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by John S. James
Last week AIDS treatment activists learned that plans for
future Phase III trials of RS-79070, an oral prodrug of
ganciclovir, had been suspended by Hoffmann-La Roche,
apparently due to concern that there are no longer enough new
cases of CMV retinitis to justify the expense of continuing
development. A smaller phase II trial, which is still
recruiting, will continue (see announcement below). The
decision was made at Roche offices in Basel.
RS-79070 is a chemical relative of ganciclovir which can be readily absorbed orally, and then is changed to ganciclovir in the bloodstream. It provides much higher blood levels of ganciclovir than the currently approved oral drug, which is poorly absorbed. Because of its lower efficacy, the oral ganciclovir which is now available cannot be used for induction (the initial high-dose treatment of CMV retinitis), and is controversial for maintenance (long-term treatment of active CMV disease after induction) and prophylaxis (prevention of CMV disease in persons who are at risk).
RS-79070 may replace intravenous treatments or ocular implants for CMV disease, with a pill which is taken once a day (twice a day for the first three weeks of treatment for the induction phase). Because it delivers ganciclovir to the body, it will have the same basic side effects of that drug. Unfortunately, current drug-development rules require large and expensive phase III trials before RS-79070 can be marketed -- even though (1) this drug serves only as a better delivery vehicle for supplying ganciclovir orally, (2) a less effective oral ganciclovir is already approved, and (3) the smaller phase II trial now recruiting will show whether or not RS-79070 is comparable to intravenous ganciclovir for induction treatment of CMV retinitis.
Project Inform, in San Francisco, which first learned of the decision to suspend development of the large trials required for marketing, is deeply concerned because it has been hearing quite good anecdotal reports about RS-79070 from physicians and patients -- and also because of reports that the number of new cases of CMV retinitis may be starting to rise again, due to more treatment failures after longer-term use of the new combination anti-HIV regimens. GMHC (Gay Men's Health Crisis, in New York) is organizing a letter of protest to Roche.
The phase II trial described below will continue -- and will provide data which might justify reviving the plans for phase III trials which could lead to general availability of RS- 79070.
Persons with newly diagnosed CMV retinitis may be eligible for this trial which compares RS-79070 with currently approved intravenous ganciclovir for CMV retinitis. After four weeks for the randomized comparison, volunteers in either group will be allowed to continue treatment with open- label RS-79070.
For the first three weeks (induction phase), both groups will receive treatment twice a day -- either with 5 mg/kg of intravenous ganciclovir, or 900 mg orally of RS-79070. After the induction, each group will receive the same treatment only once per day (maintenance phase). After one week on the maintenance dose, the blinded study will be over, and volunteers can continue treatment with RS-79070, the oral prodrug.
This trial has not been well known and so far has recruited only 13 of the total of 60 to 70 volunteers it needs -- which may have helped precipitate the decision to suspend development of the large phase III trials.
For contact information for a site in your city, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. (Note: As of May 1, this trial was not yet in the regular database at ACTIS, but the contact information was available in card file there. Also as of May 1, a Los Angeles site is possible but not yet official.)
FDA Community Meeting
On April 28 the FDA announced a public meeting to discuss possible use of viral load instead of "clinical endpoints" (usually death or the development of an AIDS-defining illness) in certain clinical trials of antiretrovirals. Persons can also submit a position paper or list of questions, in advance of the meeting.
The meeting will be held on Friday, May 16, from 1:00 to 4:00 in Conference Room G of the Parklawn Conference Center, located on the third floor of the Parklawn Building, 5600 Fishers Lane, Rockville, Maryland. The building is wheelchair accessible, and can be reached by the Washington D.C. Metro. Because of security measures, persons should allow at least 15 minutes extra time for arriving. You will need a photo ID to enter the building.
A written position paper may be submitted before the meeting to Richard Klein, HIV/AIDS Program, Office of Special Health Issues, HF-12, 5600 Fishers Lane, Rockville, MD 20857, or by fax to 301/443-4555.
If you have questions about the meeting, you can call Richard Klein at 301/827-4460, or send email to Rklein@bangate.fda.gov.
This community forum concerns a mid-July meeting of the Antiviral Drugs Advisory Committee -- not yet officially announced -- which will examine possible changes to regulations to allow sustained reductions in viral load to substitute for "clinical endpoints" (deaths or serious disease progression) now required for proof of antiretroviral drug efficacy in confirmatory clinical trials. It is widely believed that the FDA wants to make this change, and will do so after the July Advisory Committee meetings.
Under current "Accelerated Approval" regulations, antiretrovirals can be approved for marketing based on viral load reductions and similar evidence that they work. But the drugs approved this way must then go through large, long- lasting clinical-endpoint trials to prove that the viral load and other blood-test improvements translate to real benefit to patients. Due to advances in recent years in the understanding of HIV disease, these trials have become increasingly ethically problematic, and are seen by many as a huge misdirection of resources -- money, trained professionals, and not least, the trial volunteers -- which should be focused instead on more practical trials which seek answers which physicians need today.
Note: For an in-depth look at the rapidly changing thinking about AIDS clinical trials, see two articles in the current issue of SCIENCE (volume 276, April 25, 1997) -- "AIDS Trials Ethics Questioned," by Jon Cohen, pages 520-523 and "Current Problems and the Future of Antiretroviral Drug Trials," pages 548-550, by Dr. Joep M.A. Lange.
HIV Vaccines Need to Be Developed:
by John S. James
Sam Avrett is Associate Scientific Director of the International AIDS Vaccine Initiative (IAVI), a new organization encouraging the development of safe and effective vaccines for use throughout the world. Last year, Sam co-founded the AIDS Vaccine Advocacy Coalition (AVAC); he has worked with HIV prevention programs in New York City and Washington D.C., and he served with the Peace Corps in theCentral African Republic.
This interview was completed before the recent report -- published this week in NATURE MEDICINE -- about protecting two chimpanzees from HIV infection with a DNA vaccine.
AIDS Treatment News: Aside from idealism or public service, why should someone who already has HIV be interested in research to develop a preventive vaccine for uninfected people?
Sam Avrett: I think that most HIV-infected people are concerned about ending this epidemic. Vaccine research is critical because a vaccine is one of the best foreseeable ways to control the AIDS epidemic, both in the U.S. and around the world. Anyone who has worked in HIV prevention knows that, while behavioral change and condoms and clean needles go a long way toward preventing HIV, staying uninfected is hard. In the United States, studies have shown that in high-risk populations, like sexually active gay men, more than two in a hundred are newly infected each year, even with the best possible counseling. Although behavior change can do a lot, it is just not realistic to expect individual behavior change, by itself, to control this epidemic.
In terms of how basic research for a vaccine might benefit both infected and uninfected people, one possible step in developing an effective AIDS vaccine may be understanding the "correlates of immunity" -- in other words, what immune responses actually protect against the virus. If we knew this, we might be able to develop immune-based therapies for those already infected.
The body already controls HIV effectively for some time after infection, usually several years or more. We might be able to maintain this response indefinitely if we knew more about how it worked and how it was lost.
ATN: What is the status of AIDS vaccine research now?
Avrett: There are about a dozen vaccines being tested in animal studies, or small human safety studies, but none have been tested for effectiveness in large clinical trials. These include "whole-killed" and "live-attenuated" vaccine designs that have worked against measles, mumps, and typhoid; "subunit" or "peptide" vaccines made from parts of HIV proteins; "recombinant vector" vaccines that use harmless viruses to "show" HIV proteins to the immune system; and DNA vaccines, which also "show" HIV proteins to elicit an immune response.
The problem is that all of this needs more research and more funding. Researchers need better starting viruses, better animal models and immune system cells that can replicate what happens in real infection, and larger studies for conclusive results with clinical, rather than laboratory, endpoints.
ATN: What funding is now available for vaccine research and development?
Avrett: It can cost about $100 million over ten years to research and develop the average vaccine. The U.S. National Institutes of Health will spend about $150 million of its nearly $1.5 billion HIV research budget next year on AIDS vaccine research, mostly in basic science and in clinical trial preparation. The Department of Defense has budgeted about $20 million for applied research on HIV vaccines. Pharmaceutical and biotechnology companies, including Merck, Pasteur-Merieux Connaught, or Chiron, might be spending a total of $20 million or more, but no one really knows.
Is this enough? There is lots of research that is not happening because of funding. The cost of treatment and care for the 900,000 people living with HIV in the United States, let alone the 40 million people living with HIV worldwide, is astronomical. Just compared to the cost of treatment and care for the people who will otherwise become infected -- more than three million new infections every year worldwide -- the benefits of a vaccine would far outweigh the costs.
ATN: Aside from advocating for more money for research, what can the community do?
Avrett: At its best, community involvement also helps researchers with informed, honest, and impartial advice. Community advocates can support funding of research, and can provide researchers with input on research priorities, research quality, feasibility of research studies, and community education needs.
ATN: What is IAVI's role in this?
Avrett: IAVI, the International AIDS Vaccine Initiative, was started last year after several international meetings of researchers, policy experts, financial experts, and members of the HIV-affected communities identified the need for new strategies and new ways of approaching HIV vaccine development. IAVI's strategies include direct funding of others to fill important gaps in applied research and vaccine development, advocacy for international vaccine development, and collaboration with governments, funders, regulatory agencies, and private industry to encourage greater investment into HIV vaccine research and development. IAVI can complement the efforts of the NIH, UNAIDS, pharmaceutical companies, and other organizations, to ensure the development of safe, effective HIV vaccines that can be used throughout the world.
ATN: How can our readers find out more and become involved?
Avrett: First, learn more about the issue. For important background information on the current state of vaccine sciences, see the IAVI REPORT, the newsletter of the International AIDS Vaccine Initiative. You can obtain copies from IAVI; phone 212/852-8326, fax 212/852-8279, or mail a request to IAVI, c/o The Rockefeller Foundation, 420 Fifth Avenue, New York, NY 10018, or send email to email@example.com.
You could call the AIDS Vaccine Advocacy Coalition, 415/248- 1330, or check the VACT UP Web site for vaccine advocates, at http://www.vactup.org.
Also, you might be able to work with existing AIDS advocacy or service organizations to get them interested in paying attention to the need for an HIV vaccine. And it certainly would help to let your representatives in Congress hear from you, and know that you want more funding for research on HIV treatments and vaccines.
And if you live in a city with an HIV vaccine trial site [Baltimore, Birmingham, Boston, Chicago, Denver, Nashville, New York, Philadelphia, St. Louis, San Francisco, or Seattle], you can join the site's Community Advisory Board. Contact information for each city is on the VACT UP Web site, or can be obtained from IAVI at the phone, mailing address, or email above.
Note: Background on IAVI
"The International AIDS Vaccine Initiative, a not-for-profit organization, was formed in 1996 after several international consultations of researchers, policy experts, financial experts, and members of HIV-affected communities identified the need for new strategies and new ways of thinking about HIV vaccine development. IAVI's mission is to ensure development of safe, effective, preventive HIV vaccines for use throughout the world.
"IAVI strategies to achieve this mission include: 1) advocating for greater involvement of worldwide public and private sectors, 2) working with governments, funders, regulatory authorities, and private industry to create a more favorable environment for increased investment in international vaccine research and development, and 3) directly funding a highly targeted, applied research and development effort to fund others to fill gaps in existing efforts and move new vaccine products into international clinical trials. IAVI's current and future research strategies are designed to accelerate evaluation of multiple promising candidate vaccines for eventual use by populations most in need."
[From "Developing an HIV Vaccine," by Margaret Johnston, Ph.D., and Sam Avrett, M.P.H., International AIDS Vaccine Initiative, Washington, D.C.]
1st National AIDS
Extensive summaries of each day of the 1st National AIDS Malignancy Conference were written by teams of AIDS researchers and writers, who worked late into the night and made their reports available everywhere by the next day, through the World Wide Web. For U.S. medical professionals, continuing medical education credit is available online.
We have not had time to review this material, which consists of about 60 single-spaced pages including abstracts and tables, and became available as this issue went to press. Instead we will list the titles of the summary articles, so that those interested can obtain the summaries for themselves.
Note: The titles below are those of the summaries, not of the scientific papers presented at the conference. The titles and abstracts of the scientific presentations are also available at the World Wide Web address below. There are 172 abstracts online, and they are searchable by author or keyword, or can be scanned by title. Usually each of the summaries listed below reviews several related presentations.
HHV8/KSHV and the Mysteries of KS Pathogenesis: Molecular Clues & Laboratory Conundrums.
Kaposi's Sarcoma -- Populations, Prognostic Features and Staging.
An Update on Anogenital Cancers in Men and Women and Malignancies in Children.
HHV8: Risk Factors and Route of Transmission.
Non-AIDS-Defining Cancers (NAD Cancers).
Pot-Luck Monday: A Mixed Bag of Epidemiology, Risk Factors and New NCI Initiatives in AIDS-Related Malignancies.
HIV-Associated Tumors in Women and Children: Unusual Manifestations and Treatment Issues.
Kaposi's Sarcoma and HHV8.
AIDS-Related Lymphoma: Clinical Aspects.
AIDS-KS Pathogenesis: What Role Cytokines & Angiogenesis?
HHV8/KSHV: Host Range, Cellular Mimicry, Viral Oncogenes & Transactivation by TAT: The Mystery Unfolds.
AIDS-Associated Non-Hodgkin's Lymphoma: Prognostic Factors, Survival Rates, and the Effect of Its Treatment on HIV.
Clinical Aspects of AIDS-Related Lymphoma.
EBV: How the Kissing Virus Becomes Deadly.
AIDS-KS: Treatment Issues.
Treatment of Non-Hodgkin's Lymphoma in HIV-Positive Children: Cause for Hope.
These summary articles (and the abstracts of the scientific presentations themselves) are available at http://www.healthcg.com/NCIconference.
Medicaid -- AIDS Impact
On April 29 the San Francisco AIDS Foundation issued an action alert asking people to call their Congressional representatives, and members of the House and Senate budget committees, to oppose cutting Medicaid funding, and oppose "per capita caps" on Medicaid (which would limit Federal reimbursement to states to a flat rate for providing medical care for poor people with disabilities, regardless of individual differences in the cost of their care).
On May 1, the AIDS Action Council in Washington sent a separate alert on this issue.
The following is from the San Francisco AIDS Foundation:
"* Medicaid is the single most important program serving people with HIV. Seven of ten dollars spent on AIDS care come from Medicaid [Medi-Cal in California]. Medicaid provide health care to more than 90% of children living with HIV and roughly half of adults with AIDS.
"* Cutting Medicaid is not necessary. The Congressional Budget Office (CBO) has forecast, as of January 1997, that future Medicaid spending has fallen to $618 billion over the 1998-2002 period. This is below Republican proposals in 1996 for $626 billion in Medicaid spending over the same period as part of their balanced budget proposal. It is also far below projected Medicaid spending in the President's initial budget proposal of December 1995.
"* Per capita caps will squeeze Medicaid AIDS care. People living with HIV comprise less than 1% of all Medicaid beneficiaries and their health care expenses make up only 2% of total Medicaid costs. Nonetheless per capita caps which are based on paying state Medicaid programs on the basis of average costs for all people with disabilities would unfairly target people with AIDS and others with extensive health care needs. The average cost of care for a person with a disability in Medicaid is approximately $8,000/year. Without protease inhibitors or other new drugs, the average cost of care for a persons with AIDS exceeds $20,000/year in many locations. If states are reimbursed from the federal government on the basis of only the initial $8,000, then state Medicaid programs would seek ways to limit Medicaid eligibility for people with HIV/AIDS and they would seek ways to limit necessary health care services to people with HIV/AIDS in the program. ..."
"Negotiations between the President and Congress over a balanced budget agreement continue. It is possible that a deal could be struck in the next few days and it is also possible that they could fail to reach a deal at all. Cutting Medicaid is not necessary to balance the budget. The HIV community needs to weigh in forcefully at this time to let Congress know that cutting Medicaid would limit access to care for people living with HIV. Further cuts to Medicaid are unacceptable.
"The San Francisco AIDS Foundation opposes the President's proposal to cut $22 billion from Medicaid (over 1998-2002) and his plan to institute per capita caps ... While the President has also proposed $13 billion in new Medicaid spending, which we support, to help mitigate harmful effects of the welfare reform legislation that he signed, they need not come at the expense of current Medicaid beneficiaries.
"Some Republicans in Congress are countering the President's offer by proposing to accept the President's $22 billion in cuts, but without his new spending proposals. Consumers need to provide a countervailing voice in Congress to the President's and Republican calls for harmful changes to Medicaid."
San Francisco District Attorney Terence Hallinan has questioned the federal government's claim that an April raid on a San Francisco medical marijuana buyers' club was a routine enforcement action.
Early in the morning of April 21 Federal Drug Enforcement Administration agents raided Flower Therapy, breaking down the door, seizing approximately 300 marijuana plants along with other equipment and supplies and leaving a federal search warrant for employees to find when they arrived later to open the club. In statements to the press, DEA officials repeatedly characterized the raid as a routine enforcement action against a "large-scale growing operation" and insisted they had not singled out organizations connected to California's Proposition 215, which legalized marijuana use for medicinal purposes.
But the San Francisco District Attorney's office said the raid was highly unusual. "Normally it's the duty of the D.A.'s office to enforce the laws within the city," explained spokesman John Shanley. Federal drug agencies, he said, generally let local law enforcement handle the vast majority of drug cases, involving themselves only with truly massive operations, involving "tonnage, not pounds" of marijuana. "What they ended up confiscating [from Flower Therapy] was about 2 1/2 pounds, which does not warrant federal agents being involved." Hallinan's office was not even notified that the raid was going to occur.
Asked if the DEA had raided any other San Francisco marijuana distributors of similar size, Shanley said, "No, which is what makes it unusual."
On April 22 Hallinan publicly urged U.S. Attorney Michael Yamaguchi not to prosecute individuals who might be arrested in the raid's aftermath and took the unusual step of offering to testify for the defense should charges be filed. "I would testify to the fact that this group was trying to comply with the law in the state of California," he told the SAN FRANCISCO EXAMINER.
The San Francisco police, District Attorney's office, and health department have been working closely with medical marijuana buyers' clubs to develop protocols for the orderly implementation of Proposition 215, and Shanley said that Flower Therapy has been completely cooperative in that process. "Why would you want to punish someone who's played by the rules?" he asked. "This was clearly ordered by someone who opposed Proposition 215."
DEA spokesman Stan Vegar refused to respond directly to Shanley's and Hallinan's statements, but insisted the raid was "absolutely not" a response to Proposition 215. The measure "does not change our fundamental mission to enforce the drug laws," he said. "315 plants in a complex system with lights and hydroponics is a large-scale growing operation." A spokesperson for the San Francisco U.S. Attorney's office refused any comment on the case.
Meanwhile, a bill to require harsh penalties for doctors who recommend marijuana has been introduced in Congress. S40, introduced by Senator Lauch Faircloth (R-NC) would mandate an eight year prison term for doctors who recommend marijuana, as well as revocation of their DEA registration. Drug policy reform advocates say it is too early to assess the measure's chances of passage, but Eric Sterling, president of the Criminal Justice Policy Foundation, said that the mood in Congress is not encouraging. "There is a profound disconnect between the West Coast's view of this issue and Washington's," he said.
[Note: On April 30 a Federal judge issued a preliminary injunction preventing the Federal government from punishing California physicians who recommend medical marijuana to their patients under the provisions of Proposition 215. This injunction extends the temporary restraining order reported in our previous issue, AIDS Treatment News #269. Judge Fern Smith issued a 43-page ruling with the April 30 injunction. For more information about the rights of Californians under Proposition 215, a brochure is available from Americans for Medical Rights, 1-888-YES-4-215. JSJ.]