The San Francisco Examiner; Wednesday, February 11, 1998
Lisa Krieger of the Examiner Staff

Paunches, lumps in the neck, puffy cheeks and other unusual accumulations of fat are changing the body shapes of a surprising number of people taking the newer combination therapies to combat HIV.

The problem of unusual fat accumulation is becoming more pronounced in part because more people have been treated for longer periods with the combination drug therapies.

"We are in a period of ignorance about the prevalence of this problem" and how serious the long-term consequences might be, said Dr. John W. Mellors, an AIDS expert from the University of Pittsburgh.

"More patients are coming to their clinicians and saying, 'I don't look right here, what is going on?' " Mellors said at a news conference at the meeting. "We finally have recognized that there is a problem that needs investigation."

"It is not a vain issue, it is a metabolic issue that has a scientific basis, and we need to investigate it," Mellors said.

How often the unwanted side effect has occurred is not known. But the range is from 5 to 64 percent of the time, according to a flurry of papers reported by the New York Times.

The complications seem to have occurred most often among people taking protease inhibitors.

The protease paunch phenomenon has been dubbed "Crix belly," referring to the drug Crixivan (indinavir), but the name is misleading. It has also occurred among people taking the protease inhibitors ritonavir, saquinavir and nelfinavir.

A second condition, called "buffalo hump," involves uncomfortable fatty swellings at the base of the back of the neck. Some have been removed with liposuction.

Many doctors said they had paid little attention to the problem because they had not heard others discuss it. Some admitted that they tended to focus on complications that could be detected through laboratory tests, not visual observations. Others said their patients had been so delighted with the weight gain that they had not paid attention to the distribution of fat.

The potential seriousness of the problem extends well beyond appearance.

A number of people taking protease inhibitors have developed diabetes, high blood sugar and high levels of lipids in their blood. Just like people with pot bellies, people on protease inhibitors may have increased risk of heart disease.

What causes the fat deposits? No one knows, but doctors think several dynamics may be at work. Perhaps the drugs, known to be hard on the liver, interfere with its regulation and distribution of fats. Or maybe a disoriented immune system causes strange responses, like fat maldistribution.

Drug combinations

More than 200 reports at an AIDS conference this week describe new combinations of AIDS drugs, all intended to improve on the spectacular success of the three-drug cocktails credited with the steep drop in AIDS deaths over the past two years.

The goal is to concoct formulations that are more powerful, less toxic and easier to take. They would require fewer pills, taken on less rigorous timetables, with fewer side effects. Ideally, these mixes would offer a second chance to those who failed to do well on the original combos.

A few AIDS drugs are nearing the end of human testing and will be submitted soon to the Food and Drug Administration for approval. Many more are in earlier stages of testing.

Among the reports:

DuPont Merck Co. plans to seek approval in the second quarter of this year for Sustiva, or efavirenz, a powerful non-nucleoside analogue. Eight reports on the drug were presented at the meeting, including one showing that a two-drug combination with the protease inhibitor Crixivan kept virus levels below detection for 90 percent of patients after one year.

Protease inhibitors may not be an essential ingredient of the cocktail. Studies of abacavir, Glaxo Wellcome's experimental nucleoside analogue, suggest it may be combined with two older medicines in the same category to suppress HIV. This could be an option for those whose virus has grown resistant to protease inhibitors.

Several studies are looking at four-, five- and even six-drug combinations. The most common approaches test the idea of giving two protease inhibitors along with two older drugs in an attempt to knock the virus down more forcefully from the start.

Hydroxyurea, a cancer drug, is being investigated by several teams for its apparent ability to boost the power of DDI and other drugs in its class, called nucleoside analogues.

Combinations of two protease inhibitor drugs suppress HIV as effectively when they were taken twice each day instead of the usual three times in combination therapy. The drugs were Viracept (nelfinavir) and Crixivan (indinavir), made by Merck & Co.

But this combination is worrisome because resistance to one protease inhibitor generally suggests resistance to the second protease inhibitor. Thus, in deciding how to treat someone infected with HIV, said Mellors, "you do not necessarily want to play all your cards up front. . . . If failure occurs, you do not want to end up with no options."

Researchers said no one knew how long the most effective combination therapies would last. Drugs with new ways of attacking HIV will be important to the next major advance in treating the infection.

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