- 1997 Outlook
- Nelfinavir: Agouron Announces Expanded Access for Children, a Major New Trial, and Enlarged Expanded Access for Adults
- Retroviruses Conference: Where to Find Reporting on the Internet
- Medical Marijuana: Unpublished Federal Study Found THC-Treated Rats Lived Longer, Had Less Cancer
- Activist Groups and PWA Coalitions, U.S. and Canada
1997 Outlookby John S. James
|In 1996 HIV treatment advanced far more than in any other year yet of the epidemic. But no one knows whether or how much this improvement will continue.|
In the most important measure, reduction in deaths, statistics beginning to emerge suggest a drop in the death rate by at least half in the past year, in diverse populations which are receiving modern treatment.
* In San Francisco, the total number of obituaries received by the BAY AREA REPORTER -- almost all due to AIDS-related deaths -- dropped by at least half between the beginning and the end of 1996. And the January 1996 rate was already much lower than the peak, which occurred several years before. (For more information, see AIDS Treatment News #260, December 6, 1996.)
* The California Medical Facility in Vacaville, California, which treats most male prisoners in California who have serious medical conditions, had far fewer deaths at its in- prison hospice (when we spoke there for World AIDS Day, in early December 1996) than a year before. We do not have final figures for the year, but as of December 6 it appeared that the total deaths for the year would be reduced at least by half. The CMF is a leader in HIV/AIDS treatment in prison; combination antiretroviral treatment including at least one protease inhibitor (ritonavir) is used there.
* The best data so far is from a study in British Columbia, Canada, which found that the death rate for that province in the last three months of 1996 was only one third what it was two and a half years ago. Julio Montaner, M.D., of the B.C. Centre for Excellence in HIV/AIDS, attributed the reduction to improved treatment. The study has not yet been formally published, but was confirmed by the researchers after it was obtained by the media (see TORONTO STAR, January 8, page A2).
The fact that similar results occurred in very different populations who all had access to modern HIV care -- in addition to anecdotal reports of even greater reductions of deaths in medical practices specializing in HIV -- strongly suggests that this large and unexpected decrease is not due to the natural history of the epidemic. Improved treatment is almost certainly the main reason.
Also, all of the treatment effect on deaths in 1996 must have been in persons with advanced illness (which is hardest to treat in any disease) -- since those with early HIV infection or only moderate progression early in 1996 would not have died in that year anyway. The new treatments might work even better in those who start them earlier. (But no one knows for sure, since it would take years to measure survival improvement due to early treatment of HIV disease -- if meaningful data can be obtained at all, which is unlikely, since most patients would change treatments during the years it would take to run such a study).
But despite the great decrease in deaths during the last year, AIDS experts are cautious and guarded in their optimism. Anecdotally there are many reports of failures of the new anti-HIV drug "cocktails" -- either because the virus develops resistance to the drugs, or because the patient becomes unable to tolerate continued treatment and the virus returns after one or more drugs are stopped. And many patients (most estimates range between 10 and 30 percent) cannot be successfully treated with the new drugs even initially, for various reasons. As would be expected, the treatments are most likely to work in those with relatively early disease, and in those who have had little or no prior treatment with any of the drugs in the combination which is being used. Historically, the drugs have become available one by one (for many years there was only AZT), so the virus populations in many patients had a chance to become resistant to the drugs one after the other.
And the great majority of people with HIV around the world, including many in the U.S., do not have access to medical care from HIV-experienced physicians, nor access to the drugs they may need. A recent article in a European newsletter noted that most patients in Estonia die within weeks of an AIDS diagnosis, and the main AIDS organization there had just seen its first case of survival for one year after diagnosis ("Countries: AIDS in Estonia," EUROPEAN AIDS Treatment News, volume 5, number 5, pages 96-99). Even in the UK, it was recently reported that persons with HIV are only half as likely to receive modern combination treatments as in other counties, due to funding problems. And in the U.S., quality of care varies greatly by social class, and by region.
Even with access to the best care, no one knows for sure if the great improvements for some groups in 1996 will be permanent. Will deaths continue to decrease, or will 1996 be looked back on as an exception? The answer will depend greatly on what we do now -- which is why the"end of AIDS" media message is so dangerously misleading. The treatments we have must be used carefully -- and continued research and development not only remain essential, but have more opportunities now than ever before to save lives.
Upcoming Retroviruses ConferenceNext week we will attend the 4th Conference on Retroviruses and Opportunistic Infections, the most important AIDS research meeting in 1997. It is difficult to learn much in advance about what will be presented (abstract books and abstracts on disks are being sent, but no copies were available until the day this issue went to press). We do not expect major surprises, but there will certainly be important, in-depth information in most areas of AIDS treatment development, which we will cover in future issues. (See " Retroviruses Conference: Where to Find Reporting on the Internet," below, for suggestions on how to follow the conference if you cannot attend.)
1997: Protease Inhibitors* An overview of the currently available protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir), by AIDS experts at San Francisco General Hospital and elsewhere, appeared in JAMA (THE JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION), January 8. The full text is available on the American Medical Association's Web site, at:
It is a valuable summary for physicians and patients. (Deeks SG, Smith M, Holodniy M, and Kahn, JO. HIV-1 Protease Inhibitors: A Review for Clinicians. JAMA. January 8, 1997; volume 277, number 2, pages 145-153.)
* Nelfinavir (VIRACEPT(R)) is a protease inhibitor now available to some patients through an expanded access program; it could be approved for general availability early this year. It appears to have fewer side effects than the currently-approved protease inhibitors, and a somewhat different viral resistance pattern (which might improve its usefulness for patients already resistant to one or more of the other protease inhibitors). For more information on nelfinavir, see the article below.
* An important focus of research will be treatment failures with protease inhibitors. How long will high-level viral suppression last -- and in which patients? What treatments are best for patients who have failed one or more protease inhibitor regimens?
* Another research focus will be blood tests to determine which drugs a patient's virus is resistant to. Some such tests are already available to physicians, but they are still far from official approval or widespread routine use.
1997: Other Antiretrovirals
* 1592. 1592 (1592U89), being developed by Glaxo Wellcome and now in early clinical trials, is a nucleoside analog drug (in the same general class as AZT), but is much more effective than AZT in suppressing HIV. 1592 has good penetration across the blood-brain barrier; it is also important because it is a new option for persons whose virus already became resistant to AZT or other current drugs. Because of the schedule of clinical trials, 1592 is not expected to be approved in 1997. Activists are seeking a pre-approval expanded-access program, especially for those with no other treatment options, with wider access as more safety data becomes available from the trials (see "1592: Consensus Letter on Access to New Glaxo Drug, AIDS Treatment News #261, December 20, 1996).
* Integrase inhibitors. This is a new class of anti-HIV drugs, which target a different viral enzyme than the protease inhibitors or the nucleoside analog drugs target; therefore, virus which has already developed resistance to the previous drugs would not be expected to have any cross- resistance to integrase inhibitors. There has been concern for years that large companies have been less diligent in developing integrase inhibitors than they were with other classes of drugs, resulting in a lack of treatments in the pipeline after the protease inhibitors. Government researchers screened a number of chemicals as potential integrase inhibitors and published the results in early 1993 (Fesen, MR and other, "Inhibitors of Human Immunodeficiency Virus Integrase," PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE, U.S.A., March 1993, pages 2399-2403), but government agencies alone almost never develop drugs in the U.S. Only one integrase inhibitor is in human trials, as far as we know; it is Zintevir(TM) (also known as AR 77), being developed by Aronex Pharmaceuticals, Inc.
* Drugs with new targets. The recent discovery of additional receptors (besides CD4), which HIV uses in addition to CD4 in order to enter a cell, has provided new targets for antiretroviral drug design.
Also, at least one drug which targets the zinc fingers of HIV is now in human trials.
* PMPA, being developed by Gilead Sciences, is another antiretroviral worth watching. After promising results in animal studies, a human trial has been started.
* The list above is not complete, as there are many other potential antiretrovirals in various stages of research.
Other TreatmentsDue to limited time and limited space in this issue, we cannot cover many other classes of treatments, including immune-based treatments, immune reconstitution, therapeutic or preventive vaccines, and various cytokine approaches.
Some areas that we think need more attention include:
* A major problem in researching immune-based treatments has been the practical difficulties in doing immune function tests, including control of laboratory errors. More research is needed on developing flow cytometry tests for immune function (using similar technology as now used for measuring CD4 counts), because these tests usually are easy to perform, and greatly reduce the opportunities for laboratory error.
* More attention is also needed for potential treatments now often classified as "alternative" or "complementary" -- such as NAC, glutamine, or DHEA. Treatments become "alternative" because people can obtain them now, despite lack of official approval -- which strongly correlates with them being largely or completely nonproprietary, meaning that there is little incentive for formal research. Alternative/complementary treatments are much less effective as antiretrovirals than the mainstream drug "cocktails" available today -- but they may have other uses, such as the possibility that NAC might reduce the problem of abnormal sensitivity to co-trimoxazole (Bactrim, Septra) by persons with HIV. Certain nutritional treatments might reduce drug side effects, increase absorption of drugs by certain patients, or otherwise improve general health or quality of life. Since the mainstream drug- development system will not give this work the attention it deserves, due to the relative lack of financial incentives, the community needs to be involved.
Access Issues, Compliance, Standards of CareThese areas will become even more important this year. We cannot review them here, except to mention just a few of the areas that need to be watched:
Nelfinavir: Agouron Announces
|The protease inhibitor nelfinavir (VIRACEPT(R)) is not yet approved for marketing, but is available to some patients through an expanded access program. Nelfinavir may have fewer side effects than the currently approved protease inhibitors.|
On January 6 the drug's developer, Agouron Pharmaceuticals, Inc. of La Jolla, California, announced that it will make nelfinavir available "without charge to any HIV-infected child [ages 2-13 years] until the drug is approved for marketing in the United States." Safety trials have been run in children, and are expected to be presented next week at the 4th Conference on Retroviruses and Opportunistic Infections. Agouron has developed an oral powder formulation for children, while it was developing the tablets for adults.
So far no protease inhibitor has been available for children, outside of small trials, because dosage and safety studies had not been completed.
Physicians, health-care professionals, and parents interested in the VIRACEPT Pediatric Expanded Access Program can call the VIRACEPT Expanded Access Program Hotline, 800/621-7111, Monday through Friday from 8:00 a.m. to 6:00 p.m. Eastern time.
* On January 6 Agouron announced a large clinical trail to compare nelfinavir plus nucleoside analogs (AZT, 3TC, ddI, ddC, d4T) vs. ritonavir (Norvir(R)) plus nucleoside analogs. 1300 persons with CD4 count under 100 will be randomly assigned to one or the other treatment. This trial will be run by the CPCRA, an AIDS research program of the U.S. National Institute of Allergy and Infectious Diseases, and the Canadian HIV Trials Network. It seems to be well regarded by treatment activists, because both treatment arms are appropriate therapy, with neither designed to likely be weaker than the other.
For information on enrolling in this trial, call the AIDS Clinical Trials Information Service, 800/TRIALS-A.
* On January 8 Agouron relaxed the entry criteria for its expanded access program for adults (age 13 and older). "People will now qualify for the VIRACEPT Expanded Access Program if they are unable to take indinavir (Crixivan(R)) and/or ritonavir due to intolerance or prior failure and who have had CD4+ T-cell counts of less than or equal to 100 cells/mm3 during any past medical examination." Previously it was necessary to be unable to use all three approved protease inhibitors, and to have a CD4 count under 50. For information on this program, call the VIRACEPT Expanded Access Program Hotline, 800/621-7111, Monday through Friday from 8:00 a.m. to 6:00 p.m. Eastern time.
* On December 23 Agouron announced that it had applied to the FDA for approval to market nelfinavir in the U.S. The company is applying under the FDA's accelerated approval regulations for both the adult tablets and the pediatric powder formulations. These regulations allow approval based on blood-test results such as viral load, but require large human trials later to prove clinical benefit.
|The 4th Conference on Retroviruses and Opportunistic Infections will take place January 22-26 at the Sheraton Washington Hotel. Abstracts, reports (either daily, or after the conference), and audio feed and slide images, will be available through various sites on the Internet. You may want to check the following sites, which are accessible without charge, and from anywhere in the world.|
* Audio feed, slides, and abstracts: The conference organizers will broadcast (on the Internet) audio and slides of some of the major sessions of the conference, about 12 hours after the presentations. The equipment needed is a modem (with a DOS/Windows computer, either a 14.4 or 28.8 modem can be used; with a Macintosh, 28.8 is required), and a sound card. The system is optimized for either Netscape Navigator or Microsoft Internet Explorer, but other browsers may work as well. Users will see a picture of the presenter, with the slides changing with the talk as if one were in the room, and hear the audio (using RealAudio software, which can be downloaded through the site). There will also be a search engine to help skip ahead in a talk.
This system will be accessible through www.retroconference.org. The conference abstracts will be available through the same site; note that most abstracts were submitted months ago and have not been revised, but that the "late breaker" abstracts are new. (The "idsociety" Web address for the abstracts, which we published in our last issue, is being changed to the"retroconference" address, above; as we go to press on January 14, the "idsociety" address only has news and abstracts of LAST YEAR'S 1996 Retroviruses conference, and the "retroconference" address is not yet available. If you have problems connecting to the "retroconference" address, check the other sites for the latest information, or call AIDS Treatment News.)
The conference organizers hope to broadcast the State of the Art talks, the two opening sessions, and one symposium each afternoon. It may not always be possible to get permission from the presenters, however, because medical journals often consider Internet distribution to be "publication," meaning that they will refuse to publish an article if the information has been released that way.
Check the "retroconference" site for the latest information.
* As we announced in our last issue, Healthcare Communications Group has organized 16 authors and writers to produce daily reports on the Retroviruses conference, to be available the following morning. Check their site at http://www.healthcg.com -- which already has useful pre- conference summaries on pathogenesis, viral markers, antiretrovirals, immunomodulation, TB/MAC, CMV, fungal infections, and AIDS-related cancers.
* The Body, an organization which provides AIDS information on the Web, will publish reports by Ramon A. (Gabriel) Torres, M.D., Director of the AIDS Center at St. Vincent's Hospital in New York, and Andy Pavia, M.D., Director of Clinical Research for the University of Utah Health Sciences AIDS Center. Coverage will include a question and answer session with Drs. Torres and Pavia. The Web site is http://www.thebody.org.
* The International Association of Physicians in AIDS Care will have daily reports by technical writers Mark Mascolini and David MacDougall, at http://www.iapac.org.
* Extensive reports of the conference will be published on the Critical Path AIDS Project site, http://www.critpath.org.
* Jules Levin will report on protease inhibitors on http://www.aidsnyc.org/natap.
* Also, there will be many wire service and other news-media reports on the Retroviruses conference. An excellent free source for most AIDS-related daily news is the AIDS list of AEGIS (AIDS Education Global Information System), run by Sister Mary Elizabeth in Southern California. You only need an email address to use this service; you do not need access to the World Wide Web. To subscribe, send email to: email@example.com, with the message:
Note: This service sends about 15 to 20 AIDS-related news reports per day (and probably more during the Retroviruses conference). If you want to reduce email traffic, you can have the messages collected into a digest, which is sent when it reaches 40,000 characters in size. To receive the digest, send email to: firstname.lastname@example.org, with the message:
For more information about this AIDS mailing list, send the message "info aids ", or "info aids-digest " (without the quote marks) to: email@example.com. Or see the AEGIS home page, http://www.aegis.com.
Note: By agreement with the International Association of Physicians in AIDS Care, AEGIS will also send to its AIDS mailing list the Retroviruses conference reports published on the http://www.iapac.org Web site described above.
by John S. James
|AIDS Treatment News has obtained a 126-page draft report of a major toxicology study of THC, the main psychoactive ingredient of marijuana. The study was completed over two and a half years ago, and passed peer review for publication, but has been kept quiet until this month, when someone leaked copies of the draft report. As far as we know, the public has never been told about this research -- for example, the drug- reform movement seems not to have known about its existence. This work may have been hushed because its findings are not what the drug-war industry would want.|
The study gave huge doses of THC to rats and mice by stomach tube, and looked for cancers and other evidence of toxicity. First there were small toxicity studies, which used enough THC to kill some of the animals; later, two-year studies were run in both rats and mice, using doses which were still much higher than those of marijuana smokers. The two-year studies tested THC in several hundred rats and several hundred mice.
In rats, those given THC had a clear survival advantage over the untreated controls; this effect was statistically significant in all dose groups, and in both males and females. In mice (which were given much larger doses than the rats relative to body weight) there was no survival difference among the groups -- except that those given the highest dose (which was close to the lethal dose for mice) had worse survival.
In both mice and rats, in both males and females, "the incidence of benign and malignant neoplasms ... were decreased in a dose-dependent manner" -- meaning that the more THC the animals were given, the fewer tumors they developed.
The treated animals weighed less than the controls (even though both ate about the same amount of food); the researchers speculated that the lower body weight may have partly accounted for the increased survival and reduced tumors in the THC-treated animals.
The doses were large enough to cause seizures and convulsions in many of the animals, especially when they were dosed or handled. These did not start immediately, but after many weeks, depending on the dose. The researchers looked for brain lesions in animals which had seizures, but found none.
No evidence of carcinogenic activity in the rats, but there was "equivocal evidence" of one kind of thyroid tumor in the mice -- with no evidence of a dose-dependent response. Other tumors were less common in the treated animals than in the controls -- except in one case, which the toxicologists believed was due to the fact that the treated animals lived longer, and therefore had more opportunity to develop tumors.
The report includes a professionally objective review of the biological effects, possible toxicities, and possible medical uses of THC and marijuana.
The title of the report is "NTP Technical Report on the Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)- Tetrahydrocannabinol (CAS No. 1972-08-3) in F344/N Rats and B6C3F(1) Mice (Gavage Studies)." Over 35 researchers contributed to this study, and 12 others reviewed their work; several institutions, including the National Toxicology Program and SRI International, were involved. The document we received is report NTP TR 446, NIH Publication No. 94-3362, of the U.S. Department of Health and Human Services. ("NTP" stands for National Toxicology Program, which is made up of four Federal agencies within Health and Human Services.) Each page of the draft is stamped "not for distribution or attribution." In addition to the 126-page document we have reviewed here, there are 11 appendices, which we have not seen.
According to the draft, the report will be available from NTP Central Data Management, 919/ 541-3419. AIDS Treatment News requested a copy of the final report when it is ready, and also requested a copy of the draft. Now that the existence of the report has become publicly known, we have heard that draft copies are being sent if requested -- despite the notice on each page not to distribute them.
CommentIt would be wrong to interpret this study as showing a beneficial or protective effect of marijuana. The animals were given very large doses, resulting in substantially lower body weight, which may itself have caused much of the survival and tumor improvements. Also, this study used THC, not marijuana smoke -- which like any smoke contains many chemicals, some of which are likely to be harmful.
But the study does provide strong evidence that there is no significant cancer risk (if any at all) from the main psychoactive ingredient of marijuana; any such risk would be from incidental substances in the smoke. And if there is such a risk, the modern high-potency marijuana would likely reduce it, by reducing the amount of smoke required to obtain the desired effect.
Also, there is no known case of any human death from overdose of marijuana or THC, or from any other acute toxicity of these substances -- a remarkable safety record, compared with alcohol, aspirin, or many other common drugs. (The toxicology report does not say there have been no deaths, but the authors listed none, after doing an exhaustive survey of the literature.)
The literature review on the effects of THC and marijuana shows how medical research has been politically skewed (although the paper itself does not state this point). There are almost no studies of possible medical uses of marijuana, but many studies looking for possible harm. Any positive findings, therefore, can be used to support the drug war -- while negative findings (those which fail to show any effect) are usually ignored. Although many doctors and patients have reported important medical benefits, scientific studies of medicinal use have seldom been allowed to happen, since positive findings could challenge the official public- relations tactic of demonization. The drug war itself has controlled the medical research agenda, since it controls legal access to marijuana. Like most permanent wars, it strives for self preservation.
The newly available Federal toxicology study provides the best evidence yet that the risks of THC are small. What other drug would increase life expectancy of rats when given in huge overdoses daily for two years? The recent Federal attacks on medical marijuana -- against doctors and desperately ill patients -- are needlessly cruel, and bizarrely inappropriate to scientific and medical understanding.
Updated January 1997
|Since 1990 AIDS Treatment News has published a list of ACT UP or activist groups, PWA coalitions, and buyers' clubs; this year the buyers' clubs were listed separately (issue #260, December 6, 1996). We called the numbers below and included only those we could verify; some are home telephones, not offices. Within states, the listings are alphabetical by city.|
For information about ACT UP affiliates, call the ACT UP Network, 215/731-1844. For information about other PWA organizations, call the National Association of People with AIDS (NAPWA), 202/898-0414. If you know of other organizations which should be listed in this directory, please call AIDS Treatment News at 800/TREAT-1-2, or 415/255- 0588.
There are well over ten thousand AIDS organizations in the U.S. alone; only a few can be included in this specialized list. To find out about services and organizations in your area, call the National AIDS Hotline, 800/342-AIDS, 24 hours a day; for the same information in Spanish, call 800/344- SIDA, 8 a.m. to 2 a.m. Eastern time, 7 days a week.
Birmingham Alabama Task Force on AIDS 205/781-6448
Phoenix The Arizona Human Rights Fund 602/530-1660
Long Beach Being Alive Long Beach 310/434-9022
Denver PWA Coalition Colorado 303/329-9379
DISTRICT OF COLUMBIA
Washington ACT UP/Washington 202/547-6780
Clearwater AIDS Community Proj. of Tampa Bay 813/449-2437
Atlanta ACT UP/Atlanta 404/874-6782
Honolulu Life Foundation 808/521-2437
Champaign Gay Community AIDS Project 217/351-2437
Bloomington Project FIND 812/337-2221
Davenport AIDS Project Quad Cities 319/328-5464
Lexington AIDS Volunteers (AVOL) 606/278-6274
New Orleans PWA Coalition 504/524-3488
Baltimore AIDS Action Baltimore 410/837-2437
Boston ACT UP/Boston 617/492-2887
Detroit Friends Alliance 313/831-4400
Minneapolis The Aliveness Project 612/822-7946
St. Louis ACT UP Treatment Issues Group 314/918-0820
Audubon AIDS Coalition of Southern NJ 609/573-7900
Santa Fe Northern New Mexico PWA Coalition 505/820-2540
Albany ACT UP/Albany 518/861-6337
Research Triangle Park ACT UP/Triangle 919/990-1197
Columbus Ohio AIDS Coalition 614/444-1683
Bethany Other Options 800/448-2497, or 405/495-2732
Milwaukee CCARE 503/653-8738
Philadelphia ACT UP/Philadelphia 215/731-1844
Sioux Falls ACT UP/South Dakota 605/332-3966
Memphis Friends for Life HIV Resources 901/272-0855
Austin AIDS Services of Austin 512/451-2273
Salt Lake City PWA Coalition Utah 801/484-2205
Brattleboro Vermont PWA Coalition 802/229-5754
Seattle Health Information Network 206/784-5655
Morgantown Mountain State AIDS Network 304/292-9000
Madison AIDS Network 608/252-6540
Casper Wyoming AIDS Project 307/237-7833
Halifax PWA Coalition Nova Scotia 902/429-7922