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AIDS Trestment News
September 17, 1999

Contents:


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Biological Treatment Approaches, Including Tat Toxoid Vaccine

Interview with Robert Gallo, M.D.

by John S. James


Robert C. Gallo, M.D., is Director of the Institute of Human Virology at the University of Maryland in Baltimore. The 1999 International Meeting of the Institute of Human Virology: A Symposium on HIV/AIDS & Cancer Biology took place August 28 to September 2. On September 9 we interviewed Dr. Gallo about this conference.



ATN: What did you find most important at the IHV meeting?

Dr. Gallo: My belief -- and there is wide consensus on this -- is that we need not only new drugs for HIV infection, but also new approaches, new biological approaches to therapy. The problems with treatment today were predicted long ago. As in cancer, these problems will increase the longer you have intensive combination chemotherapy. If you can't eradicate the virus and people have to keep taking the drugs, you will see rising resistance and drug toxicity among some of the patients. It may become a large majority in the next few years.

Today the pharmaceutical companies are on a reasonable roll in creating new drugs. They see enough gain, and will continue to make new chemicals to target enzymes. But more is needed for the future.

New biological therapies have come, and will continue to come, from research on HIV pathogenesis. I can't emphasize enough the importance of continuing these studies, while other research continues for developing a preventive vaccine. Pathogenesis research will help the vaccine efforts as well.

ATN: What are some examples of new biological approaches to treatment?

Dr. Gallo: Targeting the chemokine receptors [such as CXCR-4 and CCR-5] is one such example. At the meeting we heard from people studying modified chemokines as potential therapies. Pharmaceutical companies are also developing smaller molecules to target CCR-5, for example.


Tat Toxoid

Another example is the Tat toxoid vaccine, which may have a role in both treatment and prevention. It has been in clinical trials in 40 people in Europe and Israel. We highlighted this work at our meeting, and it will also be highlighted at the Institut Pasteur in October.

[Background: "tat" is gene of HIV. This gene produces the Tat protein, which greatly assists HIV replication and is probably essential for HIV infection. Tat is also believed to be toxic, especially to the immune system, and may be one major reason why uninfected cells such as CD8 cells often do not work correctly in people with HIV. (Note: The word "Tat" is capitalized when referring to the protein, and not capitalized when referring to the gene which codes for that protein.)

[The body partially controls Tat by producing antibodies against it, as the body produces antibodies against other foreign proteins.

[Tat toxoid is a slightly modified form of Tat which is designed as a potential component of treatment, or of a preventive vaccine. It does not have the biological activity of Tat, so it does not stimulate HIV or poison the immune system, as Tat does. But it is close enough to Tat that when the body produces antibodies against the toxoid, these antibodies are effective against the Tat protein as well, reducing its level in the blood. Antibodies work based on the shape of the target molecule -- and the Tat toxoid and Tat protein have almost the same shape.]

We believe the Tat toxoid is important to pursue, both therapeutically and for a preventive vaccine. Led by my collaborator Daniel Zagury in Paris, we now have three years of clinical trials in 40 people demonstrating safety; and this Tat toxoid is strikingly immunogenic. But we do not expect it to be used alone, either for a therapy or a vaccine.

For therapy, we believe that the Tat toxoid will work best when combined with another vaccine that Daniel Zagury initiated and I am working with, vaccinating against alpha interferon. The two synergize. Part (not all) of the harmful effects of Tat are mediated by its activation of alpha interferon. It has long been known that alpha interferon is overproduced in HIV-positive people, and we think we have found the mechanism (published in 1998 in the Proceedings of the National Academy of Sciences, USA).

Combining the two therapeutically has stabilized CD4 counts in people without other therapy. It did not dramatically change the viral load, but it did stabilize the immune parameters that were evaluated. In studies of over 80 volunteers who were given the vaccine against alpha interferon, there were no opportunistic infections or deaths in the treatment group, compared to about 20 opportunistic infections and several deaths in the control group.

But this approach has not yet been brought to the United States in large-scale clinical trials. To get credibility and get this project moving, we have to get it into the U.S. on a large scale. There are questions about whom to treat; it would be helpful to test this treatment in people who are not using antiretrovirals for one reason or another. Certainly, this approach would not be effective in end-stage disease.

We believe it is important to use Tat which has been chemically modified, inactivated. Some researchers have argued for native, biologically active Tat -- as if a chemically dead Tat wouldn't work. We have years of experience with this, and the Tat which is inactivated works just as well, and without the danger of the toxin being put into people, who may be immune suppressed already.


Preventive and Treatment Vaccines

For a preventive vaccine, you would not combine the anti-tat vaccine with vaccination against alpha interferon. Instead, you would combine the Tat toxoid with viral antigens.

Some of the preventive vaccines being developed today might also be used as treatments, to stimulate the immune system when the virus is suppressed by HAART [highly active antiretroviral therapy]. Years ago, people tried to stimulate the immune system when the virus was high, and they didn't get very far. You can understand the reason, because the immune system was somewhat paralyzed by the HIV infection.

A recent test in macaque monkeys, presented by Veffa Franchini at the [IHV] meeting, used the canarypox vaccine after antiretroviral treatment. The animals received antiretrovirals, then those drugs were stopped, and a little later the animals were vaccinated. They did well.

There is now wide agreement that the well-known "faucet and drain" mathematical models -- T-cells die, new ones replace them, and eventually there is immune exhaustion -- are dead as explanations of HIV disease. It is clear that the uninfected T-cells are also impaired -- so we need to find out why, which is what got us into Tat research to begin with. Some soluble factors must be suppressing the normal function of some of the remaining T-cells.

Lowering the virus with antiretrovirals makes it more rational to do gross, unspecific stimulation with HIV antigens. Today the Remune trials [using the Salk HIV immunogen] can be re-evaluated -- along with the canarypox approach and other vaccines people want to use.

What if you vaccinated against Tat and alpha interferon, and did not succeed in lowering the viral load, but in time did help restore the capacity of T-cells to respond, or at least it did not get any worse. Would a vaccine like Remune or the canarypox preparation do anything? I don't know, but it makes some theoretical sense to try this and find out.

No one spoke about the envelope-only vaccine which is now going into widespread preventive trials [AIDSVAX], but most scientists believe it is not a likely candidate. I hope it does not hurt the vaccine field if it turns out not to work, as virtually everyone expects.


Other Biological Approaches

  • Next year's meeting will highlight everything we know about the new pregnancy-urine peptide that we have described in impure form, before it was identified (see "New Approaches to HIV Treatment; Interview with Robert Gallo, M.D.," AIDS Treatment News #285, December 19, 1997). Now we have identified it, and the Institute will probably be reporting that before next year's meeting. I would be very disappointed if this potential treatment does not get into clinical trials properly. When we have learned how to use it -- what route, what dose, what frequency of administration -- I would be very surprised and extremely disappointed if it does not help people.

  • Alonzo Heredia presented data on resveratrol a natural substance found in grapes and red wine, which might potentiate ddI and perhaps some other antiretrovirals; he is working with Robert Redfield at our Institute. We are working with pharmaceutical companies and will be starting two clinical trials. This research follows up on our concept of targeting cellular factors that the virus may need more than the cell does, thus widening our therapeutic targets. We (with my then co-worker Franco Lori and collaborator, Dr. Gao) first chose hydroxyurea because of speed, simplicity, availability, low cost, and so on; about six years later, it went into clinical trials for HIV. But there may be drugs better than hydroxyurea for this purpose. Resveratrol with ddI may be one such approach.

  • Frank F. Weichold, from our institute, presented evidence that some the benefit of the protease inhibitor ritonavir may be from direct immune modulation, independent of its antiretroviral effect. He suspects that the major therapeutic benefit of this drug may be the inhibition of certain chemicals (cellular proteases) which lead to abnormal apoptosis (programmed cell death) of a large number of cells, including uninfected CD8 T-cells that fight HIV. If this theory is confirmed, then new drugs might be developed specifically for this purpose.

  • Peter S. Kim spoke on the structure of gp 41 and details of viral fusion and entry -- a truly elegant piece of work. This technology may identify lead compounds which could be developed into small-molecule fusion inhibitors.

  • Anthony Fauci and Robert Siliciano both spoke about the viral reservoir and viral rebound after treatment is discontinued. What is striking here is how fast the viral rebound can be, even when there is only a small reservoir of latently infected cells. The conclusion seems to be that there must be actively replicating virus somewhere else in the body, to allow the virus to return so rapidly. We do not know where it is, but one suspicion is the gastrointestinal tract, where it is difficult to test for HIV in patients.

  • On pathogenesis, Klara Tenner-Racz presented evidence of oral transmission of SIV when a relatively large amount of this virus was applied to the tonsils of macaques [suggesting a biological basis for transmission of HIV through unprotected oral sex].

  • Part of the meeting was devoted to cancer biology, tumor immunology, and cancer vaccines. There were many important overlaps with HIV and AIDS, opportunities to apply lessons learned from one to the other. In cancer vaccines they have some of the same issues as in HIV; there should be more interchange there.

ATN: Are cancer vaccines primarily preventive, or therapeutic?

Dr. Gallo: Most of the cancer vaccines, and all those discussed at the meeting, were therapeutic. About 15% of cancers have a known viral-necessary role, however, and for these there might be a place for preventive vaccines, especially in parts of the world where these cancers are common.


For More Information

The abstracts of this meeting -- over 200 of them -- are published in the Journal of Human Virology, July/August 1999, Volume 2, Number 4. Some copies are available from the Institute of Human Virology; email your mailing address to schorr@umbi.umd.edu. Later the abstracts may also be placed on the Institute's Web site, http://www.ihv.org.



Vaporizers for Medical Marijuana

by Bruce Mirken


Technology that could alleviate a major concern about the medical use of marijuana -- the harmful effects of smoking -- exists today and is available to the public. But the research needed to scientifically verify the benefits of these devices, generally called vaporizers, is proceeding far too slowly, held back by a variety of constraints.

Vaporizers are designed to release the active ingredients of marijuana, known as cannabinoids, without actually burning the plant material. This is potentially important because it is these combustion products rather than the cannabinoids that are the source of the major health risks associated with smoking, and those risks have been cited by government officials and others as a major reason to prohibit or limit use of cannabis as a medicine.

In its report, Marijuana and Medicine: Assessing the Science Base, released earlier this year, the Institute of Medicine cited the dangers of smoking as a major drawback. The IOM stated, "Numerous studies suggest that marijuana smoke is an important risk factor in the development of respiratory disease... Because of the health risks associated with smoking, smoked marijuana should generally not be recommended for long-term medical use." The IOM suggested that researchers concentrate on isolating medically useful cannabinoids and developing "rapid-onset, nonsmoked cannabinoid delivery systems." Such systems might be similar to the inhalers used for certain asthma medicines.

While some critics argue that the IOM overemphasized the dangers of marijuana smoke, all acknowledge that the smoke does indeed contain many of the same harmful substances as tobacco smoke, including tars and carbon monoxide. "Like tobacco, marijuana tars are rich in carcinogenic compounds known as polycyclic aromatic hydrocarbons," wrote California NORML coordinator Dale Gieringer, Ph.D., in a 1996 article for the newsletter of the Multidisciplinary Association for Psychedelic Studies (MAPS). "However, cannabinoids themselves are not carcinogenic. An obvious way to protect smokers' health is therefore to minimize the content of smoke tars relative to cannabinoids."

A number of vaporizers now on the market appear to do just that. These products all work on the same basic principle: Taking advantage of the fact that cannabinoids vaporize at a temperature below that required for marijuana to burn, they use a heating element to heat the marijuana enough to release the cannabinoid vapors without setting it on fire.

One of the scientists who reviewed the IOM report prior to its publication, Harvard assistant professor of psychiatry Lester Grinspoon, M.D., urged the IOM panel to consider the advantages of such a "non-smoked respiratory delivery system for the natural plant medicine" rather than putting the sole emphasis on pharmaceutical product development. The final report, however, makes no mention of such devices.

Grinspoon, a longtime supporter of medicinal use of marijuana, charges that the omission is political rather than scientific. "What the report is doing is trying to pharmaceuticalize away the medical marijuana problem," he argues. "What they're doing now that they have to grudgingly acknowledge that this substance has some use [is to say] 'how do we make it a medicine and keep this prohibition?'"

As for the vaporizers presently available, Grinspoon says, "I've tested three such devices. There's no question that these things work. They haven't been tested in the laboratory, but there's no question that cannabinoids come off and when you look at the [marijuana] in the end it looks just like it did; it's not burnt." Two medical cannabis club managers consulted by AIDS Treatment News, Ken Hayes of CHAMP in San Francisco and Jeff Jones of the Oakland Cannabis Buyers' Cooperative, both shared Grinspoon's enthusiasm for vaporizers.

Vaporizer makers tout two advantages: Avoidance of unhealthful combustion products and more complete use of the active ingredients. Considerable amounts of cannabinoids, they say, are wasted when the herb is burned, so vaporizers are more efficient and economical than conventional smoking.

Unfortunately, the only study to examine these issues scientifically is over three years old and did not involve the vaporizers currently marketed. The study, conducted by MAPS and NORML and described in Gieringer's 1996 article, compared three different water pipes, an early Canadian vaporizer and a homemade vaporizer / water pipe hybrid to an ordinary joint [marijuana cigarette] and a joint with a cigarette filter. The smoke produced by each was analyzed for solid particulates (tars) and 3 major cannabinoids. The various smoking methods were then rated based on their cannabinoid-to-tar ratio.

Surprisingly, the water pipes performed worse than the unfiltered joint, suggesting that "water filtration is actually counterproductive, apparently because water tends to absorb THC [tetrahydrocannabinol, the main psychoactive ingredient of marijuana] more readily than noxious tars." The vaporizer without the water pipe component did best, producing a cannabinoid/tar ratio "about 25 percent higher than the unfiltered joint." (An unexplained finding, though, was that the vapors from the vaporizer contained a higher than normal amount of cannabinol, a cannabinoid that is less psychoactive than THC but which may have medicinal benefits. The THC/tar ratio for the vaporizer was somewhat lower than the unfiltered joint.) Overall, Gieringer concluded that the study shows great potential for vaporizers but that "more developmental work needs to be done."

Since that article was published a number of vaporizers have been developed and sold through a variety of outlets, including head shops, medical cannabis clubs and on the Internet. Developers of the individual products tend to claim great benefits and several have ardent fans, but at present there is no scientific data to verify the efficiency or cannabinoid/tar ratios of these devices.

AIDS Treatment News received a demonstration of two vaporizers, the VaporTech Vaporizer from Florida-based VaporTech, and the Volatilizer, from California-based Chirotech. Both products appear to do what they claim to do: vaporize the active ingredients without actual combustion. Subjectively, users report that the vapors are notably less harsh than conventional smoke, while being at least as potent and perhaps more so.

The Volatilizer, a favorite of the staff at CHAMP, consists of a wand-like device which plugs into an electrical outlet and has a round heating element at the end. The heating element is designed to fit over a special bowl, which can be used with the user's own pipe or bong. It sells for $199.95. VaporTech's unit is somewhat more complex, with about half a dozen separate pieces. The marijuana is placed in a small test tube which is placed in the unit and heated, and the vapors are inhaled through a plastic tube. Some users complain that the VaporTech gets too hot, and marijuana left in it more than a few minutes will burn, but this does not appear to be a problem if one uses the material relatively quickly. The VaporTech sells for $140 plus shipping charges.

A number of other vaporizers, which we have not had the opportunity to see demonstrated, are also available. These include the Omega Vaporizer, which is normally carried at the Oakland CBC's Hemp Store but was out of stock when this article was being prepared. Several products, including the Vaportron, VapoRizit and the British Vapouriser use a roughly similar design, with a small bowl to hold the marijuana placed over a heating element, all enclosed by a dome to retain the vapors. These relatively simple designs tend to be less expensive than the others, generally in a range from $60 - $100.

Sources of further information, including instructions for building a homemade unit, are listed below.

Although everyone we spoke to had a favorite model, there is at present no scientific data comparing the products with each other or with conventional smoking. Such a comparison would not be difficult to do with the proper equipment and lab facilities, and a number of entities are interested in pursuing such research, including CHAMP and MAPS. Money is one obstacle, notes Gieringer, as the study would be relatively expensive and there is no pharmaceutical company to finance it. The firms now marketing vaporizers are all tiny, with nowhere near the resources of even a medium-sized drug company.

The other obstacle is the continuing prohibition of marijuana, since tobacco can't be substituted for marijuana in vaporizer tests. Indeed, drug paraphernalia laws now constrain vaporizer companies from even discussing marijuana in their publicity materials, and the obstacles to medical marijuana research remain high. Chuck Thomas of the Marijuana Policy Project notes that a well-publicized easing of restrictions announced earlier this year was only a small step in the right direction. "Health and Human Services still makes it unnecessarily difficult to do medical marijuana research," he says. "The HHS guidelines still say a special Public Health Service review is necessary. The question is, why? You can study thalidomide without a PHS review, and I don't think anyone in their right mind believes that marijuana is more dangerous than thalidomide."


References and Information Sources

Dale Gieringer's article, "Marijuana Water Pipe and Vaporizer Study," which appeared in the Newsletter of the Multidisciplinary Association for Psychedelic Studies,Volume 6, Number 3, Summer, 1996 is available online at the MAPS Web site, http://www.maps.org/news-letters/v06n3/06359mj1.html.

The Institute of Medicine Report, Marijuana and Medicine: Assessing the Science Base, can be purchased from the National Academy of Sciences, (800) 624-6242 and is available free online at http://books.nap.edu/html/marimed/notice.html. Lester Grinspoon's critique of the report is online at http://www.rxmarijuana.com/iomreview.htm.

Vaporizer product information:

VaporTech: http:www.vaportechco.com, or 888-453-1996, vaportech@yahoo.com.

Vaportron (Vaporware): (888) 276-7927, or http://www.vaporware.net.

Vapouriser: http://www.virtual-shops.net/chillabong/vapouriser.html (Note: Although the information on the Web site did not make this clear, this British unit will need an adapter to be used with standard U.S. electric current).

Volatilizer: (800) 485-7305.

Omega Vaporizer: Available through the Oakland CBC, (510) 832-5346.

VapoRizit: 3089-C Clairemont Dr., Unit 34, San Diego, CA 92117, info@vaporizer.com, http://www.vaporizer.com.

A number of other Internet sites feature information on vaporizers, including basic explanations, personal experiences and do-it-yourself instructions for making your own. A Web search using the term "vaporizer" will turn up a number of listings. One with particularly extensive information is http://nepenthes.lycaeum.org/Drugs/THC/Vaporize/index.html.

Other do-it-yourself instructions are at http://www.angelfire.com/ga/greenmanspage/vaporizer.html and http://people.delphi.com/sjc/drugs/weed/mj_vaps.html.

Like much that is available on the Internet, the information on these sites, including the vaporizer plans, should be regarded as anecdotal and unverified.



Teleconference September 29: Treatment News from ICAAC Conference


ICAAC (the Interscience Conference on Antimicrobial Agents and Chemotherapy) is a major annual meeting on new antibiotics and antivirals; about 10,000 people usually attend. This year ICAAC will be in San Francisco, September 26-29.

On Wednesday September 29 there will be a one-hour conference call to discuss HIV treatment news from ICAAC. Panelists on the call are Calvin Cohen, M.D., from Boston; David Cooper, M.D., from Sydney, Australia; Roy Gulick, M.D., from New York City, Barbara Weiser, M.D., from Albany, New York, and Ron Baker, Ph.D. (moderator). Participants can ask questions of the panel during the call -- which will take place 12 p.m. Pacific time, 1 p.m. Mountain, 2 p.m. Central, 3 p.m. Eastern time.

To participate in this call, you must register in advance (first name only); to register, call 800-880-5121, Monday through Friday 9 a.m. to 5 p.m. Eastern time. Also, you can send questions to the panel in advance by email, HIVTxLive@aol.com.

You can also hear a taped replay later (no registration required); call 888-207-2647, pass code 1145, at least 24 hours after the call. And about 14 days later, a transcript will be available at http://www.HIVTreatmentLive.com.

This program is supported by an unrestricted educational grant from Roche Laboratories.



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Teleconference October 12: National Conference on Women and HIV/AIDS


The 1999 National Conference on Women and HIV/AIDS will be held in Los Angeles, October 9-12, 1999; major topics will include basic and clinical science, behavioral and prevention science, and policy and public health.

On Tuesday, October 12, panelists will discuss highlights of the meeting on a one-hour telephone conference call. The panelists are: Kathryn Anastos, M.D., Catholic Medical Centers of Brooklyn and Queens; Ronald Baker, Ph.D., HIVandHepatitis.com; Andrea Kovacs, M.D., USC School of Medicine; Sarah Rowland-Jones, M.D., Oxford University; Lillian Thiemann, HIV/HCV co-infection advocate; and Barbara Weiser, M.D., New York State Department of Health.

To join the telephone conference, you must register in advance (first name only); call 800-880-5121 Monday through Friday 9 a.m. to 5 p.m. Eastern time. Also, you can send questions to the panel in advance by email, HIVTxLive@aol.com.

You can also hear a taped replay later (no registration required); call 888-207-2647, pass code 1146, at least 24 hours after the call. And about 14 days later, a transcript will be available at http://www.HIVTreatmentLive.com.

This program is supported by an unrestricted educational grant from Roche Laboratories.



Washington Physicians' Panel on AIDS: Video Available


On September 7th a panel of four HIV specialists discussed treatment and answered audience questions at a public meeting in Washington D.C.; the panel was moderated by John S. James of AIDS Treatment News. Videotapes are available without charge from the National Community Research Initiative, Inc. until supplies run out.

The panelists are:

  • Bruce Rashbaum, M.D., on new drugs in development;
  • Douglas Ward, M.D., on lipodystrophy;
  • Michael Pistole, M.D., on HAART; and
  • Larry Bruni, M.D., on immune reconstitution.

For a copy of the video, send your name and mailing address to Gary Whaley, NCRI, 631 Pennsylvania Ave. S.E., Washington, D.C. 20003, phone 202-546-0854, fax 202-546-0890, or email ncri2000@aol.com.

This program was supported through unrestricted educational grants from over 20 pharmaceutical companies.



ISSN # 1052-4207

Copyright 1999 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.




  
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