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Protease Inhibitors' Metabolic Side Effects
Cholesterol, Triglycerides, Blood Sugar, and "Crix Belly."
by John S. James
[In the last few months we have heard increasing anecdotal reports of a condition which has been named "Crix belly." People may gain 40 pounds or more of fat remarkably quickly in the lower abdomen, and there may also be some muscle wasting in the arms and legs. The cause is unknown. This problem was not seen before the use of protease inhibitors; it is not known if it is associated primarily with indinavir (Crixivan(R)), for which it was named, or if it may be caused by other protease inhibitors as well. Nothing has been published so far.
Last month we asked Lisa Capaldini, M.D., an AIDS physician in San Francisco, what she was seeing that our readers should know more about. She said that more attention was needed to certain lipid (fat) and other metabolic problems which appear to be related to protease inhibitor therapy.
The interview below was conducted on August 8, 1997 and went to press four days later. Because this information is so new, the picture could change rapidly over the next few weeks or months. Those seeing this article at a future time should seek out the most current information then available.]
Dr. Capaldini: So far we have identified three metabolic disorders associated with protease inhibitor therapy as a class. First we saw high triglycerides; triglycerides are one of the two kinds of lipids, or fats, we measure in the blood. Most peoples' triglyceride level runs between 100 and 200. High triglycerides clinically can cause pancreatitis, and have been found to be associated with (but not necessarily cause) hardening of the arteries.
The second condition is high cholesterol in patients whose previous cholesterol levels have either been normal, or as is common with advanced HIV, low. The pattern of high cholesterol is elevation of the "bad" or LDL cholesterol, compared to the so-called "good" or HDL cholesterol. This is the unfavorable pattern of LDL to HDL cholesterol associated with hardening of the arteries, which can lead to heart attacks, strokes, and peripheral vascular disease.
The third condition is high blood sugar. Usually the levels are not high enough to cause symptoms or, to our knowledge, to cause any of the complications associated with diabetes. They are typically 110 to 150 -- which is not normal, but is not in the range usually associated with symptoms, which would be over 250.
We do know, from experience before the use of protease inhibitor therapy, that HIV infection tends to predispose people to both high blood sugars and high triglycerides. But these were usually seen in patients with much disease activity; they were almost a marker of HIV activity, and therefore were often associated with patients with unusually low cholesterol. On the other hand, it is clear that we did not have the high cholesterol problem before protease inhibitors were introduced.
It is worth mentioning that the endocrine system seems to be one of the least affected systems of the body in HIV disease; androgen deficiency is the only *common* endocrine disorder associated with HIV disease. So it is a contrast that we are seeing metabolic disorders as a result of our therapy, when were not seeing much of these problems before.
ATN: The Crix List, an electronic mailing list on the Internet, has discussions of "Crix belly", reports of people gaining 40 pounds or more in a very short time. [For more information about the Crix list and how to join it, see http://www.pinkpage.com/Crix/.]
Dr. Capaldini: No one understands what is causing this condition. In appearance, "Crix belly" is closest to a medical condition called Cushing's syndrome. People gain fat on their lower belly and flanks, and often notice a loss of muscle tissue in their arms and legs. This acquired condition is associated with a disorder of cortisol, when you have too much of it. There is no data yet to suggest that high cortisol levels are being caused by Crixivan, but it is remarkable how much Crix belly looks like Cushing's syndrome in appearance.
This condition is very disturbing to patients, especially those who started these drugs when they were asymptomatic or minimally symptomatic, and now are hoping for long-term benefits. Aesthetically it is disturbing; also, we do not know what it means physiologically.
ATN: Does it seem to be more specific to Crixivan than to other protease inhibitors?
Dr. Capaldini: That is what I have heard, and seen anecdotally in my practice -- although about 70 to 80 percent of my patients on protease inhibitors happen to be on Crixivan, so whether the effect is specific to the drug, or just seen with it more often because more patients are using that drug, is not clear.
ATN: Has there been any experience in your practice with people trying to control this condition either by discontinuing protease inhibitor therapy entirely, or by changing from Crixivan to another protease inhibitor?
Dr. Capaldini: I have no knowledge about that, either in my practice or otherwise. I have two patients who have both had terrific responses to Crixivan, in viral load and T-cell improvements, and because of that are apprehensive about switching, particularly given all the conflicting cross- resistance data that is coming out. Despite that, at least these two people in my practice are considering switching to another protease inhibitor, with the hope that it is a Crixivan-specific effect and that stopping the drug will reverse it. But we do not yet know whether it is drug specific, or whether it will reverse if the drug is discontinued.
ATN: Have you heard from Merck about this effect?
Dr. Capaldini: Not yet. I think the news is just starting to trickle down the anecdotal pathway. [Note: Merck is interested in hearing from either physicians or patients about this or any other problem with Crixivan. Call the Merck National Service Center, 800/672-6372.]
Note that there is also a separate condition which has been called Crixivan belly, which seems to be more associated with the protease inhibitors as a class, not just Crixivan -- people getting bloating or heartburn or rapid transit time diarrhea problems. But when people use the term Crix belly, they are usually referring to getting fatty tissue in the gut, with leg and arm muscle wasting.
Clinical Course, and Potential Treatments
ATN: About how often do these different metabolic problems occur, and when in the course of the therapy?
Dr. Capaldini: The metabolic conditions tend to show up after about a year of protease inhibitor therapy -- although I have seen patients' cholesterol change from abnormally low, to more normal for them, as early as three to six months into therapy. At first I thought that was a good sign, indicating that metabolism was returning to normal. It was only about six months ago that my first patient had his cholesterol level go from a normal range to a high range. In this person's case, there is a strong family history of coronary artery disease. But I have seen high cholesterol both in patients with and without such family history.
ATN: How concerned are you?
So no one should be stopping their protease inhibitor or panicking because their cholesterol has risen from say 200 to the 250 range. I have encouraged my patients to sit tight until we can discover (1) is this a stable phenomenon, or is it likely to get worse over time, and (2) are any adverse clinical outcomes likely to result?
There are well tolerated, easy to take drugs that safely lower cholesterol in the general population; they are called HMG-CoA reductase inhibitors (lovastatin, etc.), and they work by keeping the liver from recycling fat in the gut. They are quite safe. There is probably an interaction between them and ritonavir (Norvir(R)); but as we know there are very many drug interactions with that drug. So we could treat this; the real issue is should we treat it?
For people who have tried lipid-lowering drugs in the past, the prior generation were poor; they were unpredictably effective and tended to cause a lot of gastrointestinal side effects. This newer class of drugs is both reliably effective and amazingly safe. It may well be that for some patients, adding one pill a day of these drugs is an appropriate intervention; we just do not know yet.
Some patients have found that they can get their triglycerides from a high range to a lower range -- not normal but safer -- by modifying how much fat they eat. For patients who are not having trouble maintaining their weight, that is a reasonable approach. But some patients need to keep more fat in their diet just to maintain their weight; for them the lipid-lowering drug might make sense.
(3) Blood Sugar
(4) Crix Belly
Dr. Capaldini: Because we have no idea what is causing this problem, we do not have a handle on where to intervene.
Antiretroviral Treatment Strategies
ATN: Are these metabolic side effects changing your views on treatment?
Dr. Capaldini: To me as a primary care doctor, these metabolic phenomena are an excellent example of why the "hit hard, hit early, it's the virus stupid" approach may not be as straightforwardly correct as it looks. The argument behind this strategy has been that (1) we know that HIV causes the disease, and (2) we know that it is harder to control the virus when there is more virus in the body, and (3) viral load increases with time; therefore, it seems intuitively obvious that everyone should be on combination therapy as soon as they know they are HIV positive. Those of us who have questioned that approach -- not its logic, but in how it works clinically -- are concerned that we do not know the long-term safety or benefits of these drugs, and that as a general rule of thumb, the earlier in a disease you treat a patient, the more problems you may have with long-term medication side effects.
So these metabolic disorders, while they may not turn out to be associated with any long-term problems, make me feel uncertain about recommending combination therapy including protease inhibitors to patients with very early disease. My concern is *not* only because of any question about whether we can control the virus long-term with current agents, but because of the unknown trade-offs between early control of viral production and the long-term consequences of medication side effects.
In the old days of the nucleoside analogs, sequential monotherapy, AZT and 3TC etc., when a drug caused a problem it was a simple matter to stop giving it and replace it with another drug. With protease inhibitors, these therapeutic decisions are more complex. We do not feel it is safe to decrease doses, because of the possibility of developing viral resistance to the drugs -- especially because recent data suggests that once a patient's virus becomes resistant to one protease inhibitor, it may also be resistant to all of the other currently available protease inhibitors. So that makes changing dosages, stopping or starting these drugs, quite a bit more problematic than with the other HIV drugs.
ATN: What should patients do now?
Dr. Capaldini: If they get these side effects, they should *not* stop their drugs and then call their doctor. These metabolic side effects do not seem to be causing any short- term risk -- yet it is quite risky to stop and start protease inhibitor therapy, because of the danger of the virus becoming resistant. Unfortunately it will probably take six to 12 months for us to even have practice guidelines for these lipid disorders.
Discussion with Carl Grunfeld, M.D., Ph.D.
Note: After the interview AIDS Treatment News talked to Carl Grunfeld, Professor of Medicine at the University of California San Francisco, who is studying these conditions. He emphasized several points:
* In 1992, before the protease inhibitors, his group reported a 33% decrease in LDL cholesterol (a large decrease) due to HIV infection. Abnormally high cholesterol levels which people had anyway may be returning due to effective antiretroviral treatment.
* His group first reported the high triglycerides associated with HIV infection. Others reported that this effect was increased with ritonavir (other drugs were not tested).
* The blood sugar problem is rare. And a full spectrum of conditions has been reported; there does not seem to be any pattern resulting from protease inhibitor treatment.
* The weight gain, etc. should not be called Crix belly, because it may not be specific to Crixivan -- or even to protease inhibitors as a class. A handful of cases may have occurred before protease inhibitors. To him as an endocrinologist it has not looked like Cushing's syndrome -- but if physicians suspect Cushing's syndrome, they should test patients for that, and this issue could be settled.
* No one knows what is causing this condition; and so far, no one has shown that it is harmful. Standard body composition measurements have failed to show the nature of the problem. As a next step in the research, Dr. Grunfeld suggested measuring regional body composition, using CT, or MRI, or possibly DEXA. Regional body composition is an experimental technique, and protocols will need to be developed.
Taxol Approved for Kaposi's Sarcoma
On August 5 Bristol-Myers Squibb announced that the FDA had approved Taxol(R) (paclitaxel) "for use in second-line treatment of AIDS-related Kaposi's sarcoma." The drug had already been approved for use in cancer treatment.
An independent analysis by Michael Marco of the Treatment Action Group strongly supported the approval, noting that "Taxol as second-line therapy has double the response rate and twice as long duration of response as DaunoXome which is indicated for first-line therapy." [Community Consensus Position Paper Regarding Approval of Bristol-Meyers Squibb's NDA for Taxol (Paclitaxel) for Second-Line Treatment of Kaposi's Sarcoma in People With AIDS, July 23, 1997.]
A confusing series of disputes, caused ultimately by changes in the business of medicine, has led to the disbanding of the Conant Medical Group [Dr. Conant's dermatology practice has not been affected]. To assure continuity of care, some patients will need to decide whom they want to stay with, arrange for the transfer of their medical records, and perhaps also change their designation of primary care provider at their HMO. In case of doubt, contact your provider's office to learn what actions, if any, you need to take.
An August 7 letter to patients provided new contact information for some of the providers formerly with the Conant Medical Group. Virginia Cafaro, M.D., Jon Kaiser, M.D., Lisa Lewis, M.D., Martin Kramer, PA-C, Pat Sanders, FNP, and Gordon Sanford, PA-C., can now be reached through a message number, 437-5433, fax 437-5434. They are located in a new office at Davies Medical Center, Castro at Duboce, in San Francisco.
Mark Illeman, FNP, is with Drs. Stephen Becker, Alison LaVoy, Jeremy Berge, and Lawrence Goldyn at 923-6560, fax 922-0263, in the Potrero Hill Medical Group, 2300 California St., Suite 306.
Medical records for all former Conant Medical Group patients are at the Potrero Hill Medical Group. Patients can obtain copies of their records, or have them sent to the physician of their choice. In case of questions, contact the Potrero Hill Medical Group at 923-6560.
Note re Quest: Confusion has occurred because two different HIV medical organizations in San Francisco are named Quest. Margaret Poscher, M.D., asked us to clarify that "Quest, a primary care group," which is owned by her, is entirely separate from "Quest Comprehensive Health Care Systems," which purchased the Conant Medical Group. Dr. Poscher told us that she has supported the concept of Quest Comprehensive Health Care Systems creating a national HIV practice network, but that it has no role in the management of her practice.
Comment: Managed Care
These difficulties at one of the leading HIV medical practices in the country highlight the need for more public and professional attention to issues of managed care and other changes in medicine today. California is ahead of most of the U.S. in the use of managed care -- so what happens here, for better or for worse, has national importance.
Traditionally, physicians were usually paid for the services they performed; a drawback of this system was the financial incentive to overtreat, since the more procedures and tests they used, the more the doctors got paid. To control the resulting inflation of health-insurance costs, employers started shifting to HMOs (health maintenance organizations), which usually pay doctors a fixed amount per patient to provide whatever care is necessary -- a system called capitation. The drawback here is a financial incentive to undertreat, and to avoid expensive patients.
Unless other arrangements are negotiated, capitation rates are often the same for a patient with a serious condition like HIV or cancer, as for a healthy person who needs little medical care. This makes it impossible for an HIV specialty practice to survive, since they will lose money on almost every patient.
This is the pressure which is forcing specialists in HIV, cancer, and some other fields to combine into large groups of physicians. These physician groups can negotiate with HMOs to handle the care of their HIV infected patients -- with or without capitation -- at a rate which covers the cost of care. Large groups can also cut costs and generate income in ways which individual practitioners and small groups usually cannot -- from economies of scale, to developing standard protocols for both quality and efficiency, to running clinical trials, to vertical integration with their own laboratory, pharmacy, and other services (which individual physicians or small groups are usually forbidden to do).
Few patients, physicians, or others involved think that these changes are all bad, or all good. Clearly there are potentials for kinds of abuses which particularly harm persons who are seriously ill. Until we have workable healthcare reform, public vigilance, advocacy, and sometimes aggressive pressure will be required.
IDSA Annual Meeting,
The Infectious Diseases Society of America will hold its annual meeting in San Francisco, September 12-16. While not focused on AIDS, there may be important new AIDS information presented.
Registration is $230 non-member, with reduced rates for members or for fellows in training. For more information, call the IDSA at 703/299-0200.
The abstracts will be placed online starting the first day of the meeting, at the IDSA site, http://www.idsociety.org.
A partial program is available there now.
1998 Retroviruses Conference:
Deadlines for registration, scholarship applications, and community press applications for the 1998 Retroviruses conference, planned for Chicago in early February, will be released around August 15. They were not available when this issue went to press on August 12, however.
The information will be posted on the World Wide Web, www.retroconference.org.
AIDS Treatment News
by John S. James
AIDS Treatment News has not raised its individual subscription price for over 10 years, since we started the newsletter. Now we need an increase to assure our long-term stability and independence. All our subscription prices will increase up to 20%, starting September 1.
Grace Period for Current Subscribers
(1) If your renewal is currently due and you have received a renewal notice dated before September 1, you can pay that notice at the old rate -- even if you pay after September 1, when the price for new subscribers goes up.
(2) Through September 15, any other current subscriber can add up to one year to their subscription at the old rate. To do this, call our office at 800/TREAT-1-2 or 415/255-0588, Monday through Friday 10 a.m. to 4 p.m. Pacific time.
Consensus Letter: Peter Duesbergby John S. James
Project Inform is circulating a consensus letter addressed to the National Academy of Sciences, concerning "the continuing public campaign of Peter Duesberg to convince the public, people at risk of HIV infection, and people already infected that HIV poses no threat to them and that current treatments for the disease and recreational drug abuse are in fact the cause of the disease." The immediate event which led to this letter was the publication of large advertisements headlined "Breakthrough Discoveries in Scientific HIV/AIDS Research" in three gay newspapers in San Francisco. The ad, for a talk by Dr. Duesberg on August 9, included "two symbols of scientific credibility, the Seal of the University of California, and reference to his 1986 appointment to the National Academy of Sciences."
The letter has been endorsed so far by over 20 AIDS organizations, including AIDS Project Los Angeles, San Francisco AIDS Foundation, ACT UP/Golden Gate, AIDS Research Alliance, Community Research Initiative on AIDS, and Critical Path AIDS Project.
For a copy of the letter, which is still open for endorsements, call Project Inform, 800/822-7422, or fax a request to FAIR (Foundation for AIDS & Immune Research) in Los Angeles, 310/471-4565.
We have become increasingly concerned about the promotion of the idea that HIV is harmless, and that accepted medical treatments are useless (or are the cause of AIDS). A number of people are using these teachings to justify rejecting all medical care for HIV infection, and ignoring guidelines for reducing HIV transmission -- seriously threatening their own health and that of others.
Nine years ago Dr. Duesberg spoke in the same auditorium, at the Metropolitan Community Church in the Castro district of San Francisco, sharing the stage with an advocate for unconventional syphilis theories. At that time the building was packed, with people struggling for space near a doorway or window where they could hear. This year there were empty seats in the auditorium, which holds about 300 -- although the toll-free 888 number, set up to take registrations for the free event, had announced that it was full.
We distributed the following flyer outside the meeting.
Duesberg -- And You
When you hear Peter Duesberg, Ph.D., you should know:
* Despite his tenure at the University of California, his ideas are rejected by almost 100% of AIDS scientists and doctors. They are not taken seriously.
* Dr. Duesberg and his followers are not medical doctors; they do not treat patients. As far as we know, there is no doctor in the U.S. or anywhere else who treats patients according to Duesberg's ideas.
But Duesberg is an excellent, persuasive public speaker. He knows how to sound reasonable, use humor, and include statements that are true, important, and meaningful to people. He offers an easy, comforting approach to HIV. This is why he has been able to influence people to trust him and reject their doctors' advice.
* New treatments have greatly reduced AIDS deaths, hospitalizations, and other complications. Many people who were disabled are now going back to work. Several years ago, the BAY AREA REPORTER filled an obituary section every week (as many as 37 death notices in a single week); in the last year, there have usually been four or five in each issue, some of them unrelated to AIDS. (The newspaper has not changed its policy of immediately publishing all obituaries received.)
* Competent medical care for AIDS does not necessarily mean taking drugs; many patients are healthy without drugs and choose to leave well enough alone for now, with their doctor's support. What is important is to see a doctor who is experienced with HIV, to be monitored so that options can be considered and treatment started when it does become necessary. Treatment for HIV infection, like treatment for any serious illness, must be individualized for each patient. No single approach or philosophy fits all.
* Unfortunately there is now an organized, well-financed campaign which encourages people with HIV to reject lifesaving medical care. People have heard Duesberg say that HIV does not cause AIDS and that drugs do, and have rejected all medical care for HIV infection (and safer-sex precautions as well). Medical experts agree that without treatment, almost everyone with HIV will ultimately progress to AIDS and death. Persons who wait until they need emergency care have much worse treatment prospects than those who start earlier.
Do not make life and death decisions after hearing only one point of view -- especially a view entirely rejected by medical professionals. Many credible AIDS resources are available in San Francisco. Some examples:
* Project Inform runs a hotline (558-9051, 9 a.m. to 5 p.m. Monday through Friday, or Saturday 10 to 4, Pacific time). It also has excellent written information available without charge, and a volunteer program which includes training on AIDS, HIV, and treatment options.
* ACT UP/Golden Gate meets in the Castro every Tuesday evening, focusing on getting new treatments developed faster, and on access, insurance, and housing issues. For information, call 252-9200.
* Healing Alternatives Foundation has an AIDS treatment library at Market St. near Valencia, with information about both mainstream and alternative treatments. For schedule and other information, call their voicemail at 626-2316.
* Many Web sites have excellent AIDS information. For example, see http://www.aegis.com; http://www.projinf.org; http://hivinsite.ucsf.edu; http://www.hopkins-aids.edu; or http://www.iapac.org.
* Also note the National AIDS Hotline, run by the U.S. Centers for Disease Control, where you can speak to information specialists who can answer questions about AIDS or provide local referrals; call 800/342-AIDS, 24 hours a day every day of the year. [For Spanish-speaking information specialists, call 800/344-SIDA, 5 a.m. to 11 p.m. Pacific time every day; for TTY, 800/AIDS-TTY, Monday through Friday 7 a.m. to 7 p.m. Pacific time.]
* For a point-by-point refutation of Duesberg's statements, see THE EVIDENCE THAT HIV CAUSES AIDS, an 8-page fact sheet prepared and published by the U.S. National Institutes of Health, at http://www.niaid.nih.gov/factsheets/evidhiv.htm. For details and references, see THE RELATIONSHIP BETWEEN THE HUMAN IMMUNODEFICIENCY VIRUS AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME, also by the NIH; this report, with about 20 pages of text and about 500 references, is at http://www.niaid.nih.gov/publications/hivaids/all.htm. These papers were published in 1995, and would be stronger today since new information (including results from improved treatments) could be included.
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ISSN # 1052-4207