AIDS Treatment News
New Approaches to HIV Treatment: Interview with Robert Gallo, M.D.
by John S. James
Robert C. Gallo, M.D. is Director of the Institute of Human Virology, located at the University of Maryland in Baltimore. The Institute focuses primarily on AIDS research; it was started in 1996 with start-up funding from the State of Maryland and the City of Baltimore. We asked Dr. Gallo to discuss some of its current research projects.
Dr. Gallo: The Institute's focus is experimental medicine, to bring discovery from the laboratory to the clinic. It is not a basic science institute, but it does include basic science.
Our main mission, aside from preventive AIDS vaccines, is continued study of the biology of HIV and the host response, and the mechanisms involving their interaction that lead to disease processes; this is commonly called pathogenesis. From these studies we look for findings that have potential clinical uses. We also do some research on cancer, multiple sclerosis, and a few other diseases, but about 80% of our work is in AIDS.
We have people studying the molecular biology of HIV, and also a variety of herpes viruses that are relevant to HIV disease. Others are studying the immune response to infection. One unit, about five people now, is working on chemokines and their receptors. [Note: Chemokines are chemicals produced by the body which attract certain immune cells to the sites of various infections and which, as Gallo and his co-workers discovered in 1995, can be natural inhibitors of HIV.] Another unit, investigating the pathogenesis of Kaposi's sarcoma, overlaps us with the clinic and links us to the cancer center of the University of Maryland; this group is attempting to purify a protein from the urine of pregnant women, which we now call HAF [see below]. We also have a molecular endocrinology unit that studies the role of hormones in a variety of diseases, headed by Dr. Bruce Weintraub, M.D., who used to head a similar division of a laboratory at the U.S. National Institutes of Health (NIH). We brought in a number of people from NIH.
That gives you a flavor. The vaccine program is fairly large, the clinical division is very large, and has established outreach to nearby hospitals. A diagnostics division will try to refine some of the viral quantitation and other diagnostics, not only limited to HIV.
We have excellent facilities, 100,000 square feet of modern laboratory space in a 200,000 square foot building in the center of Baltimore. We are within the complex of the Medical Center of the University of Maryland, so the university hospital is about a block away. Also nearby is the Veterans Administration hospital, which is also part of the University complex.
The Institute of Human Virology has been in operation for about a year now.
ATN: How is its work funded?
Dr. Gallo: We received three years of funding, $12,000,000 total, from the state of Maryland and the city of Baltimore. Maryland's Governor Glendening, whose brother died of AIDS, has been very supportive. He was a former professor here at the University of Maryland. His push led to this Institute; he played a leadership role. And Baltimore mayor Kurt Schmoke has a deep concern about AIDS here in the city.
After the three-year period we will have to hustle like everybody else, with less state support and no longer city support.
We are obligated by our contract with the State of Maryland to try to form a biotechnology company. This is a change from the early years, when such things were frowned on; now they are important. The company will help us go from the lab to clinic; hopefully it will allow us to make some of our projects self-funding, as we are spending far too much time on money issues now.
We do not have an endowment; there is no person's name on our Institute of Human Virology. We are looking for that kind of endowment, which would give us the flexibility to follow up on important developments immediately, without waiting to bring NIH funds in.
ATN: How is the Institute organized administratively?
It is divided into five divisions. They are: Basic Science, headed by me; Clinical Virology, headed by Robert Redfield, M.D., from Walter Reed, and forming a unique division within the University of Maryland School of Medicine; Epidemiology and Diagnostics, by William Blattner, M.D., from the National Cancer Institute; Vaccine Research, essentially 100% HIV preventive vaccines, headed by cellular immunologist George Lewis, Ph.D.; and Animal Models, by Joseph Bryant, D.V.M., also from the National Institutes of Health.
These five divisions are all coordinated and overlapping, working and meeting together. Dr. Redfield has an HIV outpatient department not only in the hospital, but also right in this building, which I believe is unique for a research building.
ATN: What are some of your own projects at this time?
Dr. Gallo: My personal chief focus is trying to develop biological approaches to contain HIV in a person already infected. Sometimes, perhaps most of the time, this involves the manipulation of or targeting of a cellular factor. Remember that viruses in general need cells to replicate; they are not like bacteria, fungi, or protozoa, in that viruses cannot reproduce outside of a cell nor do they have a metabolism of their own.
One has to be more subtle in targeting a virus, therefore, because a virus mostly uses the host cell mechanisms to reproduce itself, more than the protein products encoded by the viral genome. So we try to think of cellular factors that the virus will need more than the cell, so that if you inhibit them somewhat, you might avoid toxicity, but interfere with the virus. There also could be less chance of escape mutations with this approach [than with ordinary antiretroviral drugs], because the human cell does not mutate like the virus.
We also feel that such research would open novel areas. The pharmaceutical industry is already well set up to target the enzymes of the virus; we could not even begin to compete with them there. What are needed are new avenues, new ideas, new approaches, and these are what we try to do -- to think of the way the virus uses the cell to reproduce itself and how it causes disease.
An example would be the levels of the building blocks for making DNA inside the cell. The HIV enzyme that makes DNA -- reverse transcriptase -- needs a higher concentration of the building blocks of DNA, the nucleotide pool, than does our cellular DNA-making machinery. We argued years ago that if we could lower the building blocks for DNA modestly, we might avoid toxicity but interfere with HIV. That led to the hydroxyurea trials.
Another cellular factor most HIV variants need is the CCR-5 receptor, to enter macrophage-type cells, at the beginning of infection. By blocking it with the chemokines RANTES, MIP-1a and MIP-1b (which we found are potent inhibitors of these) -- you might stop early infection.
This approach might also help in later infection, but then you would need something else in addition to protect the T- cells as well.
MDC (Macrophage Derived Chemokine)
Dr. Gallo: We recently discovered that MDC, another chemokine, also specifically blocks HIV -- not limited to the virus which infects macrophages, but all types of HIV. We hope that it can go into the clinic as we learn how to mass-produce this substance and rule out any unwanted toxic effects -- or modify the molecule if necessary so there would not be any inflammatory toxic effects. This is one of our main lines of research today.
How does MDC work? The other chemokines seem to work by simply binding the receptors. The evidence is very strong that this binding downregulates the number of molecules on the cell surface [making it harder for the virus to enter a cell, if it needs to use those molecules for entry].
However, MDC works against all the variants of HIV that we have studied. It cannot be just by blocking. But there is some precedent for factors binding to their receptors and down-regulating nearby receptors. We suspect that when MDC binds by some mechanism, it downregulates all of the chemokine receptors. Ongoing work here now is investigating the molecular mechanism. Work by my colleague Tony Devico and also Alfredo Garzino-Demo is focused fully on these questions.
We are trying to bring such chemokine studies into primates now; that is work of Fiorenza Cocchi, who was the lead author of the first paper showing that some chemokines block HIV infection (the macrophage tropic HIV variants), the RANTES, MIP-1a, and MIP-1b paper.
We are also studying chemokines and rates of progression to disease. Will their levels help to predict progression? So we are also asking whether chemokines could be immune correlates of an effective vaccine -- in addition to our program to try to bring them to therapy.
These are the kinds of projects it is hard to get funding for -- the obvious questions, the applied questions. It is strange but true.
ATN: What does get funded instead?
Dr. Gallo: The NIH grants need to be hypothesis-driven, to be more fundamental. If you have something that you think is ready to bring to the clinic, there is usually not a grant mechanism for that, at least not with enough money to do a small clinical trial -- and to develop the approach by doing the pharmacokinetics, and doing monkey studies. Although this work is obviously important, there is not money for it in the usual NIH granting mechanisms.
We are also looking at combining part of one chemokine receptor with part of another, so that the final receptor is a mixture, or chimera. And the same with chemokines themselves. We are empirically testing to see what effect some of these chimeras can have.
We are interested in uninfectable people. Do some of them overproduce chemokines, not just have receptor mutations?
ATN: What are you learning about HCG and Kaposi's sarcoma? [Note: HCG, human chorionic gonadotropin, is an approved drug today, and is being studied as a potential KS treatment. It is obtained from the urine of pregnant women.]
Dr. Gallo: We are trying to identify a protein -- not HCG -- which is found in the urine of women in the first weeks of pregnancy. This unknown substance is found in some commercial preparations of HCG, as a contaminant. So if you use HCG for treating KS, it is like a needle in a haystack -- using the whole haystack to give you the needle. This makes clinical results difficult, and almost meaningless if you get a negative result. How much of the drug do you use? How should you administer it? All these are unknowns when you are dealing with such a crude mixture, most of which has nothing to do with what you want.
Obviously the goal is to purify this unknown substance. Again we face a serious practical problem -- who funds collecting large amounts of urine, concentrating the urine, purifying the protein? We are talking to NIAID (U.S. National Institute of Allergy and Infectious Diseases) about it; they have been very good in listening and advising and trying. But in the end, these practical ideas are the hardest to get funded.
We have called this protein HAF -- HCG-associated factor. This name will only be temporary. When we identify the protein, it will get the right name. It is possible that the substance is already known, but not used before in this context.
Where are we with this research? In collaboration with Steve Birken at Columbia University we have started to purify the molecule; and so far, it has multiple activities. You could argue that since it is not pure, there could be different molecules for each of these activities. I don't think so, because they are co-purifying, so far, through quite a number of steps.
The activities are:
What is the status today? People are using HCG which has been pre-tested to show that HAF is present. And we know there is benefit to some people with Kaposi's sarcoma.
When we purify HAF we will have the right molecule. That could be much more potent, unless we begin to lose activity in purification by modifying the molecule. But once it is stabilized, this substance should be thousands of times more active [than the HCG preparations which are commercially available today].
ATN: When do you expect to identify the active molecule?
Dr. Gallo: We hope that in 1998-1999 we will have achieved our goal. We have major collaboration with the protein chemistry core facility at Columbia University, and its head, Dr. Birken, He is into the problem, and he is one of the best in the world for this type of problem. We hope that within a year, the substance will be purified, and we move on to the IND [permission from the FDA to test a new drug in humans], after doing the toxicology and other preclinical work.
ATN: We have heard that changes at the FDA may make the drug development easier.
Dr. Gallo: That would be great for us.
We are also going to re-start some of the studies of the hydroxyurea mechanism. Dr. Redfield wants to bring it here clinically. We want to know why it synergizes more with ddI than AZT. Our hypothesis was that it would synergize with both -- but yet I hear it does not with AZT. That is peculiar; it needs to be understood.
HHV-6 (Human Herpes Virus 6)
Dr. Gallo: We are also studying a virus we discovered ten years ago, herpes 6. What is it doing, if anything, in late-stage HIV infection? Most people are infected with this virus. But in the lab, it is very potent at harming T-cells, when it is actively replicating. In most people it is not replicating. But in some HIV-infected people, it is.
How can we demonstrate that it is having a harmful effect? The only way I know is to find a specific inhibitor of this virus. Here we need collaboration with a drug company. We have not established that yet. We have tried; people were not interested for AIDS. They were also not interested in the infant disease roseola, which this virus causes. Maybe now that researchers at NIH are claiming that HHV-6 plays a role in multiple sclerosis there will be more interest.
Protecting Uninfected Cells
Dr. Gallo: In another area, we have a substantial collaboration with Daniel Zagury, of the University of Paris. Here the goal is to try to "de-narcotize" the uninfected T-cells in HIV-infected people. The mass of T-cells, as you know, are not infected; but their ability to grow is inhibited. We think we understand part of the reason -- that it has to do with an HIV protein that is excreted that has this effect, as well as certain cytokines, especially alpha interferon, which are overproduced in HIV-infected people.
We have a way to lower the levels of these molecules. In the laboratory, this restores the ability of T-cells to grow properly. Dr. Zagury has already brought this approach to clinical trial. For the last four years he has been lowering the levels of alpha interferon by a vaccination program, i.e., he actually vaccinates against this normal but over-produced cytokine by denaturing it and making it immunogenic. He is also starting clinical trials to lower the level of some HIV-secreted proteins [such as tat], which may work as a toxin to cells at a distance. We are trying to get funding, about half a million dollars, to bring a clinical trial here to Baltimore as quickly as we can.
ATN: One question on this technology: How do you vaccinate to lower the level of something that is already in the body?
Dr. Gallo: You make a denatured form of it, that is immunogenic when you test it. You have to test it in humans. In this case it worked. If you modify something, put the same molecule in a different configuration, you can generate antibodies against it; the body sees it as foreign. So you look for a way of doing this that also creates an immune response against the original molecule. The approach is unorthodox, but it is not novel. Therapeutically it may be novel.
We were talking with a company this month about funding. We have argued that their current immunological approach to stimulate the immune system with HIV "fragments" (cores) might be greatly improved if the relative anergy of the uninfected T cells can be overcome. I believe this is possible with the approach we are involved in with our collaborator, Daniel Zagury, in Paris, i.e., reducing interferon alpha and the HIV-1 tat protein by vaccinating against these molecules. [Otherwise] it is not likely to be very effective. We are trying to think of ways that NIH could help fund a program which combines these two approaches.
We will form our own biotech company; our contract with the State of Maryland requires us to do that. So far it has been slow to get this company going, mostly because of extreme caution in the university; committees have to evaluate each step.
ATN: What are your hopes for the future of the Institute?
Dr. Gallo: The new Institute of Human Virology will allow us to directly bring our research into clinical testing. This is the first time in my career I have been in this position. We hope that in future years we will have left behind an international research center of first class, one that contributes to its community, and hopefully contributed to the end of AIDS.
1592 (Abacavir): Do Not Rechallenge After Hypersensitivity Reaction
by John S. James
In the experience to date with the experimental antiretroviral abacavir (1592U89), about 3% of patients have developed a systemic hypersensitivity reaction. Initially this reaction is usually not severe and will go away by itself within a couple days of stopping the drug. But if it does occur, the patient must not try the drug again; if they do, a serious and potentially life-threatening condition can develop within hours.
The initial reaction usually begins from a few days to four weeks after starting abacavir. At first there is low-grade fever, nausea (with or without vomiting), and malaise (not feeling well, as with the flu); these symptoms build up over a few days. There is usually a rash, although sometimes it is not noticed by the patient. As soon as the fever and flu-like symptoms occur, the drug must be stopped, or the symptoms will become increasingly severe. After discontinuation the symptoms will disappear rapidly, and there seems to be no further problem, as long as the patient never tries the drug again.
But when abacavir has been tried again, high fever, severe nausea and vomiting, and rash (not severe) have developed within hours. In four of these cases there was life- threatening low blood pressure. These patients were hospitalized with intensive care. No deaths have occurred.
This problem appears to be entirely manageable by recognizing the small percentage of patients who cannot tolerate abacavir and must stop using it permanently. (Those who discontinue for other reasons may be able to re-start.) Glaxo is planning research to determine the mechanism of action of the hypersensitivity, which currently is unknown. At this time there is no way to predict which patients are likely to develop it. About 2,000 people have taken abacavir so far, and the drug's overall safety appears to be good. Clinical trials continue to accrue patients and the abacavir development program continues unchanged.
Glaxo Wellcome is educating physicians, researchers, and volunteers in clinical trials about abacavir hypersensitivity; information has also been shared with the FDA. Anyone suspecting that they have developed hypersensitivity to abacavir should speak with their investigator or physician immediately.
Adefovir Dipivoxil (PREVEON) Expanded Access Begins
Adefovir is a prodrug of PMEA, which has been discussed as a potential antiretroviral for many years. (PMEA should not be confused with the related but more powerful PMPA, currently in phase I/II trials as an experimental treatment for HIV; both PMPA and adefovir are being developed by Gilead Sciences, of Foster City, California.) PMEA is in a class of drugs called nucleotide analogs (distinguished from nucleoside analogs such as AZT, ddI, or d4T); nucleotide analogs need less processing by the body to be changed into their active form.
Early results from phase I/II trials have shown that adefovir alone has modest anti-HIV activity (about an average half-log to 0.7 log reduction in viral load), but is active against virus which has developed resistance to AZT, 3TC, and other approved nucleoside analogs. Little or no HIV resistance to adefovir has been found in patients so far. Adefovir also has activity against CMV and a number of other herpes viruses, and against hepatitis B; it is currently in trials to test for these uses. It is taken as a capsule once a day (at the same time each day), with or without food. It needs to be combined with L-carnitine, a nutritional supplement which will be supplied by this program, because adefovir has been found to reduce L-carnitine levels in the blood in previous trials. The side effect of greatest concern at this time is kidney toxicity; Gilead requires monthly blood and urine tests to detect this or other problems early.
To be eligible for the new expanded access program, a patient must be at least 13 years old, have failed at least two nucleoside analog RT inhibitors and one protease inhibitor, and within the last two months have had a CD4 count of 50 or less, and a viral load of at least 30,000 by PCR (the Hoffmann-La Roche test) or at least 15,000 by bDNA (the Chiron test). Patients must not qualify for other open trials of adefovir. They must not be pregnant, and both men and women must be willing to use contraceptives to prevent pregnancy. There are several other laboratory criteria, including serum creatinine less than or equal to 1.5 mg/dL, and urine protein less than or equal to 1+. Patients are permitted to combine other experimental antiretrovirals with adefovir (including efavirenz, and 1592).
Only the adefovir and the L-carnitine will be supplied by this expanded access program; all other expenses, including laboratory tests and doctor visits, "will be the responsibility of the patient."
The two concerns we have heard at this time are the potential kidney toxicity with long-term use of the drug, and also the CD4 and viral load restrictions on entry into the program.
In clinical trials to date, a serum creatinine level of 2.0 or above has been seen in about 4% of patients who have received the drug for six months or more; this problem seldom develops in the first four months. The reason for the concern is that experience with other drugs has shown that serious kidney damage can occur before there are obvious clinical symptoms. The danger is that as adefovir becomes more widely available, doctors and patients may become complacent after seeing no problems for several months, and skip the laboratory testing. The expanded access program requires monthly laboratory tests, including serum creatinine, urine protein, and urine glucose. (The urine tests can also be done at home, with dipsticks which are commonly used by diabetics, in addition to the monthly testing in the doctor's office.) At this time Gilead is using a cutoff of 2+ on the urine protein test, and 2.0 or above on serum creatinine, to identify those at higher risk of renal complications. Also, glucose in the urine could be a sign of kidney toxicity. Any of these laboratory abnormalities requires prompt evaluation, and probably drug discontinuation or dose reduction. So far the abnormalities have been mild to moderate, and reversible when the drug was stopped or the dose reduced.
The most common side effects of adefovir are gastrointestinal, including nausea and vomiting. Sometimes these less serious problems are managed by reducing the 120 mg per day dose to 60 mg per day. Guidelines for dose reduction will be provided to physicians.
Community advocates are also concerned about the current restriction of this program to patients with a CD4 count under 50 and a viral load over a cutoff value. The program also requires that "the treating physician is unable to construct a viable combination of antiretroviral agents for therapy based on current treatment guidelines and the patient's previous antiretroviral agent use"; advocates want this kind of criterion only, without the specific CD4 or viral load numbers, to allow physicians flexibility to put together the strongest possible new antiretroviral combination for a patient after previous treatments have failed. There will be a procedure for requesting exemption from certain entry requirements, when there is a strong medical reason for doing so.
For More Information
For more information about the adefovir expanded-access program, call Gilead Sciences at 800-Gilead-5 (800-445-3235); press 1 when requested by the voicemail. The office is open 8 a.m. to 5 p.m. Monday through Friday Pacific time.
For more information about clinical trials with adefovir dipivoxil, call the AIDS Clinical Trials Information Service, 800-TRIALS-A; or call 800-GILEAD-5 and press 3 on the voicemail. The largest clinical trial at this time is CPCRA 039, now open in about a dozen U.S. cities, adding adefovir or placebo to a stable antiviral regimen in patients with a low CD4 count (usually 100 or less).
San Francisco: Eviction Legislation Protects Some with Major Illness
According to ACT UP/Golden Gate, owner move-in evictions have increased over 400% in San Francisco in the last year, and many people with AIDS have been losing their housing. Often the vacated units are converted to condominiums or tenant-in-common ownership.
New York: One-Day Treatment Information Forum, January 17
Topics include HIV therapy overview, pathogenesis, the brain and HIV treatment, latent virus and lymph tissue, opportunistic infection prophylaxis today, and thymic transplant research for HIV.
To register, call 888-26-NATAP or 212-219-0106, 10 a.m. to 6:30 p.m. Monday through Friday, or fax to 212-219-8473.
AIDS Treatment News Index, 1997
(Numbers are issue numbers, not page numbers)
|12th World AIDS Conference||283|
|141W94 (protease inhibitor)||284, 275|
|1592 (abacavir)||285, 284, 283, 282, 276, 275, 273, 271|
|1592 Access Coalition||273|
|1st National AIDS Malignancy Conference||270|
|access to care||280, 267|
|access to treatment||283, 276, 275, 273, 270, 269|
|activism||279, 278, 267|
|Activist Groups and PWA Coalitions||263|
|ADAP||280, 276, 271, 269|
|ADC (AIDS dementia complex)||282|
|adefovir||285, 278, 264|
|AID FOR AIDS||280|
|AIDS Prevention Act of 1997||268|
|AIDS Research Institute||284|
|AIDS service organizations||282|
|AIDS Treatment News||271|
|alpha lipoic acid||268|
|BAY AREA REPORTER||263|
|Becker, Dr. Stephen||280, 278|
|blood drug levels||282|
|California ADAP list||271|
|Capaldini, Dr. Lisa||277|
|Centers for Disease Control||266|
|Chinese traditional medicine||282|
|cidofovir||283, 271, 264|
|CME (continuing medical education)||262|
|communication of medical information||262|
|Conant Medical Group||277|
|conferences, meetings -- lists||272|
|death rate decline||266, 265, 263|
|Deeks, Dr. Steven||281|
|deletions in HIV||280|
|efavirenz||284, 279, 278|
|FDA||273, 271, 270, 267|
|FDA reform||284, 276|
|Federal funding||280, 270, 269|
|Feigal, Dr. David||273|
|FORTOVASE||283; see also: saquinavir|
|Gallo, Dr. Robert||285|
|Gay and Lesbian Medical Society||278|
|Geneva conference, 1998||283|
|Glaxo Wellcome||284, 276, 275, 273, 271|
|Gore, Vice President Al||269|
|Guidelines, Antiretroviral (U.S.)||274|
|Health Insurance Portability and Accountability Act||275|
|Healthcare Communications Group||275|
|Henry, Dr. Keith||281|
|herpes, acyclovir resistant||283|
|hit hard hit early||282|
|HIV InSite||284, 275, 267|
|HIV Medicines for Guatemala||280|
|HIV Prevention Act of 1997||276|
|Ho, Dr. David||282|
|Hoffmann-La Roche||270, 268|
|IDSA Conference, 1997||279|
|Infectious Diseases Society of America||277|
|Institute for Human Virology||285, 284|
|International AIDS Vaccine Initiative||270|
|International Conference on AIDS Wasting||281|
|International Conference on AIDS Research||269|
|International Conference, 1998||283|
|International Foundation for Alternative...||281|
|Internet||281, 278, 275, 274, 271,|
|270, 267, 264, 263, 262|
|Internet -- Federal sites||275|
|Johns Hopkins University||275, 264|
|Kaposi's sarcoma||285, 277|
|Lalezari, Dr. Jay||283|
|Los Angeles||270, 265|
|Lymphoma Action Group||284|
|managed care||280, 278, 277|
|marijuana||270, 269, 265, 263|
|Maryland, University of||285|
|McCormack, Thomas P.||276|
|MDC (macrophage derived chemokine)||285|
|Medicaid||276, 270, 269|
|medical information online||275|
|medical research organization||278|
|Medicare Parts A and B||276|
|most favored customer||280|
|needle exchange||280, 278|
|nelfinavir||271, 269, 267, 265, 263|
|nevirapine||280, 271, 269|
|New York City||270, 265|
|nutrition||268, 265, 264|
|patient assistance programs||265|
|pediatric||275, 274, 267, 263|
|per capita caps||270|
|Principles of Therapy, HIV||274|
|protease inhibitors||284, 282, 281, 273, 265, 264|
|protease inhibitors side effects||277|
|quality of care||280, 278|
|Retroviruses conference (1997)||265, 264, 263, 262|
|Retroviruses conference (1998)||284, 278|
|returning to work||276|
|ritonavir||269, 267, 265|
|Ryan White CARE Act||276|
|Saag, Dr. Michael||279|
|Saba, Dr. Joseph||283|
|San Francisco||270, 265|
|San Francisco AIDS Foundation||282|
|San Francisco Bay Guardian||281|
|saquinavir||283, 274, 269, 268|
|second generation protease inhibitors||265|
|Smith, Denny||269, 264|
|standards of care||274|
|strains of HIV||282|
|surrogate markers||284, 271, 270, 267|
|survival||276, 274, 266|
|TAG (Treatment Action Group)||264|
|tape recordings available||279|
|Tobias, Tadd||275, 271, 269|
|travel, hotel arrangements||283|
|treatment failure||282, 281, 278|
|treatment rejectionists||278, 267|
|U.S. Supreme Court||274|
|United Against AIDS International||280|
|University of California||275, 267|
|vesicular stomatitus virus||279|
|viral load||282, 273, 271, 270, 265|
|viral load measurement||279|
|viral resistance||283, 282|
|Walker, Dr. Bruce||284|
|World Wide Web||284
ISSN # 1052-4207
Copyright 1997 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.