Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
L. Joel Martinez
AIDS has generally been associated with body changes. Designations of "slim disease" and "HIV wasting" have been constant reminders of the dramatic, often devastating changes that can occur. Often "looking like one has AIDS" is as demoralizing a pronouncement as the initial diagnosis of HIV infection.
Medications used to treat HIV infection have also been associated with body changes. Who can forget "AZT butt," the unflattering moniker for the zidovudine (Retrovir) -induced myopathy, which resulted in the loss of gluteal muscles?
Physicians and researchers are now seeing further, more dramatic changes. Some of the changes affect the physical shape of the body. Other changes are biochemical and are manifested silently in the blood of the patient.
Why should the HIV-infected patient be concerned? Changes in the shape of the body can be disfiguring and psychologically detrimental. In the extreme, these changes can become crippling. Changes in the levels of certain fats and tolerances of sugars in the blood of the patient, on the other hand, appear to place the HIV-infected person at some risk for heart problems and diabetes.
These body and blood changes have been lumped together into the catch-all term "lipodystrophy." Technically, lipodystrophy refers to the loss of fat from tissue. One of the first studies looking at a large population of patients, however, described a syndrome of "peripheral lipodystrophy" where patients were observed to lose fat in their arms, legs, face and upper trunk. This Australian study also noted some of the changes in the blood chemistries of the participants that seem to accompany the loss of fat. (Carr, AIDS, 12:F51, 1998) Since that study many have referred to the all the changes, including fat loss, fat redistribution and biochemical blood changes as "lipodystrophy." While this designation is not precise, it is common.
Physicians and researchers began to follow metabolic changes in patients more closely once it became apparent these changes were different from the classic forms of wasting seen in AIDS. To date body changes observed and reported in the literature include the following:
Patients affected with these changes have been tested to see if they were suffering from an endocrininological disorder called Cushing's disease. Cushing's is caused by the excessive presence of cortisol in a person's body. Cortisol is a hormone produced by the adrenal glands in conjunction with a signal from the pituitary gland. Excessive cortisol levels produced by body abnormalities or through the over-use of cortisone derivative drugs causes symptoms such as buffalo hump, fat accumulation in the abdomen and glucose intolerance. Tests performed on the patients did not indicate Cushing's. Some commentators, however, speculate that even in the absence of Cushing's some subtle metabolic changes involving the adrenal/pituitary axis may be involved.
How prevalent are these abnormal body changes? It depends. At the 6th Conference on Retroviruses and Opportunistic Infections (CROI), Carr reported an incidence of 83% in a study of 116 patients. (6th CROI, Abstract 641, 1999.) In this study patients were asked if they had noticed body changes. Despite the high incidence of self-reporting, only 11% reported their changes as "severe." By contrast in a retrospective review of 272 medical charts Boix reported only a 2% incidence of protease inhibitor-induced lipodystrophy. (12th World AIDS Conference, Abstract 12398, 1998.)
The true number according to Morris Schambelan of the University of California in San Francisco is probably somewhere in between, but closer to the upper limit. (6th CROI, S3)
The abnormalities and changes noted in the blood of patients are thought by many to be directly associated with this lipodystrophy and fat redistribution. Experts disagree on whether the fat and blood abnormalities form a part of a single syndrome. The chemical changes noted in the blood include:
Early in the epidemic it was noted by scientists that triglycerides became elevated in persons infected with HIV. It was thought that elevation of triglycerides might be responsible for wasting. In a study on the use of zidovudine, Mildvan (The Lancet, 339:453, 1992) noted that triglycerides actually decreased during zidovudine therapy and that there was no causal connection between triglyceride elevation and progressive wasting.
The elevation of alpha interferon is responsible for the decrease in triglyceride clearance. It appears, too, that reduced clearance is complicated by an increase in new lipid production (Hellerstein, Journal of Clinical Endocrinology & Metabolism, 7:559, 1993). Finally, scientists have determined that persons can have a genetic predisposition to hypertriglyceridemia. (6th CROI, Abstract S3, 1999)
There have been several reports of glucose intolerance and insulin resistance in patients on protease inhibitor therapy. These abnormalities do not seem to be related to the development of fat redistribution. A 62% incidence rate of glucose intolerance was seen among 98 patients on protease inhibitor therapy. (6th CROI, Abstract 647, 1999) However, in a different study where patients were tested prior to initiating protease inhibitor therapy it was found that 25% had impaired glucose tolerance. (6th CROI, Abstract 650, 1999) This finding suggests that HIV-infected subjects may be predisposed to glucose abnormalities even before they initiate protease inhibitor therapy.
Contrary to Mildvan's findings, newer medications, especially protease inhibitors, were implicated early in raising the triglyceride levels of patients. These new drugs also affect cholesterol levels. (Danner, The New England Journal of Medicine, 333, p.1528 and Markowitz, The New England Journal of Medicine, 333, p. 1534) The pattern of these abnormalities seems to be as follows:
This pattern of abnormalities increases the risk of atherosclerosis, but not to the point of abandoning antiretroviral treatment in favor of heart disease risk reduction. In a study of 2,825 patients comparing the incidence of myocardial infarction in patients taking indinavir versus patients taking non-protease inhibitor regimens the data suggest that the risk of myocardial infarction is not increased by indinavir (6th CROI, Abstract 658, 1999). Similarly, a study of patients receiving care at the Kaiser HMO in California reviewed data bases for coronary heart disease in patients on and off protease inhibitors and concluded that after one year of follow-up protease inhibitor use does not appear to increase the risk of coronary heart disease (6th CROI, Abstract 657, 1999).
While these studies might seem persuasive, it should be noted that the mean follow-up for patients was approximately one year.
A much smaller Canadian study of 48 asymptomatic patients on various stable HAART regimens compared patients at various stages of HIV/HAART associated lipodystrophy (HAL). Members of the first group had no HAL; members of the second group had fat depletion only; and members of the third group had peripheral fat depletion and visceral fat accumulation.
When the lipid abnormalities in the three groups were analyzed the researchers noted a progressive process. While lipid abnormalities were found even in the first group these abnormalities progressively got worse in the second and the third group (6th CROI, Abstract 646, 1999). This type of progression does not bode well for the future.
These lipid abnormalities are of concern for heart disease, but other risk factors must also be added into the equation. The National Classification of Coronary Heart Disease Risk Factors Other Than LDL Cholesterol include the following:
These risk factors increase the risk of heart disease in patients who may already be compromised by the lipid abnormalities of HIV disease and treatment.
Several theories have been proposed to explain fat redistribution, lipid and glucose abnormalities. Experts in the field of HIV wasting and nutrition, like Donald P. Kotler, MD, of Columbia University College of Physicians and Surgeons contend that HIV, itself, may be the culprit. Kotler points out that these types of abnormalities occur with other chronic diseases and that the types of abnormalities described above occur also in persons who have never taken a protease inhibitor. The nature of immune suppression caused by different agents or the immune restoration caused by them may be responsible for these abnormalities.
Other researchers have described a molecular explanation for the abnormalities. (Carr, AIDS, 12F51, 1998) noting that the binding site for the protease inhibitors is similar to some degree to a site on a human protein involved in lipid metabolism. If this is the case, the protease inhibitors may be interfering with this protein and may be affecting the natural lipid metabolic mechanism.
Most recently Italian researchers reported on a cross-sectional study of 306 HIV-infected women seen as outpatients in a clinic at the University of Milan. Fat redistribution was noted in 10.5% of the women. A progressive enlargement of the breasts and abdominal girth and wasting in the lower limbs characterized it. These changes were not associated with lipid or glucose abnormalities. Of the 32 women found to have fat redistribution, 20 were on protease inhibitors, but interestingly all of the 32 were on lamivudine (Epivir). The researchers noted that the only variable significantly associated with the fat redistribution were prolonged antiretroviral therapy and a viral load of more than 10,000 at initiation of therapy (Gervasoni, AIDS, 13:465, 1999).
This and other studies suggest that agents independent of protease inhibitors may cause the fat redistribution abnormalities.
If in fact protease inhibitors are largely to be blamed for these complications then it may be possible to reverse the deleterious effects by eliminating the protease inhibitor in the treatment regimen. In a study, 60 patients with lipodystrophy who were taking a protease inhibitor with their regimen were randomized to one of two arms. In group I the subjects took stavudine (Zerit), lamivudine and nevirapine (Viramune). Group II participants took stavudine, didanosine (Videx) and a protease inhibitor. Prior to the randomization all participants had maintained a viral load of less than 400 copies for at least 6 months. At twelve weeks all remained virally suppressed and cholesterol levels had decreased significantly in the nevirapine group. Anthropometric measurements had improved in the nevirapine group, although the changes were not statistically significant. (6th CROI, Abstract LB14, 1999) In another study efavirenz (Sustiva) was substituted for indinavir. At eight weeks there was a slight improvement in glucose intolerance, but also a mild elevation of cholesterol and triglycerides. (6th CROI, Abstract 669, 1999) These studies were too short to determine if there is any significant long term effect of substituting another class of drug for the protease inhibitor.
Other therapies that were tested included metformin (6th CROI, Abstract 672, 1999) which decreased visceral fat but not central adiposity. Troglitazone led to some improvements of lipodystrophy symptoms (6th CROI, Abstract 673). Finally, human growth hormone (Serostim) use resulted in some resolution of fat redistribution although it was reported that these symptoms returned upon discontinuation of the drug. (6th CROI, Abstract 675; Torres, personal communication)
Anecdotal reports of plastic surgery for correction of the fat redistribution abnormalities appear to have mixed results. Physicians warn that while liposuction for visceral (outside the muscle wall) fat may be done, liposuction of central fat is dangerous and not recommended.
Many questions with respect to the true nature of these phenomena remain. Are all these changes interrelated? Can they be traced to a single class of drugs? How are they tied in to previous conceptions of wasting?
The causes and reasons for these abnormalities are not well understood. It is, therefore, difficult to assess what, if any, therapy to pursue. Some protease-sparing regimens appear to be sufficiently potent to maintain significant viral suppression. Yet the long-term consequences of such regimens have not been validated. If protease inhibitors are to blame for these complications it may be possible for some to begin or modify their regimens to exclude a protease inhibitor. This is a more likely scenario for the naïve patient or the patient in early treatment. It is less of an option for the drug-experienced patient.
Other interventions such as human growth hormone must be validated in clinical trials. The same is true for oral hypoglycemics. With respect to treatment in anticipation of potential coronary arterial disease (CAD), it important that patients and physicians understand that while the risk at this moment is not considered significant by many, two other elements factor into this equation. The first is that patients may increase their risk of CAD by things like smoking, eating diets high in fats and not exercising. The second factor is the passage time. While the risk of CAD may be small now, the indicators of risk may continue to rise and they should be watched carefully.
Anthropometric: pertaining to the measurement of the human body and its parts.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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