Internet Update from the AIDS Treatment Data Network
Information from the XII International Conference on AIDS, Geneva, Switzerland. June 28-July 3, 1998

Side Effects of Anti-HIV Drugs

A number of presentations in Geneva were about side effects from anti-HIV drugs. Many anti-HIV drugs have been approved for prescription based on short-term studies, some only six months long. Because the studies were so short, side effects that take longer to show up may not be seen until after a drug is approved. The four approved protease inhibitors -- indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir) and saquinavir (Fortovase) -- all have side effects that didn't show up until after people had been taking the drugs longer than the original study periods.

The side effect that got the most attention in Geneva is a condition called lipodystrophy. Two symptoms of lipodystrophy are:

Losing weight in the face can make someone's eyes look sunken and their cheekbones stick out. This look of extra fat around the belly and weight loss from the face, arms and legs can make someone look like they're malnourished, or not getting enough food. Some people have also developed fatty lumps at the back of the neck, sometimes called buffalo humps.

Besides the changes in fat and weight loss that can be seen, other side effects that can't be seen may also be symptoms of lipodystrophy. Side effects people are getting that show up in their lab work are:

Studies of Cholesterol and Triglyceride Levels
1. Researchers at the University of Minnesota have found high levels of cholesterol and triglycerides up in some people taking protease inhibitors. High levels of cholesterol and triglycerides are associated with risk of heart disease. Dr. Keith Henry, who wrote this report, is worried that even small increases in cholesterol may be serious because they can represent a large increase in what are called low-density lipoproteins (LDL, sometimes known as "bad" cholesterol), along with a decrease in high-density lipoproteins (HDL - these aren't so bad). To make matters worse, the high triglyceride levels that are also part of this problem can make it harder to measure cholesterol levels correctly. Dr. Henry recently reported two cases of a heart condition called coronary artery disease in people taking protease inhibitors.

In Geneva, Dr. Henry reported that 28 people out of 121 in his practice taking protease inhibitors have seriously high levels of cholesterol and triglycerides in their blood. To try and treat the problem, he's following guidelines from the National Cholesterol Education Program (NCEP). Thirteen of the 28 people are trying diet and exercise plans in hopes of reducing their cholesterol and triglyceride levels. The other 15 people are using drugs that lower cholesterol. More time has to go by before we can tell if the diet and exercise or the drugs work. Other serious side effects seen in his clinic include four new cases of pancreatitis, three cases of diabetes, one heart attack, and one new case of angina, a heart disease.

2. Researchers from the Walter Reed Army Institute looked at information from 340 people. Ninety-five people were not taking anti-HIV drugs, 87 people were taking HIV drug combinations without protease inhibitors, and 158 people were taking combinations that included protease inhibitors.

The researchers found that cholesterol levels were about normal in people taking no HIV drugs. In people taking combinations without protease inhibitors, cholesterol levels were only a little above normal. In the group taking combinations including protease inhibitors, cholesterol was higher than normal. The largest changes in cholesterol levels were seen in people taking combinations that included two protease inhibitors, ritonavir (Norvir) and saquinavir (Fortovase, Invirase).

3. A study from Switzerland looked at blood levels of both cholesterol and triglycerides. The study compared 94 people taking anti-HIV drug combinations with protease inhibitors to 16 people taking anti-HIV drug combinations without protease inhibitors. Triglycerides were high in about two thirds of people taking protease inhibitors. The highest triglyceride levels were seen in people taking ritonavir and ritonavir combined with saquinavir. Cholesterol levels were high in a little over half the people taking protease inhibitors.

Studies of Changes in Body Shape
1. Other Geneva presentations looked at changes in body shape. The largest study done so far is from a group of researchers in Australia. The researchers think the changes in fat levels are a symptom of lipodystrophy.

To study lipodystrophy, the researchers looked at 195 people. 116 were taking protease inhibitors as part of their anti-HIV drug combination, 32 weren't taking protease inhibitors, and 47 people without HIV were studied as a comparison. More than half of the people taking protease inhibitors noticed changes in body shape. The changes included:

Technical measures of fat showed that the arms and legs had lost fatty tissue. Blood work showed high levels of triglycerides, lower amounts of HDL cholesterol, and higher levels of insulin and a related protein called C peptide. One person developed diabetes.

The average time on protease inhibitors before the development of lipodystrophy was 13 months. Although all available protease inhibitors appear to have the potential to cause these problems, the double combination of ritonavir and saquinavir was associated with more problems than any protease inhibitor alone.

The lead doctor on this study is testing a theory that all of the side effects are related directly to protease inhibitors. HIV protease, which is the part of HIV that protease inhibitors block, has similarities to proteins in the body that help with processing fats. If protease inhibitors are blocking these natural proteins, it may explain the side effects described above. A study looking at this possibility is ongoing, and results should be available within a few months.

Exactly how many people taking protease inhibitors will have changes in body shape is not clear, because different studies used different methods to decide if body shape had changed. The Australian study used "self-report." Self report means that people reported to the doctors if they noticed changes in their body shape. Since people usually spot changes in body shape easily, self report seems to be a good way of collecting information on lipodystrophy. Other studies used various lab measurements which give different results. Other differences between studies may be because of how long people had been taking protease inhibitors. Symptoms of lipodystrophy usually show up as a long-term side effect.

2. A study by a team of researchers in Rhode Island looked at lipodystrophy in women. Out of 116 women taking protease inhibitors, 21 reported changes in body shape.

3. A study from France found lipodystrophy in 12 out of 100 people taking protease inhibitors. These 12 people had been taking protease inhibitors for an average of 14 months. All had experienced loss of fat from the legs, and five had also lost fat tissue from the face. All had high levels of triglycerides in their lab work, higher insulin levels, and abnormal glucose tolerance test results. The glucose tolerance test measures the body's ability to use sugars properly. No one in the study developed diabetes.

Studies of Blood Sugar and Diabetes
1. A group of German researchers looked at how the body uses glucose and insulin in people taking protease inhibitors. Insulin is a substance used by the body to process, or metabolize sugars properly. Diabetes is the medical condition that results when there isn't enough insulin. People with diabetes have to take insulin so their body can process sugar properly.

This study compared 67 people with HIV taking protease inhibitors to 13 people that were not taking any treatment. The study also included 18 people without HIV as a comparison. More than half the people taking protease inhibitors had lower sensitivity to insulin, meaning there were problems with how their bodies processed blood sugar. No one had full diabetes.

Other presentations looked at blood sugar, or glucose levels in people taking protease inhibitors. Although high glucose levels were common, cases of diabetes were rare.

2. A German study found high glucose levels in 84 out of 783 patients (11%) taking protease inhibitors.

3. A Spanish study found high glucose levels in 45 out of 298 patients (15%), and two developed diabetes.

4. Out of 216 people taking protease inhibitors in a California clinic, 25 (11.5%) had high blood glucose levels.

5. One French study reported three new cases of diabetes in people taking protease inhibitors. None of the three had any personal or family history of diabetes.

6. Over a three-year period up to January 1998, the HIV Telephone Consultation Service received 26 reports of protease inhibitor-associated diabetes out of 1300 calls. The HIV Telephone Consultation Service is a national resource for Health Care professionals. The service is run by San Francisco General Hospital and provides expert advice on HIV treatment. The number is 800-933-3413.

Dealing with Lipodystrophy
The side effects reported here appear to be linked to protease inhibitors, but further research is needed. A GI doctor in New York who's been treating people with HIV for many years isn't convinced all the problems are caused directly by protease inhibitors. He thinks some of the problems could be because of lowered viral loads and higher T4 cell counts. He also notes that the Walter Reed Army Institute study described here shows a definite link between high levels of fats in the blood and protease inhibitors.

Some people report that switching protease inhibitors has gotten rid of lipodystrophy symptoms. One study presented in Geneva tried switching 21 people with lipodystrophy to a different protease inhibitor, in this case nelfinavir (Viracept). After three months, seven people saw some improvement in their symptoms. The Australian group is looking at whether switching to a combination of anti-HIV drugs without a protease inhibitor will get rid of lipodystrophy symptoms.

Only one Geneva report was about treating lipodystrophy. A New York doctor tried human growth hormone (Serostim). Although there were some improvements in body shape, levels of fats in the blood did not change significantly. A larger study is ongoing.

Some people are trying alternative and nutritional approaches that may help with lipodystrophy. None have been studied in clinical trials. A summary of possible alternative treatments for lipodystrophy is in the May 1998 Being Alive newsletter.

Current recommendations are that people should be sure to report any changes in body shape to their healthcare provider. Regular tests of fats in the blood, called fasting lipid tests, should be done. Dr. Andrew Carr, who works with the Australian research group, recommends that anyone taking a protease inhibitor also be given glucose tolerance tests to help monitor for lipodystrophy.

In a recent interview by Anne-christine D'Adesky of Out Magazine's new HIVPlus supplement, Dr. Carr was asked how he was currently dealing with cases of lipodystrophy. He responded:

"My approach currently is to stop all antiretrovirals and re-evaluate viral load and CD4 counts after 3 months or so. I do not do this if a patient has prior AIDS or a CD4 count less than 200 or so before commencing their protease inhibitor."

Stopping treatment would depend on the seriousness of the lipodystrophy, including how many of the associated side effects were present. Ongoing studies should soon provide clearer answers about dealing with lipodystrophy.

This report is partly based on Dr. Kotler's excellent reports from the Geneva conference, which can be found on the Clinical Care Options for HIV website. The Network sincerely thanks Edward King and the rest of the team at Clinical Care Options for HIV for their comprehensive daily coverage of the Geneva Conference.

Internet links with more information:

Geneva Reports
Last modified: 1/25/99
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