Protease Problems

Since protease inhibitors (PI's) were added to the chemical arsenal for fighting HIV, many people living with HIV have been literally snatched from the brink of death. HAART (highly active anti-retroviral therapy) regimens containing protease inhibitors, while not effective for everyone and certainly not a cure, have helped many drop their viral loads to undetectable and raise their CD4 counts to numbers previously unattainable. PI-containing regimens have allowed legions of people living with HIV to return to active full lives. Death rates have been slashed in half, and the incidence of serious opportunistic infections has fallen significantly. But, in the midst of all this good news, disturbing and potentially dangerous side effects are raining on the protease parade.

There are currently four licensed PI's on the market: nelfinavir (Viracept), indinavir (Crixivan), saquinavir (Inverase, Fortovase), and ritonavir (Norvir) and more are in the pipeline. We have less than three years of actual clinical experience with these drugs. As more people take these drugs for longer periods of time, more data becomes available on their treatment effects (how well they suppress HIV viral load), durability (how long PI-containing regimens will suppress HIV viral load), and their side effects (unwanted actions of the medications).

Lipodystrophy is the medical term for the most prominent of these serious side effects. Lipodystrophy involves the body's abnormal metabolism of fat. Although tales of these unattractive changes have been circulating among PLWA's for years, it wasn't until the Fifth Annual Retrovirus Conference in Chicago this year that data was presented by researchers to other scientists and clinicians. One of these documented changes is an expanding waistline, known as truncal obesity (or "whale-waist", as one of my friends puts it). As this effect was first noticed by those taking Crixivan it became known as "Crix Belly". It is now known to occur with all four of the PI's, and is more aptly named "protease paunch." Other visible changes include dorsocervical fat pads, which are deposits of fat at the neck ("buffalo humps"), and thinning of the legs, arms and face. In some instances the face becomes so wasted that the person is gaunt and haggard appearing. The extremities become thin and stick-like, with thinning skin. Sometimes severe wrinkling of the skin occurs. Women find that their abdomens protrude, their hips narrow and they increase their breast tissue by as much as two cup sizes. At first, people experiencing these changes were so grateful at being given a second chance at a healthier life that they bore them silently. Most, however, were frightened at this sudden distortion of their body image, some becoming ashamed of the way they looked. Many even resorted to liposuction and plastic surgery, surgical procedures not without risk, to rid themselves of the fat accumulation. What has alarmed most clinicians, treatment advocates and public health workers, however, is that more than a few PLWA's have decided to quit taking protease inhibitors in order to try regain their previous body image. This leaves them vulnerable to rising viral loads, declining CD4 counts and subsequent serious opportunistic infections. Quitting PI's also risks the widespread development of multiple drug resistant HIV.

These abnormalities of fat metabolism are unsightly to those who experience them, and add to the social stigma of being HIV positive. Lipodystrophic changes may also be risk factors for other health problems. Despres, in a review article published in the summer 1998 issue of Canadian Journal of Diabetes Care, surmised that truncal obesity may correlate with a worsening cardiovascular system and an increased probability of developing diabetes mellitus. (It is interesting to note that lipodstrophy among insulin-resistant diabetics is a well-described phenomenon.) Possibly more dangerous to good health than the visible lipodystrophies are the invisible ones, including the ones that show up on blood tests. Internal signs of the body's abnormal metabolism of fat include a raised triglyceride level and a raised cholesterol level. Triglycerides and cholesterol are two types of fat needed by the body in normal amounts. Triglycerides are normally found in the blood at levels generally less than 325 mg per deciliter of blood; Cholesterol ranges under 280 mg per deciliter of blood, although the most healthy range is under 200 mg/dL. When either are raised to abnormally high levels they may increase the person's risk of developing cardiovascular diseases, such as heart attacks, strokes, and blocked arteries affecting circulation to the legs and lower body. Persons taking protease inhibitors have found, in some cases, that their triglyceride levels zoomed over 1000 mg to as high as 1700 mg or more.

The last noticed side effect is an increase in the amount of fat deposited around internal organs, such as the heart, kidney, liver, and pancreas. This puts a strain on these organs and predisposes them to dysfunction. Although these researchers discovered this phenomenon by performing CAT scans on volunteers, Despres's article mentions studies that correlates truncal obesity with increased internal fat deposits.

Although interest in the effects and causes of lipodystrophy is intense, generating many research studies, relatively few are far enough along to have been published in the scientific literature. These studies peg the incidence of lipodystrophy among HIV-positive PI users between 11% and 64%. This wide range reflects different methods of collecting data. The studies demonstrating the lower incidence relied on self-reported changes in body appearance. The studies declaring the higher incidence measured lypodystrophic changes via blood tests and CAT scans in addition to self-reported and clinician-reported changes in body habitues. A small case study series done in France (1997) examined 8 men with partial or generalized lipodystrophy that developed 2 to 12 months after beginning indinavir therapy. A short-term follow-up after the discontinuation of therapy revealed no resolution of the lipodystrophic changes.

One of the abstracts presented at the Geneva 12th World AIDS Conference detailed a study of 8 men who developed dorsocervical fat pads after initiating PI therapy. Since these "buffalo humps" resemble the changes seen in a syndrome called Cushing's Disease that involves the abnormal metabolism of the cortisol hormones produced by the body, these subjects underwent intense cortisol level testing. Not one of them had the abnormalities associated with Cushing's. The investigator's concluded that abnormal cortisol metabolism did not play a part in these men developing lipodystrophy, but felt that they did not have enough evidence to blame PI's.

Miller, et. al., studied subjects with abdominal symptoms consistent with lipodystrophy via CAT scan, measuring the amount of fat surrounding the abdominal organs. They found a significant difference in the amount of fat in men with lipodystrophy compared to normal controls. Although this is also a hallmark symptom of Cushing's disease, the study discussed above did not support Cushing's as a cause.

These and other published studies underscore the need for more research. Little research has been done on women, for instance, although there is plenty of anecdotal evidence that women also suffer from lipodystrophy. There are no published studies investigating lipodystrophy in children.

The published data to date describe the phenomenon of lipodystrophy in PI users, but none can explain why it is occurring. This is because the phenomenon is a complicated one. Some but not all HIV-infected individuals who take protease inhibitors develop lipodystrophy. It occurs in HIV-positive people who do not take protease inhibitors. It even occurs in HIV-negative individuals. Some researchers think the syndrome is a side effect of PI therapy, some think it an effect of HIV in itself. Others think that it may be a combination of the two, with or without other unknown factors that trigger the development of the syndrome. No one as yet has an answer. One prominent theory, championed by Kotler, is that PI's interfere with the functions of cytochrome p450 and other proteins involved in fat metabolism in the liver.

Although lipodystrophy is unsightly and a potential health hazard, most clinicians currently recommend continuing PI therapy, as the risks of discontinuing therapy that is working are known and severe. If you are having signs of lipodystrophy, tell your health care provider. Discuss with him or her methods of reducing blood lipid levels, triglycerides and cholesterol, including drug therapy for extreme cases. (Many lipid-lowering drugs also involve the cytochrome p 450 system. Pros and cons of their use must be carefully considered on an individual basis.) See a nutritionist to learn dietary approaches to controlling fat levels. Initiate an exercise program, if you have not already, that involves both resistance exercises and aerobic conditioning. Most importantly, do not stop your PI therapy on your own. Doing so will jeopardize your chances of controlling your disease in the future. Instead, look around your area for lipodystrophy studies and consider joining them. Stay up-to-date on what is discovered about this syndrome. (A good way to do that is to continue to read the STEP Perspective and to frequently visit STEP's website at The Body. Most of all, keep an optimistic outlook, we are all fighting together.

References

1. Lo, J.C. et al, "Buffalo Hump in Men with HIV-1 Infection." The Lancet. Vol. 351. March 21, 1998. pp 867-870.

2. Kotler, Donald P. Truncal Obesity, "'Crix Belly' -- Is it what it appears to be...or something else?" Online at www.healthcg.com/hiv/updates/feb98.

3. Letters in Lancet, Vol351, June 6, 1998. "Abnormal fat distribution and use of protease inhibitors." (1) Wurtz, Rebecca. pp 1735-6. (2) TTY Ho, et al. pp 1736-7.

4. Alcorn, Keith. "Lipodystrophy Update." AIDS Treatment Update. Online at www.nam.org.uk/atu/64part2.htm, issue 64, 4/98.

5. Miller, et al. "Visceral abdominal-fat accumulation associated with use of indinavir." The Lancet. Vol 351, March 21, 1998. pp 871-875.

6. Viraben and Aquilina. "Indinavir-associated lipodystrophy." Journal: AIDS. Vol 12., issue 6 pp F37-F39. Online at www.chapmanhall.com/ai/ai120601.abs.html.

7. Strain, Wm. "Lipodystrophy Cause Unknown." Online at www.apla.org/apla/9803/lipodystrophy.html

8. Baker, Ronald. "Unusual Side Effects Due to HIV Therapy?" BETA July 6, 1998 pp6-7.

9. AIDS Treatment Review #26/27. "Metabolic Problems and PI's." Online at 204.179.69/network/trs 2627.html#meta.

10. Despres, J-P. "Waist circumference as a clinical assessment of viseral obesity, a risk factor for type 2 diabetes and cardiovascular disease." Canadian Journal of Diabetes Care. Vol 22, no. 2 Summer 1998 issue.

Fighting Fat Naturally Unwanted fat and high cholesterol levels are both a blow to self-image and a real health problem. Synthetic drugs can help these fatty problems but often come with side effects and dangers of their own. Naturopath Brad Lictenstein has seen an increasing number of patients with alarmingly high cholesterol levels. He reports some of his patients having triglyceride levels 10 to 17 percent higher than normal. This is not only dangerous to the cardiovascular system, putting people at risk for heart disease, but a threat to other organs such as the pancreas and liver. These two organs can already be overstressed by anti-HIV drugs, and many of the synthetic drugs used to lower cholesterol can compound the problem, because they are toxic to these organs as well. Excess triglycerides accumulate in the liver itself, causing something colorfully known as "fatty liver." Kidding aside, pancreatitis and liver disease are life-threatening problems. Dr. Lichtenstein recommends following some basic guidelines to help lower cholesterol the natural way. He notes that the suggestions given in the following list do not guarantee lower cholesterol, especially in people with super-elevated levels. However, all the strategies listed will be beneficial to the cardiovascular system, have antibacterial, antiviral, and antiparasitic effects, and stimulate the immune system. Eat Garlic and Onions: Studies have shown that 4,000 mg of fresh garlic (roughly 1 to 4 cloves) a day lowered cholesterol by 10 to 12 percent. Aged garlic loses some of its potency, but still showed a 7 percent reduction of cholesterol levels. Raw garlic is best because cooking destroys the cholesterol-lowering quality in the garlic. Raw garlic is also helpful for viral and bacterial infections, and is a potent antiparasitic that helps with gastrointestinal disorders resulting from prolonged use of drugs such as Bactrim or Dapsone. If bad breath is a concern, take odorless garlic in pill form -- it is just as effective. Take Niacin, Vitamin B3, or Inositol Hexaniacinate Supplements: All of these have similar properties and work to reduce cholesterol. Inositol hexaniacinate does not produce the hot flashes that the other two nutrients have been known to cause. Recommended dosing of all three is the same: 500 mg three times a day with food for two weeks, then increase to 1,000 mg per day. Take Gugulipid Supplements: This exotic-sounding herbal medicine is an extract from the mukul myrrh tree. Several studies have been done on this compound; in one, participants on gugulipid lowered their cholesterol by 25 to 35 percent and decreased their triglyceride levels by 22 to 30 percent in a 4- to 12-week period. There was no reported toxicity from its use. Recommended dosing is 25 mg of guggulsterone 3 times a day. Decrease or Avoid Consumption of Animal Products: They are nature's only source of cholesterol and contain saturated fat. Eat Fiber: All fruits, vegetables, grains, and legumes aid in digestion and absorb and eliminate fats. Avoid Caffeine: Decrease or stop drinking caffeinated beverages such as coffee, Coke, and tea. Stop Smoking: What more can we say? Exercise: Include both aerobic (to help the cardiovascular system) and anaerobic (to build lean muscle mass) exercise on a regular schedule.

Back to STEP Perspective Fall 1998 contents page.