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Protease Inhibitor Side Effects
Take People by Surprise

December 1997/January 1998

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Ellen, a 42-year-old white female bookkeeper, has been on triple combination therapy for the last 12 months. During this time she has had an undetectable viral load. But, Ellen relates, "The most unusual development has been breast enlargement. My breasts got round, full and plump and they stand out like the dancers in Las Vegas who have had implants." She continues almost with disbelief, "I was a 34A [bra] cup and went to a 36D cup. I went to my doctor who told me that I should go find a boyfriend. We did not realize it was the Crixivan. I should send the drug company the bill for my new bras." Ellen has found an e-mail discussion group,, instituted so that people can share their experiences on Crixivan (Merck's protease inhibitor indinavir). There are hundreds of entries each month from individuals reporting all manner of possible side effects, including other women like Ellen, who say the changes in their bodies remind them of when they were pregnant.

Over the last year a growing number of patients on protease inhibitor-containing regimens have reported a variety of unusual symptoms. These range from changes in body composition and blood sugar and lipid levels to hemolytic anemia to abnormal bleeding in HIV-positive hemophiliacs. It is clear that many people are experiencing unexpected metabolic changes after starting combination therapy. What is not clear is the exact cause or the potential for permanent damage.

Triglyceride, Cholesterol and Blood Sugar Levels

As of May 1997, there were 83 reports to the FDA of new or exacerbated cases of diabetes or hyperglycemia (high blood sugar) in HIV-infected patients who were receiving protease inhibitor therapy. As of November 1997, the number of reports had increased to 230. Of the 83 original cases, 27 required hospitalization, including six that were life threatening. Fourteen of the patients, who were known to be diabetic at baseline, experienced loss of glucose control. Average time to onset was 76 days after initiating protease inhibitor treatment, but in some reports symptoms appear in as little as four days. Five cases resulted in ketoacidosis, a serious diabetes-related condition that is characterized by a fruity mouth odor, nausea, vomiting, dehydration, weight loss, and if untreated, coma or death. The initial 83 reports led the FDA to issue a Public Health Advisory in June. Physicians were warned that protease inhibitors may contribute to these conditions and advised to closely monitor patients' glucose levels.

Diabetes and hyperglycemia were reported in varying degrees for all four protease inhibitors, although no causal relationship has been established. The FDA maintains that these events occur infrequently and does not recommend that patients stop using protease inhibitors. At this early stage, with such a limited number of cases reported, the benefits still outweigh the risks. In addition, many patients who developed diabetes while on protease inhibitors were able to control the condition with treatment. Nonetheless, all four protease inhibitors were required to revise labeling to include this potential side effect.

Michael Dube, M.D., of the Los Angeles County-University of Southern California Medical Center, has become increasingly concerned that protease inhibitors alter the way the body handles blood sugar (glucose). He so far has conducted research on eight non-diabetic patients before and after starting indinavir. When he administered oral glucose to the patients, Dr. Dube found some reduction in the amount of insulin secreted in all eight after two weeks on indinavir, but these results could not be duplicated at eight weeks.

(Insulin is a naturally occurring hormone released by the pancreas in response to increased blood sugar levels. The hormone regulates the body's use of sugar as well as some of the processes involved with fats, carbohydrates and proteins. Inadequate secretion of insulin results in hyperglycemia and the signs of diabetes, including heightened thirst and hunger, increased urination, weight loss without apparent cause, fatigue and dry, itchy skin.)

Dr. Dube notes that glucose and lipids are intimately linked. In fact, there have been many reports of elevated levels of such lipids as triglycerides and cholesterol in patients on protease inhibitor therapy. Excess lipids in the bloodstream can lead to arteriosclerosis (hardening of the arteries) and heart disease. John Gerber, M.D., of the University of Colorado, explained how he handles elevations in blood triglycerides in his patients, "I figure when triglycerides get above a thousand (normal levels are 35-200 mg/dl), I choose to stop the medication. This is because of my concern regarding pancreatitis. I have not seen pancreatitis in any reports, but we know high triglycerides can precipitate this condition."

Dr. Gerber also elaborated on the combination of protease inhibitors and cholesterol lowering agents for those patients who have experienced high cholesterol levels. He stated certain drugs, such as lovastatin and simvastatin, both used to lower cholesterol, are metabolized in the liver by the cytochrome P450 family of enzymes, specifically the 3A4 pathway (CYP3A4). The protease inhibitors are also metabolized by this pathway, so there is a potential for drug interactions at this site that might lead to side effects. Abbott's protease inhibitor, ritonavir, actually inhibits the CYP3A4 enzymes. This means a person taking ritonavir might not break down lovastatin and simvastatin adequately, leaving high levels of these drugs in the bloodstream. Dose adjustments might be needed to avoid possible toxicities that could be fatal. "I think people need to pay attention to drugs that are metabolized by 3A4 and have a very low threshold in regards to toxicity," Dr. Gerber stated.

Red Blood Cell Destruction and Hemorrhaging

This past summer, Merck added a warning label to indinavir as a result of 20 cases of hemolytic anemia. The condition causes a premature destruction of red blood cells, and the most common symptoms are fatigue, jaundice and discolored urine. The condition progresses rapidly and requires treatment, including possible discontinuation of the protease inhibitor.

People with hemophilia have had special concerns about protease inhibitors and blood loss: The FDA notified physicians in July 1996 of the first 15 reports of spontaneous bleeding among hemophiliacs treated with one of the protease inhibitors. There are now at least 55 such reports worldwide. At the 6th European Conference on Clinical Aspects and Treatment of AIDS held in Hamburg last October, there was a presentation (abstract 380) on 17 Spanish hemophiliac patients who had indinavir added on to prior AZT/3TC. Five of the seventeen (29.4%) experienced bleeding, including three hematomas.

Hematomas, in which blood flows into body tissues and causes swelling, have been the most commonly reported serious bleeding. However, there have been some cases of hemarthroses, or bleeding into a joint. This is the type of hemorrhage most common among hemophiliacs. Again, the FDA has stressed there is no conclusive evidence that links such occurrences specifically with protease inhibitor use but does recommend that health care providers monitor hemophiliac patients for spontaneous bleeding episodes whenever any of the protease inhibitors are used.

Changes in Body Composition

Perhaps the first unusual symptoms to be seen in people taking protease inhibitors were growths of atypical fat-like tissues in the stomach (popularly called "Crix belly," although other protease inhibitors may have similar effects) and upper back ("buffalo humps"). Other patients, such as Ellen, began to notice breast enlargement. These abnormal fat deposits can be accompanied by loss of mass and strength in the limbs and buttocks, as in the case of another participant on the Crix-List. This patient described muscle wasting in the arms, chest and legs as well as fatty growths in the upper back and neck area that increased in size after starting indinavir. The benign growths were surgically removed and diagnosed as "lipomas" (tumors consisting of fat cells). Other postings to the list describe the condition as "lipodystrophy" (an abnormality in the use of fats in the body). Whether these fatty growths are related to the increases in blood lipids has not been determined.

In a presentation at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) this fall, Peter Ruane, MD, of the Tower ID Medical Associates in Los Angeles, described buffalo humps in nine of his patients (poster I-185). One patient opted for surgical removal of the growth through liposuction, and another is considering the option. Interestingly, all of the patients had elevated levels of serum triglycerides and seven of nine had elevated serum cholesterol.

Adon Rios, MD, an oncologist in Houston who has specialized in AIDS treatment and research from the beginning of the epidemic, does not see buffalo humps as clearly harmful, but an unexplained fatty growth of tissue is always a concern for an oncologist. As with Dr. Ruane, some of his patients have had their buffalo humps removed surgically.

Symptoms of this condition include general discomfort when patients lie on their back during sleep or maintain their neck in an upright position while awake. No clear cause or damage has been identified with the condition, though most of the patients developed the condition shortly after initiating triple combination therapy with protease inhibitors, indinavir in particular.

Cushing's syndrome, a condition with similar physical manifestations, has been ruled out for the time being. Although patients with Cushing's syndrome also develop hump-like growths in the neck and stomach regions, this is due to a high level of the hormone cortisol, which has not been observed in the people with HIV who exhibit similar growths.

In a recent letter to The Lancet (RL Hengel et al. The Lancet. Nov. 29, 1997; 350(9091): 1596), a group of doctors from Emory School of Medicine in Atlanta reported on a patient who developed a buffalo hump within six months of beginning treatment with indinavir. Blood tests revealed only minimally elevated blood glucose levels. Electrolytes and cholesterol were at normal levels. Further testing ruled out Cushing's syndrome. This abnormality was diagnosed as benign symmetric "lipomatosis," an uncommon condition consisting of unusual tumorlike accumulations of fat in body tissues, usually seen in male alcoholics. Various reports also indicate an association with glucose intolerance and hyperlipidemia (an excess of fat in the blood).

But the Atlanta patient was not an alcoholic. His viral load was too low to assay, and he has continued on his regimen without any worsening of the fatty growth. In their letter to The Lancet, his physicians conclude, "The temporal association between starting his medications and developing his 'buffalo hump,' the effect of protease inhibitors on P450 enzymes, and the recent associations between indinavir use and glucose and lipid metabolism lead us to believe indinavir may be implicated in the development of benign symmetric lipomatosis."

Plans for Future Research

There is as yet no hard data to indicate that this desultory list of symptoms is connected to protease inhibitor use or if any of the conditions are linked to each other. The Forum for Collaborative HIV Research has proposed conducting controlled prospective studies to shed light on which of these abnormalities, if any, are due to protease inhibitor use and why. Several investigations are in development. The first will be a survey to assess the prevalence and nature of metabolic symptoms that are occurring in patients with AIDS. It will consider changes in weight and weight distribution, along with the background medical and family history of participants. The second study will follow a group of people on antiviral therapy and collect data over time on triglycerides, cholesterol, glucose, testosterone, cortisol, insulin and other factors as well as body fat composition. Other studies are needed to evaluate the pathogenesis of arteriosclerotic heart disease.

About 70% of patients on protease inhibitors are on indinavir. According to a representative from Merck, the company plans to have greater communications with clinics and patients regarding these unusual conditions. A site on the World Wide Web may be established to answer questions, as with other cases of unexpected side effects. At least for now, Merck requests that people not refer to atypical fat growths around the mid-section as "Crix belly." The company had no comment regarding the bill for Ellen's new bras.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
See Also
An HIVer's Guide to Metabolic Complications
More Research on Lipodystrophy and Other Metabolic Complications