively. Some develop insulin resistance, which increases the risk of diabetes. "We don't really know why high cholesterol occurs in patients on protease inhibitors, but we do know that patients with high cholesterol are at risk of heart disease," says Zucman.

Given the scary news, he warns that people with HIV and their doctors should carefully consider this risk and take steps to minimize it. Since 1997, falling AIDS death rates have reflected the enormous progress made with new anti-HIV drugs, which have halted active HIV infection and improved the immune health of many people. "We thought we had all the answers," said Dr. Donald Kotler of St. Luke's-Roosevelt Hospital Center in New York, "because no matter what we would do to patients, they would get better." Two years later, many aspects of lipodystrophy are being hotly debated, including the exact cause of the problem.

There is mounting evidence that the longer people stay on potent anti-HIV drug regimens, the greater their chance of developing lipodystrophy. To date, an estimated one-third to one-fourth of people on HIV therapies are already affected, according to specialists at the Cannes nutrition conference. "One of the more puzzling aspects of the disorder is not everybody gets these things," said Dr. George Griffin, professor of Infectious Diseases and Medicine at St. George's Hospital Medical School in London. He thinks that looking into why some people on active treatment do not have the problem might be a profitable area of research. Some worry that it's just a matter of time before others develop the problem. In January, a French study of 642 people showed that, after 18 months on protease inhibitors, 78 percent had some evidence of metabolic disorder.

Nor is this side effect limited to use of protease inhibitors, as was first thought. A battery of new reports presented in June showed that nonprotease drugs also cause symptoms closely resembling lipodystrophy, although lipid or insulin abnormalities aren't always seen. The syndrome may also take longer to develop with nonprotease drugs.

The one bit of good news is that at least one drug, human growth hormone (Serostim), appears to partly or completely reverse the symptoms of lipodystrophy, based on prelimary reports, while other lipid-lowering drugs can reduce the risk of cornonary heart disease, pancreatitis, and diabetes.

Reversing The Problem
At Cannes, Jill Cadman, a researcher working with Dr. Gabriel Torres, a leading New York City HIV physician, presented an update on the use of growth hormone in 10 people with "buffalo humps" and/or "central adiposity" (fat deposits in their bellies). Eight patients saw improvement or complete resolution of the fat in their abdomens; five of six saw improvement of the "buffalo humps."

Cadman said that one woman had reduced her bra and pants by two sizes after four months on growth hormone. But her condition returned after she was unable to continue taking the medication (once her insurance company refused to pay for the very expensive treatment). On a more positive note, Serostim was recently added to the list of drugs covered by Medicaid.

At the nutrition conference, another researcher, Dr. Stefan Mauss, a gastroenterologist from Dusseldorf, Germany, described an HIV patient who had developed abdominal obesity after years of taking various antiretroviral drugs. Mauss said the patient's condition regressed after he was given a course of treatment with growth hormone. He presented before-and-after CAT (CT) scans of the man's abdomen that clearly showed the disappearance of visceral fat and the appearance of increased lean muscle.

"As far as I know," Mauss stated, "this is the first case in which we have shown with CT scanning that growth hormone can reverse visceral abdominal fat." Mauss said that when the fat regressed, the patient who was on a four-drug regimen (d4T, ddI, nevirapine, hydroxyurea) was taken off growth hormone. Several weeks later, he began suffering symptoms again and the growth hormone treatments were resumed.

Minor and transient side effects have been reported in some patients taking Serostim, including swelling of hands and feet, muscle stiffness or pain, carpel tunnel syndrome, hyperglycemia and possible allergies. Discuss these risks with your doctor, including potential drug-drug interactions.

Prevention Steps
Dr. Zucman has had success using cholesterol-lowering drugs such as atorvastatin (Lipitor) to lower the risk of heart attack. The normal range for cholesterol level is 140 to 229 mg/dl; above 240 is viewed as high risk for coronary problems. In Zucman's studies, a two-month course of atorvastatin brought down cholesterol levels in his patients from a baseline total about 296 mg/dl to less than 200 mg/dl. Their levels of LDL cholesterol-so-called "bad" cholesterol-fell from just above 200 mg/dl to 133 mg/dl, a 35 percent drop. "Atorvastatin seems to be very effective in lowering cholesterol levels in these patients," Zucman said. "Patients had excellent tolerance of the drug. During the two-month period, I saw no harmful side effects that prevented keeping HIV levels under control." Others are using Gemfibrozil to reduce lipid levels.

A word of caution: Atorvastatin and other cholesterol-reducing drugs in the "statin" family may interact with anti-HIV drugs that are metabolized through similar liver pathways. Zucman is now studying this very issue. Most of Zucman's patients were taking Crixivan, and he's found no part-icular reaction between that protease inhibitor and atorvastatin. However, a few patients were taking the protease-inhibitor combination of Fortovase and Norvir. In these patients, there was a significant fall in protease-inhibitor levels in the blood, requiring suspension of atorvastatin treatment. "When the atorvasatin was discontinued, cholesterol levels returned to pathological levels," Zucman said.

Other strategies can lower high triglyceride levels, thus decreasing the risk of pancreatitis. The normal level for triglycerides is about 4 mmol/l; 10 mmol/l is the threshold value for developing pancreatitis. In a study of 20 French patients on protease inhibitors, Dr. Marie-Caroline Meyohas of Hopital Saint Antoine, Paris, found that adopting a diet to reduce fats and sugars for six months brought down triglyceride levels from a baseline of 20 mmol/l to 7.5 mmol/l. "There was a very considerable decrease, with 85 percent of the patients going below the 10 mmol/l threshold for pancreatitis," said Meyohas, adding that the reduction persisted for at least six months.

Not everyone agrees that a change of diet will help. Marijka Batterham, a researcher from the Royal Prince Alfred Hospital, Sydney, Australia, found that dietary fat appeared to play a very small role in the development of fat-redistribution syndrome in her studies. "Many people with HIV/AIDS have been reviewing their dietary fat intakes, despite lack of evidence that this condition is influenced by dietary factors," she said, adding that more research is needed before dietary restrictions should be placed on people living with HIV.

Metformin, an anti-diabetes drug, also lowers triglyceride levels and can decrease insulin resistance but it can cause or worsen kidney problems and result in weight loss. Another drug, Troglitazone, can impair liver function and should be used with caution, since HIV drugs may also affect the liver. The same caution applies to Oxandrin, a 17-alkylated steroid used to treat HIV wasting, which may stress the liver and increases LDL cholesterol (the "bad" kind) levels. Experts suggest resistance exercise for building up muscle and countering wasting.

Stopping or Switching?
Instead of swallowing yet another pill, some people have decided to stop taking their HIV meds altogether. In a French study publicized in June, involving 14 patients on nonprotease regimens who developed signs of lipodystophy, T. Saint-Marc and J.L. Touraine of Hopital E. Herriot, in Lyons, France, found that stopping d4T for six months improved metabolic and fat abnormalities induced by d4T. Interestingly, some patients kept losing fat for the first two months after they stopped taking the drugs. But as experts point out, that's a risky strategy, since HIV may bounce back during that time.

What about switching over to a nonprotease regimen? Here, the news is also mixed. Dr. Esteban Martinez of the Hospital Clinic, Barcelona, Spain, examined 23 patients, 12 men and 11 women, who were taken off protease inhibitor regimens when they developed fat disorders. They were put on regimens with nucleoside reverse transcriptase inhibitors and nevirapine, a non-nucleoside reverse transcriptase inhibitor. The patients were able to keep their viral loads below limits of detection and their high triglycerides and high cholesterol levels were normalized with the change to nonprotease therapy.

More recently, a London group found that prior protease therapy can be a risk factor for developing lipodystrophy while on nonprotease regimens. An Australian team led by S. Mallal also showed that nucleoside analog drugs cause slow or progressive fat loss that is accelerated by adding a protease inhibitor, particularly drug regimens containing d4T.

Another study, by P. Mercie of the Groupe d'Epidemiologie du SIDA in Aquitaine, France, found signs of fat and lipid disorder occuring in patients who had never taken protease inhibitors. Their study singled out 3TC and d4T, but others finger the other nonprotease drugs as well. A Milan group reported that dual nonprotease regimens can cause the problem, while Australian researchers think two symptoms, lactic acidosis and liver dysfunction, contribute to HIV fat and lipid problems in people on nonprotease regimens.

Ed Sussman covers science issues for United Press International.