AIDS TREATMENT NEWS Issue #303, September 18, 1998
John S. James

Treatment activists are increasingly concerned that the research needed to understand and control lipodystrophy is not being coordinated properly, with some of it not done at all. Patients and advocates have certain advantages in calling attention to these problems, as they can speak more freely than corporate or government officials, or even academic researchers who may need to cultivate relationships to maintain funding. Activists are less constrained by organizational interests and positions, or professional territories they have staked out. In this article we did not quote individuals, because the overlap and consensus of many ideas would make implied authorship misleading.

Here are some of the problems we have heard repeatedly, and suggestions for improvement:

* Lack of research on mechanisms.

If medical researchers knew what caused these problems, how they arose and developed, it might be easy to find effective remedies. Theories have been proposed, but the only widespread consensus today is that no one much knows what is going on.

This situation calls for consulting with leading researchers in many areas (including those who have not worked in AIDS before), to find plausible leads for potential mechanisms, and ideas for feasible, productive research. Someone in a clinic or lab may already have a lead which could be a major advance, but for various reasons, including commitment to other projects, they cannot develop it. There needs to be a coordinated program which can receive, evaluate, and prioritize these ideas, and act on them when appropriate.

Even in the unlikely event that no good research leads are available, it is still possible to do empirical research--for example, by running hundreds of commercial and research tests on a few patients and a few normal controls, looking for unexpected differences which might suggest new leads for further investigation.

Research to find mechanisms does not necessarily have to wait for an agreed definition of the problem. Intensive laboratory testing could be done with only a few similar patients--or even only one patient. Successful understanding and treatment of one individual would almost certainly produce knowledge which could also be used for many others, although not for all.

* Flight of the pharmaceutical companies.

Again and again we are hearing from activists that pharmaceutical companies are not funding studies of problems with their drugs, because they do not want to know about or raise the profile of these issues. The mechanism research noted above, which might bring new problems to light, may be particularly disfavored; companies can have some incentive to support a clinical trial which could show that their product causes less problem than a competitor's.

The adverse effects associated with use of protease inhibitors were not expected, not sudden and dramatic, and slow to be recognized. Persons and organizations alike often first respond to this kind of problem by trying to ignore it away--which can create a corporate culture of denial. No one wants to be the messenger who brings attention to their organization's problems.

What can be done to get corporations to take more responsibility for serious safety issues with their products? One approach is to build consensus among medical professionals, corporate scientists, the FDA, academics, and the patient community about what research is needed. If this does not work, we may need to consider the legal responsibility of a corporation if it does not research well- founded safety concerns which have been brought to its attention.

* Task force needed for coordination and leadership in government and elsewhere.

Activists agree on the need for a task force which would include government agencies (FDA, NIH, and perhaps CDC and others), industry scientists, physicians and researchers in academia and elsewhere, and patient advocates. This group should include members or consultants who have critical expertise in metabolic or other fields, even if they are not familiar with HIV and AIDS.

* Need for a definition.

Lack of a generally accepted definition of the problem has made it hard to compare the work of different research groups--leading, for example, to very different findings on how often these problems occur.

* Better use of existing data.

Automated databases of patient information, cohort studies, registries of patients with certain symptoms, and data from clinical trials which were run for other purposes, should be considered as a relatively inexpensive kind of research, since it does not require conducting new trials. Activists realize, however, that much of this data has serious limitations. Important blood work may not have been collected--especially since many of the laboratory tests needed for studying lipodystrophy are not reliable unless the blood is drawn while fasting, and it is often difficult to get study volunteers to schedule morning visits because of interference with their jobs.

Planning and Research Already Underway

Probably the most advanced effort to plan and conduct research to address the lipodystrophy problem is within the AIDS Clinical Trials Group (ACTG), run by the U.S. National Institute of Allergy and Infectious Diseases. The ACTG cannot address all of the research needs, however, because it specializes in running large clinical trials and collecting high-quality data, but is not well organized to conduct the basic-plus-applied research to understand the biochemical mechanisms underlying a clinical problem (although the data it generates will eventually be useful for this purpose).

The ACTG is planning a major study, called ACTG 384, primarily to compare certain treatment combinations including nelfinavir (a protease inhibitor) vs. regimens including efavirenz (a non-nucleoside reverse transcript inhibitor) vs. regimens with both; this complex study will run for up to three years. Included in ACTG 384 is a metabolism substudy, called A5005s, which "is designed to evaluate changes in glucose regulation, lipid metabolism, and body fat distribution in a subset of 345 subjects" (quoted from the protocol). The substudy will measure "insulin resistance, fasting lipid profiles, cytokines, cortisol, sex hormones, and body composition by measurements of weight and BIA at baseline and periodically during the study; in addition, oral glucose tolerance testing and regional body composition by DEXA scanning will be performed at a limited number of sites" (quoted from METABOLIC CONSEQUENCES OF HIV DISEASE AND TREATMENT: AN OVERVIEW OF CURRENT KNOWLEDGE AND RESEARCH, Forum for Collaborative HIV Research, June 1998). Since some volunteers will be switched onto or off of protease inhibitors (due to the failure of their initial regimen, whichever it was), resulting changes in metabolic parameters can be followed. But since this study is mostly blinded and lasts for three years, the information will not be available soon.

Another group, the Forum for Collaborative HIV Research, an independent public-private partnership to facilitate discussion and collaboration in HIV treatment research, is planning a meeting to bring together all the pharmaceutical companies working in antiretroviral drugs, clinical researchers in metabolic and gastrointestinal complications of HIV, patient advocates, physicians and other healthcare providers, and representatives from government agencies. This meeting's purpose is to discuss the design, implementation, and funding of a study to determine the incidence of metabolic complications (which patients are getting what problems)--what this study should look like, how many people it should measure, how long to follow them, where to place the study, and how to get it paid for. The reason for the focus on incidence of the symptoms is to provide the data necessary to develop a comprehensive definition of lipodystrophy.

Some treatment activists believe that neither of these efforts will address the whole problem. ACTG 384 will produce useful data eventually, from a handful of specific drug regimens; its main focus is to compare a protease-inhibitor regimen with a non-protease-inhibitor regimen, not to find either the causes or treatments of lipodystrophy. The Forum for Collaborative HIV Research is also not focused on causes or treatment, but on preliminary steps of studying incidence in order to create a well-informed definition of the problem.

Meanwhile, independent medical groups and researchers are reporting their data. At the ICAAC conference later this month (Interscience Conference on Antimicrobial Agents and Chemotherapy, September 24-27 in San Diego), one oral session titled "Metabolic Effects of Protease Inhibitors" will include about 10 different presentations; a separate poster session, "Toxicity and Metabolic Effects of Antiretroviral Therapy," will have almost 20.

Comment

Our provisional analysis is that the most serious missing piece in the research picture today is the lack of small, laboratory-intensive studies designed to elucidate the biochemical mechanisms of lipodystrophy. As noted above, mechanism studies do not need to wait for a definition. And the ACTG corporate culture of large, multicenter trials does not encourage the flexibility to move rapidly in changing research designs in response to new information--although of course the trials can generate crucial supporting data.

The pharmaceutical companies seem best equipped to do these studies for their own drugs, but the legal system may be creating perverse incentives to ignore the problem instead. The law seldom requires a company to conduct or fund any particular study. But if the research does happen and a problem is discovered, the company may have to do something to avoid lawsuits later--even though there may not be anything to do immediately (other than pulling the drug off the market, which nobody would want unless the problem is very serious). Could an implicit strategy which amounts to legal protection through ignorance be behind the reluctance to investigate lipodystrophy problems expeditiously?

Electronic Mailing Lists for More Information

The most direct and current information about lipodystrophy is on Internet email lists, where patients discuss their own experiences and treatments, and research findings as well. Two of these lists are particularly relevant:

* LIPIDLIST: "This is an Internet forum for PWA/PWHIVs and others to discuss and relate their experiences and problems related to metabolic complications being seen today in HIV disease. Recent observations of changing levels of lipids (triglycerides and cholesterol) and altered body shape such as abdominal paunch, buffalo hump, enlarged breasts, and thinning of the face and extremities have led to more interest in this phenomenon. Ideas for research and action, discussion, and anecdotes are all welcome." (From the LIPIDLIST Welcome message.)

LIPIDLIST is sponsored by ACT UP/Golden Gate in San Francisco; it originated from a public forum held at the 12th World AIDS Conference in Geneva. Subscribers usually receive one or two messages a day.

To subscribe to LIPIDLIST, send an email message to: listproc@critpath.org. The first line of the message should be:

subscribe lipidlist <first> <last>

where <first> and <last> are your first and last names (omit the angle brackets).

* CRIX-LIST: "CRIX-LIST is an Internet discussion list for people who are currently taking, anticipate taking, or are interested in Crixivan." Other treatments are also discussed.

CRIX-LIST currently transmits about 15 messages a day. To avoid getting too many email messages, you may want to subscribe to the Digest version, which combines each day's messages into a single transmission.

CRIX-LIST has been archived back to January 1997, so you can obtain the earlier messages if you want.

Instructions for subscribing to and using CRIX-LIST are at http://crix.pinkpage.com.

Information about other AIDS-related email lists is available on the HIV InfoWeb site; see http://www.infoweb.org/treatment/index.html.

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