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AIDS Trestment News
December 4, 1998

Contents:


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Major Vaccine Project: Largest AIDS Research Grants Ever to Two "Most Promising" Approaches

by John S. James


On November 26, IAVI (the International AIDS Vaccine Initiative) announced grants totaling over $9,000,000 to develop two different kinds of vaccines, which were picked by a panel of experts as among the most promising in the world. The first human trials should begin in about a year. IAVI has also negotiated unique intellectual property arrangements, to make vaccine development attractive to industry, while also assuring that the vaccines will be accessible to developing countries.


DNA Plus MVA Vaccine

One of the research programs, led by researchers at Oxford University and the University of Nairobi, will combine two vaccines which may work well together. One consists of DNA for HIV core proteins; it is produced in genetically engineered bacteria. When injected, this DNA is taken up by cells in the body, which then produce those proteins -- hopefully stimulating the desired immune response against HIV. Four years of preliminary work have already been done in developing this vaccine.

The other technology to be used in this vaccine is MVA (modified vaccinia Ankara), a harmless virus used in smallpox vaccines. In this case, the vaccinia virus has been modified to encode certain HIV core proteins; the virus carries the DNA for these proteins into the cells. The virus does not replicate in humans, however.

In both mice and monkeys, this dual-vaccine approach has been shown to produce strong T-helper and CTL (cytotoxic T lymphocyte) responses. Phase I safety testing will be done at Oxford, followed by phase I, II and II/III trials in Kenya.

Other research teams are developing HIV vaccines which use the DNA or MVA technology, but this is the only project which will use them together. Another team at Oxford is using the two together, to develop a vaccine against malaria.


The VEE Replicon Vaccine

A second vaccine uses a delivery system called VEE replicon, first tested at the University of North Carolina at Chapel Hill and the U.S. Army Medical Research Institute of Infectious Diseases, and then in commercial development by AlphaVax Human Vaccines Inc. of Durham, North Carolina, for several diseases not including HIV. The IAVI project will fund the development of an HIV vaccine using this technology, which employs a non-virulent form of Venezuelan equine encephalitis virus (VEE) to carry HIV (or other) genetic material into human cells. The replicon does reproduce in human cells, but it does not produce infectious progeny. This vaccine produces both cellular and humoral immune responses, and targets lymphoid tissue.

This vaccine technology has protected monkeys against a highly pathogenic strain of SIV -- providing better protection than otherwise achieved except with a live vaccine, which has safety problems. In a separate experiment, it also protected monkeys against the Marburg virus, which is related to Ebola.


Intellectual Property Innovation

IAVI has also developed innovative business arrangements on intellectual property, to combine "the best mechanisms of the for-profit and not-for-profit sectors to achieve our goals," according to Lita Nelsen, director of the technology licensing office of the Massachusetts Institute of Technology (MIT), who was IAVI's principal advisor on intellectual property issues.

The basic arrangement is that IAVI invests money in promising technologies, in return for rights or other agreements that assure that the results will be available to the public sectors of developing countries, at a cost based on production cost. This way the company gets needed investment at an early stage of product development -- allowing it to move faster in producing the vaccine -- without interfering with its most valuable market, which will be in the developed countries. "Developing country" is defined according to World Bank criteria, and the "public sector" means government and non-profit organizations in those countries.

"By addressing these issues early and systematically, IAVI seeks to more effectively advance its overall mission. For-profit companies are where most of the world's vaccine development expertise resides. IAVI and its partners are creating the win-win situation necessary to fully engage the expertise of the private sector in this challenge. In doing so, they may also be able to help others successfully negotiate these issues to ensure that development moves ahead rapidly and access issues are addressed early on." (from "IAVI Intellectual Property Backgrounder," November 26, 1998).

"The current paradigm, where vaccines are developed in the industrialized world and sold exclusively there at high prices to recoup R & D costs, should not be acceptable for any vaccine, and certainly not for AIDS," said IAVI's president, Seth Berkley, M.D. "Developing countries should not be forced to wait 10 to 15 years for an AIDS vaccine to trickle down to them. We need to start now to ensure that a successful AIDS vaccine will be made available simultaneously in developed and developing countries."


Funding

IAVI began in 1997, with funding from the Rockefeller Foundation and public support from Princess Diana. Other supporters include the Alfred P. Sloan, Starr, William H. Gates, and Until There's A Cure Foundations; the World Bank; UNAIDS; Fondation Marcel Merieux; the UK Government; Levi Strauss International; and Glaxo Wellcome, in addition to individual donors. Crusaid, the Elton John AIDS Foundation, and others have contributed to the vaccine development effort.


For More Information

More information on the International AIDS Vaccine Initiative, on the vaccines, and on the intellectual-property arrangements is available at http://www.iavi.org.



Disability and Returning to Work: Proposed Change to Let Disabled Keep Benefits

by John S. James


On November 30, The New York Times reported that President Clinton will include in his budget a proposal to allow many persons who are officially disabled to return to work -- without losing their medical benefits on the grounds that since they can work, they are no longer disabled. A similar proposal already had strong bipartisan support in Congress -- it almost made it into the omnibus bill that Congress passed just before it adjourned -- and probably will become law in some form.

Since the details will matter, we asked benefits expert Tom McCormack what our readers should know about these proposals. While not yet familiar with the details of the president's plan, McCormack worked extensively in drafting the Congressional version (known as the Jeffords-Kennedy Work Incentives Improvement Act), as a consultant to the Title II Community AIDS National Network. Here are some of the issues he suggested for advocates to watch:

  • Already, under current law, medical benefits can continue (in some situations) when disability income benefits stop due to work; unfortunately most people are not aware of this. For example, the "Section 1619" program allows a person on SSI who goes back to work and earns too much to keep the SSI income, to still be able to keep Medicaid even if his or her income goes into the lower-middle-class range. And persons who get SSDI (and therefore can get Medicare, too, after two years), can keep Medicare even if SSDI stops due to work; in addition, for these people special welfare programs can help pay the Medicare premiums, well into the middle-income range. These are Federal rules, so they apply in all states.

    But the bigger problem under current law is that the Social Security Administration conducts continuing disability reviews (CDRs), to call in whole classes of people, or particular individuals, to see if they are still disabled. If they are found to be no longer disabled, they lose their medical benefits as well as their disability income -- even if they have no way to afford the medicines which are keeping them well, and will quickly become disabled again without the medical benefits.

  • The Jeffords-Kennedy bill would have allowed improved vocational rehabilitation, and enhanced Medicaid/Medicare benefits, for persons going back to work; for example, states could get extra money to remove the Medicaid cap on prescriptions.

  • This bill would have allowed states to receive extra high Federal Medicaid matching funds, if they gave drug and other early intervention services to pre-disabled persons who were at risk of becoming disabled, but could avoid becoming disabled by early medical care. This provision was mainly at the request of advocates for the mentally ill and mentally retarded, but could also be critically important for persons with HIV who are not yet "disabled." States would have been able to decide whether or not to participate, but they would get more money if they did.

  • The Jeffords-Kennedy bill did not include one provision it clearly should have had. Today, Federal rules are unclear on whether working persons who still have the underlying condition that led to their disability can keep Medicare or Medicaid if they are found to be no longer disabled enough for disability income checks. This is important because many people are in remission -- they are currently able to work, and therefore not "disabled" today -- but no one knows how long the remission will last. If they lose their status as disabled, it may be difficult to re-establish it later if they become unable to work again.

According to McCormack, current law, if read literally, seems to suggest that a person who still has the condition on which he or she received the determination of disability should not lose their disability status for medical-treatment purposes -- even if they are currently in remission, able to work, and no longer disabled enough for disability income payments. But the Federal regulations implementing the law have been written so that if someone flunks the disability review they lose medical care as well as disability income.

So McCormack and others tried to get the Jeffords-Kennedy bill to clarify the intent of Congress -- so that, for example, if someone became disabled due to HIV disease, but later was able to go back to work, they would not then lose access to their medical care, since they still had the underlying condition (HIV disease). McCormack explained that this provision did not get into the bill only because of the desire to avoid anything that might have raised controversy, in the failed hope of getting the legislation into the omnibus bill (in which case it would have been law today).

The New York Times article suggests that the Clinton proposal is particularly targeting rules which discourage people from working, for fear of losing their medical care if they do. For example, people who lose Social Security disability benefits because they return to work would be able to keep Medicare, and could buy Medicaid coverage under rules which could be set by the states.

  • Advocates should be aware that when this disability reform is debated, the official figures for the cost of new legislation may be unrealistic, greatly overstating the cost. This is because the computation of the cost cannot consider the savings from people no longer needing disability income since they are back at work (and who also may not need the government medical programs eventually, as they become established at work and obtain private insurance). These savings cannot be included in the cost estimates, due to laws that Congress passed years ago about how the Federal budget should be computed. This means that advocates may need to bring the savings estimates separately into the public debate, or it will look like this disability reform is costing much more than it really is.

For more information on these issues, call Tom McCormack at 202-479-2543.



Low-Dose Cyclosporin: Government Trial Recruiting, CD4 Count Over 500

Baltimore, Cambridge, Chapel Hill, Chicago, Cleveland, Denver, Galveston, Los Angeles, New York, San Francisco, Seattle


ACTG 334 is a small, 16-week clinical trial using many laboratory measurements to study low-dose cyclosporin in persons with HIV. Cyclosporin suppresses some immune responses, and is used in higher doses in organ-transplant patients to help prevent rejection of the new organ. This study is important for several reasons:

  • For many years there have been hints from anecdotal reports and small studies that cyclosporin or other immune-suppressive drugs may have a role in HIV treatment. But little prospective (planned in advance) research has been done -- and most of the research on cyclosporin in persons with HIV was conducted over 10 years ago, when much less was known about the immune system, and when many modern laboratory tests of immune function were not available.

  • One theory of why immune-suppressive drugs could be useful is that AIDS is not really an immune deficiency, but rather immune dysregulation, with some parts of the system being over-active -- including CD4 T-cells, which allow HIV to reproduce only when they are activated.

  • Studies of cyclosporin in persons with HIV will help to address the widespread bias against allowing them to receive organ transplants. (Transplant recipients often need long-term cyclosporin treatment, so it is important to know if this drug could cause any problems unique to persons with HIV.)

  • Cyclosporin also seems to have anti-HIV activity which is separate from its immune-suppressive effect (which could slow HIV replication by reducing the number of activated T-cells which can be infected). A cyclosporin variant, code-named NIM 811, has strong anti-HIV activity without the immune-suppressive effect of cyclosporin itself; unfortunately, in 1995 Sandoz Ltd. (which since merged with Ciba-Geigy Ltd. to form Novartis), stopped development of NIM 811, apparently because the company is focused on transplant drugs rather than anti-infectives.(1) A recent paper has suggested where to look for molecular targets which could be used to develop other drugs with the anti-HIV activity of cyclosporin but without its immune suppressive activity.(2)


ACTG 334 Entry Criteria

ACTG 334 is a phase II, placebo-controlled study of cyclosporin and immune activation in persons with HIV; its purpose is to advance knowledge of the disease, but there is no reason to expect that patients will benefit directly from the treatment. Some persons will want the extensive test results, many of which are not available commercially.

Volunteers must have a CD4 count greater than 500, and a viral load greater than 600. They may either be on no anti-HIV treatment, or be taking two nucleoside analog drugs (e.g. AZT plus 3TC, or d4T plus ddI). They cannot currently be using protease inhibitors, nor NNRTIs (such as efavirenz or nevirapine), although past use is allowed. They must not be planning to change their anti-HIV medications during the course of this 16-week study.

A total of 9 study visits (plus 5 additional short visits to have a skin test read) will be required; volunteers will be paid a small compensation for their time (the amount can vary by site). The following tests will be run: soluble IL-2 receptors, beta-2 microglobulin, neopterin, CD-25, CD-38, HLA-DR, lymphoproliferative assay, apoptosis, DTH (skin test of immune function), viral load, proviral DNA, and HIV microculture.

The cyclosporin dose in this trial is 2 mg/kg twice a day (a total of 4 mg/kg per day). Half of the volunteers will be assigned to a placebo group, and they will not receive any cyclosporin.


For More Information

For more information about ACTG 334, including how to contact a site near you, call the AIDS Clinical Trials Information Service, 800-TRIALS-A.

Note: ACTG 334 should not be confused with a separate cyclosporin study, being run by ViRx, Inc., in three California cities: Palm Springs, San Francisco, and San Jose. The ViRx study is for persons with somewhat more advanced HIV disease (CD-4 count between 300 and 600). For more information about this study, call the ViRx office, 415-474-4440.


References

1. Loftus, R. Sandoz axes cyclosporine research. GMHC Treatment Issues December 12, 1995; volume 9, number 12.

2. Kinoshita S, Chen BK, Kaneshima H, and Nolan G. Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. Cell November 25, 1998; volume 95.



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IDSA Conference: Abstracts on the Web

by John S. James


The 35th Annual Meeting of the Infectious Diseases Society of America (Denver, November 12-15, 1998) had almost 800 oral or poster presentations -- 186 of which mentioned "HIV" in the abstract or title. You can search the abstracts online (see below). Note that these published abstracts were submitted well before the conference, and the researchers cannot update the online copies with new information which they may have presented at the meeting itself.


Major HIV Topics Covered

HIV-related topics at the IDSA conference included antiretroviral therapy (with a section on salvage therapy), HIV transmission and prevention, HIV care delivery and economics in the U.S. and elsewhere, perinatal transmission and HIV in children, lipodystrophy and other adverse effects of drug therapy, drug resistance, opportunistic infections, tuberculosis, hepatitis B and C, post-exposure prophylaxis of HIV, physician experience, patient adherence, basic research on HIV biology and pathogenesis, newer antiretrovirals (including hydroxyurea, and FTC), new diagnostic tests, and vaccines.

IDSA presentations that were not AIDS-specific included evidence that CMV infection may be a risk factor for heart disease (in the U.S., CMV infects more than half of the population by age 20); and a report that syphilis has reached an all-time low in the U.S. (but is concentrated in certain areas, with 6% of U.S. counties, mostly in the South, accounting for 85% of newly reported cases in 1997).

Summaries of several of the most important HIV-related sessions -- written by Frederick L. Altice, M.D., Assistant Professor of Medicine at Yale -- are online at The Body, http://www.thebody.com.

AIDS Treatment News did not cover this IDSA meeting in person.


Searching the IDSA 98 Abstracts

The abstracts of the IDSA conference were submitted in advance, and those which were accepted for presentation are available online. You can search these abstracts -- almost 800 of them -- for any word or for combinations of words, at the IDSA Web site, http://www.idsociety.org. (At the site, select "IDSA Meetings & Conferences," then "1998 Annual Meeting Abstracts," then "Abstracts-On-Line®.") The first time you use this software, you will be asked to make up a user name and password; remember these for faster access next time.

The software at the site allows you to create a "personal itinerary" -- a collection of results from multiple searches -- which can then be printed in order, without repeating abstracts which turned up in more than one of your searches. Also, the personal itinerary feature is helpful if you want to print a large number of abstracts or titles (or save them locally on your computer).


Comment: Conference Confusion

The IDSA conference received little attention for a meeting of its size -- a result of historical accident, especially the fact that there are too many AIDS-relevant meetings in the fall and too few in the spring. Until recently, the IDSA meeting was coordinated with ICAAC (the Interscience Conference on Antimicrobial Agents and Chemotherapy, an annual meeting organized by the American Society for Microbiology); the IDSA meeting was two days before or after ICAAC, in the same city and usually the same hotel, so it was easy to attend both. Those IDSA meetings were much smaller -- several hundred physicians sitting in a single hall all day, hearing ten to 20 top-quality lectures by leading physician-scientists, primarily reviewing changes in the field, rather than presenting original research findings.

Now the organizations have ended their coordination, and the IDSA meeting has expanded to compete with ICAAC as a large, multi-track forum for presentation of new medical and scientific information. So ICAAC, IDSA, and the International Congress on Drug Therapy in HIV Infection are bunched together -- between the World AIDS Conference (in June or July, even-numbered years only), and the important Retroviruses conference in January or February. Researchers do not know whether to present at ICAAC or IDSA, as the audience is split since it is hard to attend both.

Meanwhile there is a lack of similar conferences in the spring. So if a research advance misses the Retroviruses conference, the researchers may not present it at all until next summer or fall -- often more than a six-month delay.

A solution would be for IDSA to hold its research conference in the spring, so that it does not compete with ICAAC for the same presentations -- as is now the case not only in AIDS, but in other areas as well. Then researchers could present their results more quickly, at whichever meeting happened next, and more people would attend both.

Another helpful conference innovation would be a public online forum where researchers could add new information to their conference abstracts at any time, if they chose to do so.



4th International Congress on Drug Therapy in HIV Infection: Summaries on Web


Next-day summaries of the 4th International Congress on Drug Therapy in HIV Infection (November 8-12, Glasgow, Scotland) are available at http://www.healthcg.com/hiv. Also, the complete program is currently online at the official Web site of the conference, http://www.hiv98.com.

This conference focused on HIV clinical practice now and in the future.



New Drug Pricing: Progress on World AIDS Day?

by John S. James


On December 1 Glaxo Wellcome announced a price for ZiagenTM (abacavir, 1592), which was less than many had feared. Glaxo will charge wholesalers $3,540 per year ($9.70 per day), with discounts to the ADAPs (AIDS Drug Assistance Programs in the various states) bringing the cost to those programs to around $3,000 per year. This is significantly less than the price of DuPont Pharma's SustivaTM (efavirenz), which had led to community protests and to reluctance of ADAPs to cover the drug.

Ziagen is not yet approved for marketing, but approval has been recommended and could come this month.

Also DuPont Pharma announced modest price concessions -- promising not to raise the price of Sustiva for at least three years, and to guarantee for five years an additional 5% rebate for ADAPs, which it offered in October.

As this issue goes to press on December 2, early community reaction to these announcements has been mostly positive or mixed.



ISSN # 1052-4207

Copyright 1998 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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