Subject: New AIDS Treatments, US Demonstrations Date: Mar 25 1988 (443 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS issue # 53, March 25, 1988; also published (in part) in SAN FRANCISCO SENTINEL, same date. CONTENTS: [***** appears here at each new item] Top San Francisco Health Official Urges Faster Drug Trials HIV Clinical Care Program Opened By Columbia University Student Health Services Nationwide AIDS Demonstrations, April 29 - May 7 Immunotoxin Treatment for AIDS? New MAI (Mycobacterium Avium Intracellulare) Treatments ***** Top San Francisco Health Official Urges Faster Drug Trials San Francisco's Director of Health, David Werdegar, M. D., M. P. H., departed from his prepared testimony to the Presiden- tial Commission on the Human Immunodeficiency Virus Epidemic to call for much faster clinical trials of drugs to reduce illness and death from HIV infection, at hearings on March 25 in San Francisco. The oral testimony, on the fourth of six recommendations to the Commission, was as follows: "I believe in greatly accelerated clinical trials. When you look at our projections to 1993 you can see that the clock is ticking. The current national cooperative drug trial system is cumbersome and unduly long; it just won't produce the results fast enough. "And there are other approaches. We could do community- based trials in high-prevalence areas. We'd be perfectly happy to do it here in San Francisco under Health Department auspices. We can get clinical trials, large scale, with controls, going tomorrow. The current clinical trials, I'm afraid, are just leaden-footed." The prepared text reads as follows: "Greatly accelerated clinical trials of potentially useful drugs to reduce the morbidity and mortality of HIV infection. The national cooperative drug trial approach is unduly long and cumbersome. It should be supplemented by speedier mechanisms. As our own projections show only too well, time is of the essence. "Community-based trials in high prevalence areas is one such approach. The Health Department in San Francisco, for example, would welcome the opportunity to conduct large scale clinical trials locally, utilizing the San Francisco General Hospital, the Public Health Hospital, community hospitals and practitioners, and the University of California Health Science Center. These could get under way promptly." The other five recommendations concerned a comprehensive national plan; Federal block grants for education, prevention, and treatment, directly to the health departments of cities seri- ously affected by the AIDS epidemic; financial incentives for the development and support of long-term care services; continued support of anonymous and confidential testing programs; and legislation to prevent discrimination in jobs, housing, and health insurance. We find the research recommendation particularly noteworthy, as it is one of the very few times that any government official has broken with the official line that we're moving as fast as we can, Science can't be rushed, there is no faster way -- and too bad about those now infected. Dr. Werdegar's statement also hints that the central issue in treatment research is NOT financial. What we need most -- quick, practical trials which could be integrated with ongoing patient care -- would cost relatively little, much less than the ineffectual research programs now in place, and far, far less than the cost of care of perhaps hundreds of thousands of cases of unnecessary terminal illness. ***** HIV Clinical Care Program Opened By Columbia University Student Health Services A new program at Columbia University for care for HIV-posi- tive students could provide a model for universities and other institutions as well. The clinic will offer anonymous antibody testing and coun- seling. Lab work for the antibody test will be done by New York City; counseling by the Gay Health Advocacy Project, which is assisting the University's health service in setting up the pro- gram. All costs will be included in existing student health cov- erage; the program is designed to keep costs low. At the initial visit, HIV-positive students will be given a standard medical workup, including an anergy panel and lymphocyte subset, to be repeated every three or six months. Those who show a drop in T4 cells, or HIV symptoms, will be referred for consul- tation to an AIDS expert at St. Luke's/Roosevelt Hospital, which is affiliated with Columbia University. Students will also be referred to a seropositive support group, to meet periodically. To start the project, a nurse-practitioner from Community Health Project of the Gay and Lesbian Community Center, which has much experience working with people with AIDS, will see patients and also train one physician and two nurse practitioners at Columbia's Student Health Services. This project, starting on an experiment with an evaluation after six months, will open March 30. For more information, call Columbia University Student Health Services, (212) 280-2878; ask for Laura Pinsky, Gerard Ilaria, or Paul Douglas. ***** Nationwide AIDS Demonstrations, April 29 - May 7 A network of AIDS advocacy organizations including ACT UP (AIDS Coalition To Unleash Power -- chapters in New York, Boston, Los Angeles, San Diego, Rochester, Philadelphia, New Jersey, New Orleans, and elsewhere) and similar organizations such as AIDS Action Pledge and the ARC/AIDS Vigil (San Francisco), MASS ACT OUT (Boston), OUT (Washington, DC), C-FAR (Chicago), and several chapters of the National Association of People with AIDS will conduct coordinated demonstrations and other actions in over 30 cities to focus public attention on the need for effective action on AIDS. Some of these actions will include nonviolent civil disobedience; others will be educational forums, fundraisers, etc. Persons who want to help out in AIDS advocacy could use this organizing effort to meet others in their area. A coordinating group called ACT NOW (AIDS Coalition to Net- work, Organize, and Win), set up by these groups, organized com- munication for this effort, which is called Spring AIDS Actions '88. Each local group has determined and planned its own actions. For more information, including how to contact the group in your area, call the ACT NOW national coordinator Terry Beswick, (415) 647-7972, or write ACT NOW, P. O. Box 146694, San Fran- cisco, CA 94114-6694. ***** Immunotoxin Treatment for AIDS? A San Francisco immunologist has proposed using immunotox- ins, a technology already tested in humans as an experimental cancer treatment, in the treatment of AIDS and ARC. Alan S. Levin M. D. of Positive Action Healthcare in San Francisco, who is presenting the idea this week at a meeting of the AIDS Medical Resource Center Physicians Association in Chicago, based the pro- posal on a model (theory) of the development of AIDS, a model he derived from recently published work of a number of researchers. (For background on Dr. Levin and Positive Action Healthcare, see AIDS Treatment News #47, January 1, 1988). Even though the proposed AIDS treatment has not yet been synthesized -- let alone have any clinical data supporting it -- we are interested in the proposal for several reasons: * The technology of immunotoxins has developed far enough that creating one for AIDS would be almost routine; according to Dr. Levin it could probably be ready for human testing within six months, if unforeseen problems do not intervene. We do not know of any other researchers developing an AIDS treatment based on immunotoxins; a computer search of the literature turned up only one reference, a published letter which suggested this approach in 1986. * Dr. Levin is in an excellent position to develop the treatment. His wife, Vera S. Byers Ph.D., M. D., is an expert in making monoclonal antibodies and immunotoxins. Dr. Levin has already started to assemble a scientific team for the project. * Aside from a treatment possibility, the theory itself sum- marizes what a number of leading researchers are now learning about AIDS, and addresses several troubling questions such as how HIV can cause AIDS when it only infects a tiny fraction of T- helper cells (an issue raised by retrovirologist Dr. Peter Dues- berg, who has argued that HIV could not cause AIDS). Levin's model also explains why no animals get AIDS, even if they can be infected with HIV; this question could be important for develop- ing strategies for future research, for example by suggesting more emphasis on human immunology rather than animal models. The Theory We interviewed Dr. Levin for this article but explained the theory in our own words; any errors are our own responsibility. This explanation is complex because the theory depends on several concepts from immunology; readers who find it confusing can skip to the "Proposed Treatment" section, below. The central element of Dr. Levin's theory is that part of the protein of HIV imitates part of a human protein which has a key role in the immune system. (Proteins consist of sequences of simpler chemicals known as amino acids; a virus may happen to have the same amino acid sequence within one of its proteins as is found in a human protein.) This unfortunate coincidence not only enables HIV to infect human T-helper and certain other cells; it also explains -- according to the theory presented here -- how later immune dysfunctions develop, through mechanisms well known to immunologists. And fortunately this explanation sug- gests several approaches to treatment. The theory arose from a question. AIDS depletes the T- helper cells, but HIV infects very few of them at any one time, less than one in ten thousand. The body could easily replace these cells. Therefore if HIV is causing the damage (and there is much evidence that HIV is the sine qua non of AIDS, whether or not it is the sole cause or may also require cofactors) it must be depleting the cells by some means other than directly infect- ing and killing them. Levin's model is not new research but rather a coherent sum- mary of a number of findings of others. His theory proposes that HIV does its damage primarily by causing cells to produce an AIDS-virus protein, called gp 110 (or gp 120, another name used for the same substance), which circulates in the blood. Gp 110 (gp 120) includes the sequence which allows HIV to attach to the CD4 molecule -- which is the receptor site on the T-helper (T-4) group of white blood cells. This sequence causes the gp 110 (gp 120) protein to attach to T-helper cells, just as HIV does when it infects the cells. This protein cannot reproduce, as it is not the whole HIV virus, only part of it. But it causes damage in other ways. The gp 110 (gp 120) molecule can attach itself to more than one cell, causing clumps of T-helper cells to fuse together into giant clusters called syncytia. These cells stop working and soon die. In this way, a single cell which is infected by HIV and secreting the gp 110 (gp 120) protein can cause the destruc- tion of many healthy T-helper cells elsewhere in the body. In addition, the immune system recognizes gp 110 (gp 120) as a foreign protein, and forms antibodies against it. Presumably these antibodies do help to reduce its concentration. But since gp 110 (gp 120) contains the sequence by which HIV matches the CD4 molecule (the receptor on the T-helper cell), an antibody against this AIDS-virus protein can also act against the human protein sequence which normally uses the CD4 receptor site. As a result, communication between T-helper cells and certain other cells, such as macrophages (see below), becomes disrupted. (It might be helpful in understanding this process to visu- alize an antibody and its corresponding antigen as a key which fits the lock. Like the key and the lock, the antibody and antigen fit because the shapes match exactly. When the body is invaded by a foreign organism (the lock), it produces an antibody (the key) which precisely fits the protein from that organism -- and usually no other. But unfortunately the AIDS-virus protein gp 110 (gp 120) -- the lock -- happens to fit a key which is already in normal use in the body (the CD4 molecule, which is the T-helper receptor site to which the AIDS virus attaches itself in order to enter and infect the cell). Therefore when the immune system makes new antibodies to gp 110 (gp 120), these new keys not only fit this AIDS-virus protein, as intended. They also fit the "lock" (found on other cells such as macrophages) which was intended to use the "key" on the T-helper cell. Therefore these antibodies intended to attack the AIDS-virus protein also attack the normal cells such as macrophages, interfering with communication between the macrophages and T-helper cells and perhaps doing other damage as well.) Normally macrophages, which are large immune-system cells which can circulate in the blood or remain in various organs of the body, engulf foreign organisms such as bacteria or fungi. Later they present the foreign proteins to T-helper cells, which instruct other cells to make antibodies specifically targeted against the invading organisms. The antibodies which the immune system produces against gp 110 (gp 120) interfere with this pro- cess. After the macrophages present antigen to the T-helper cells, these cells in turn secrete chemicals called growth factors (such as colony-stimulating factors, abbreviated CSF), which cause the maturation of new T-cells and other cells. When the antibodies to gp 110 (gp 120) interfere with the macrophages, these chemicals are not secreted in the normal amounts, resulting in further depletion as the new cells which should have matured do not do so. (One new treatment, called GM-CSF, is being tested for a deficiency of white blood cells often found in AIDS, especially after treatments with certain drugs such as AZT. GM-CSF is a colony stimulating factor given to correct for a shortage of this substance, a shortage which could be caused by the mechanism out- lined above.) Besides the damage described above, the AIDS-virus protein gp 110 (gp 120) causes harm indirectly in still another way. Nor- mally after the immune system makes antibodies, it makes antibo- dies against the antibodies themselves. These, called anti- idiotype antibodies, help to turn the immune response off. But this AIDS-virus protein contains the sequence which matches the CD4 molecule on the T-helper cell. Therefore its antiidiotype antibody can also act against the T-helper cell -- further interfering with the normal functioning of the immune system. All of these forms of damage come about because the HIV virus -- and its gp 110 (gp 120) protein -- has a sequence which mimics a key human protein in the immune system. And according to this theory, the reason animals do not develop AIDS from HIV is that they have different proteins, which HIV does not mimic. Proposed Treatment: An Immunotoxin An immunotoxin consists of an antibody chemically attached to a toxin -- a preparation intended to kill specific cells. The antibody targets the right kind of cells and binds to them, but the antibody itself does not kill the cell. The toxin kills the cell; the antibody is custom made to bring the toxin only to a specific group of cells, a group which must be immunologically distinct in some way. For AIDS, the proposed treatment will use an antibody which seeks out the gp 110 (gp 120) protein but not any normal human protein. This antibody will carry a toxin to the HIV-infected cells which are producing gp 110 (gp 120); these cells can be recognized because they have this protein on their surface. The immunotoxin will kill these infected cells, greatly reducing the amount of gp 110 (gp 120) being produced. Dr. Levin believes that it should be possible to reduce the level of this AIDS-virus pro- tein by 100 times through the use of an immunotoxin. This treatment will not be a complete cure; it would not eliminate the virus entirely, as some cells infected with HIV show no outside evidence of infection. And of course there may be unforseen difficulties in creating a practical drug. But the approach, already in use for cancer, certainly deserves serious attention for AIDS. We do not know of anyone developing this approach until now. If you have heard of any work on immunotoxins for AIDS, please call John S. James, (415) 255-0588, or Dr. Alan Levin at Positive Action Healthcare, (415) 788-7545. Note: for a copy of Dr. Levin's presentation on immunotox- ins send a #10 self-addressed stamped envelope (2 ounces postage) to: Alan S. Levin M. D., Positive Action Healthcare, 450 Sutter St., Suite 1138, San Francisco, CA 94108. ***** New MAI (Mycobacterium Avium Intracellulare) Treatments A friend of ours who is a medical professional (not a physi- cian) recently called a number of physicians and research centers to find out about treatments for MAI, for his lover who has AIDS. He suggested that we pass on what he learned to our readers. He heard that a year ago there were no good treatments, but today there are at least two treatment protocols, each of which combines a new drug with traditional anti-tuberculosis drugs. But physicians differ greatly in their approach to MAI; for exam- ple, those on the East Coast are more likely to treat it than those on the West. Most physicians believe that MAI is not life threatening, but a few believe that it kills many people. Persons with normal immunity can occasionally get pulmonary MAI, but persons with AIDS usually have a systemic infection in the bloodstream; it must be diagnosed by culturing the organisms from the blood. MAI can also affect the bone marrow and cause anemia. Symptoms include night sweats, high spiking fevers, cough, loss of appetite, and general fatigue. The illness may be misdi- agnosed as flu. Often no one suspects MAI until the blood cul- ture is done. Because the organisms grow slowly, the culture takes two weeks. One treatment now being tested at several California univer- sities combines a new drug, ciprofloxacin, recently made avail- able by prescription, with three older TB drugs: rifampin, ethambutol, and amikacin. The disadvantage of this combination is that amikacin is toxic, and must be given intravenously for a month. Another treatment combines an experimental drug ansamycin (also called rifabutine, or rifabutin) with ethambutol and clofazimine. This regimen has the advantages of less toxicity, plus the fact that ansamycin may have anti-HIV activity. The disadvantage is that ansamycin must be obtained specially from the Centers for Disease Control; it can take two weeks for delivery, and only a month's supply is sent at one time, so plan- ning is necessary to avoid running out; make sure your physician reorders two weeks in advance each month. (Incidentally we have been hearing good things about ansamycin; it is a drug to watch.) These treatments do not always work, as there are different organisms which cause MAI, and not all are susceptible to any one drug. Even when the drugs do work, they usually do not kill the organisms completely but reduce their level in the blood. Physi- cians recommend that treatment be continued indefinitely; unfor- tunately MAI treatments can sometimes interfere with AZT therapy. Better treatments for MAI are expected, as a new generation of mycobacteria drugs is now being developed. Meanwhile this disease will become a more serious problem, mainly because fewer people are dying of pneumocystis. MAI develops slowly, and usu- ally occurs, if at all, late in the course of AIDS, often about a year after the first attack of pneumocystis. Incidentally our friend responded well to the ansamycin (rifabutin) treatment, after six weeks. For more information about MAI treatments, physicians should check through professional contacts. Also, a number of articles have been published about all of the above drugs in the treatment of MAI or related diseases. ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display