AIDS TREATMENT NEWS Issue #192, February 4, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: LTR Inhibitors, a New Kind of Potential AIDS Treatment: Interview with Arthur B. Pardee, Ph.D. AIDS Research Databases Now Free to Community Organizations, Public Libraries, and Individuals HIV-Infected Health Care Workers: New Legal Guide Available Prevention Funding: No New Dollars in PresidentUs Budget for 1995 New California Law Requires Off-Label Coverage California Drug Assistance Program Adds New Medications ***** LTR Inhibitors, a New Kind of Potential AIDS Treatment: Interview with Arthur B. Pardee, Ph.D. by Charles Davidson and John S. James In a paper published in March 1993, Chiang J. Li and others at Dana Farber Cancer Institute and Harvard Medical School reported results of laboratory tests which identified three substances which should be investigated as potential treatments for AIDS or HIV.(1) The three are curcumin (an antioxidant and anti-inflammatory agent found in turmeric, the mild spice used in curry), topotecan (an experimental treatment now in phase II/III trials for cancer, but never tested in patients as a treatment for HIV), and beta- lapachone, a plant derivative which has not been tested in humans. The researchers found these three by screening selected substances for activity against the LTR (long terminal repeat), which is the Ron-off switchS of the HIV virus; when the RswitchS is off, the virus is not being stimulated to reproduce. After these tests, all three substances were tested against live HIV, and all showed activity in both acutely and chronically infected cells. In short, this new approach to finding AIDS treatments has quickly found three attractive potential candidates -- substances which are available, already in human use in two cases, active against both acute and chronic HIV infection in cell cultures, and which work by a completely different mechanism than standard treatments. To help the AIDS community understand LTR inhibitors as an approach to drug development, AIDS TREATMENT NEWS interviewed Arthur B. Pardee, Ph.D., who is head of the group which initiated the research cited above. Dr. Pardee is Professor of Biological Chemistry and Molecular Pharmacology at Dana- Farber Cancer Institute and Harvard Medical School, and Chief of the Division of Cell Growth and Regulation at Dana-Farber. He is a member of the National Academy of Sciences, and has co-authored 400 technical papers and other publications. He is a molecular biologist; two other researchers on the project, Clyde S. Crumpacker, M.D., and Bruce J. Dezube, M.D., have run AIDS clinical trials for years. The laboratory test for LTR inhibitors is well established in basic research. (The particular version of the test used by PardeeUs group was donated by the HerzenbergUs laboratory at Stanford University -- which has studied NAC, an experimental HIV treatment which may reduce LTR activation indirectly.) Dr. PardeeUs team has used this test to study anti-HIV properties of available, known, nontoxic compounds -- to look for a new class of potential drugs which target the on-off switch of the virus. And they have used the same test to show that these kinds of HIV inhibitors may work far better together, in certain combinations which block different paths involved in LTR activation.(2) (This recent paper, on combining a Tat inhibitor with pentoxifylline in laboratory tests, was described in AIDS TREATMENT NEWS #188, December 3, 1993). Clearly this line of work should be pursued rapidly -- especially since other approaches have had only limited success. But much of this research is not funded; only the fact that the laboratory tests are inexpensive enabled it to be done at all. The problem seems to be that searching for AIDS treatments by screening for LTR inhibitors has not yet become an influential part of the mainstream thinking, which has focused on other kinds of drugs -- mostly AZT, etc., or high-tech approaches which may not be ready for years. One great barrier stopping new AIDS drugs today is the lack of funding and other support for preclinical work needed to move promising ideas from the laboratory into early human tests. This barrier is now impeding the practical development of LTR inhibitors, slowing or preventing the fairly obvious research steps that are needed next. Background for Non-Technical Readers After HIV infects a cell, its genetic information becomes part of the DNA (the genetic inheritance) of the cell. Each cell contains a complete copy of all the personUs DNA -- the information needed to construct all the organs of the body. Of course not all of this DNA is active in any particular cell. Instead, complex regulatory mechanisms determine which genes are expressed, and when. (Each gene is a part of the DNA which codes the information for creating one protein.) When a cell has been infected and contains the HIV DNA, that DNA is often inactive, not making new virus or doing any other harm. Only when the HIV is activated is it harmful. Various different substances can increase or decrease this activation, and many of them have their effect through the LTR (the long terminal repeat of the AIDS virus). An LTR inhibitor is a compound which prevents or reduces this activation, and thereby blocks viral replication and other viral functions. There is a rapid, inexpensive test which can be used to screen substances to identify the ones which show promise as LTR inhibitors. This test, created by genetic engineering, uses living cells which have additional, artificially added DNA. This additional DNA includes the LTR of HIV (or of another virus being studied), together with a RreporterS gene. A reporter gene is a gene which produces a protein (usually an enzyme) that can easily be detected in the laboratory (for example by causing a color change in a test tube). In the test cells, the reporter gene is controlled by the HIV LTR, so that it produces its protein only when the LTR is activated. To run the test, the cells are treated with a chemical (such as tumor necrosis factor) which is known to activate the LTR, and the resulting activity of the reporter gene is observed. A substance being tested can be added; if it inhibits the LTR, it will turn off or reduce the activity of the reporter Gene. This test is easy to do, and it does not require live HIV, so it does not require the elaborate safety precautions needed to work with HIV itself. It can be done in most laboratories, and could quickly screen many substances to look for potential LTR inhibitors. Positive results must be confirmed using laboratory tests with the live virus, but this only needs to be done for the much smaller number of substances which show good results from the initial screening. (These screening programs often test hundreds, or even thousands, of random chemicals to find one which may have value. PardeeUs group had better success looking for LTR inhibitors -- three found out of a dozen chemicals tested -- because they were not funded for mass screening, and instead used intelligent guesses about what was likely to work.) Of various factors which increase HIV activity by activating the LTR, the most powerful is the protein produced by the Tat gene of HIV. Another important cause of viral activation is excessive levels of a different protein, NF-kB (NF-kappa B) -- which (unlike Tat) is normally present in the body. Each of these binds to the LTR (at different sites), activating HIV. NF-kB can be induced by a variety of stimulants, including T-cell activation, inflammation, bacterial products, and oxidative stress. Other research groups had found that HIV is much more active when both the Tat protein, and also high levels of NF-kB, are present.(3) It appears that the two together act in concert in a way that is far more than additive; in one experiment, NF-kB alone upregulated the virus by 16 times, Tat alone by 80 times, and both together 388 to 760 times, depending on the concentration of Tat used. Dr. Pardee and his colleagues have built on basic research to find potential LTR inhibitors, and especially synergistic combinations of these compounds. Recently Debajit K. Biswas, Ph.D., and others showed that a combination of drugs that inhibit both NF-kB and Tat worked much better than either one alone -- so much better that the concentrations of both drugs (pentoxifylline, and the Roche Tat inhibitor Ro 24-7429) could be reduced ten times, and still give the same inhibition as the larger concentration of either one alone.(2) This paper gives some insights as to why the Hoffmann-La Roche trials of its Tat inhibitor failed to reduce viral activity in humans. Since NF-kB activity is likely to be excessive in people with HIV, due to oxidative stress caused by infections, it may be necessary to combine a Tat inhibitor with another treatment (such as pentoxifylline) to reduce NF- kB activity. Further improvements may be made by adding other LTR inhibitors with different mechanisms of action. The scientific search for LTR inhibitors also led Dr. PardeeUs lab to investigate topotecan, which inhibits a DNA- unwinding enzyme which upregulates many genes (in other words, makes them more active), including those governed by the HIV LTR. This inhibitor, now in use in cancer trials but never tested in persons with HIV, can be tolerated in patients at a concentration that is 200 times that which inhibits 80 percent of viral production in laboratory tests.(1) Dr. PardeeUs lab is also considering a number of substances to modify levels of pro-inflammatory cytokines, secreted by certain immune cells, which upregulate the LTR. (In addition to pentoxifylline to decrease TNF, another example is tenidap, to inhibit IL-6 production). Also, as certain enzyme systems become upregulated in people with AIDS, inhibitors of these pathways might also be targets for inhibiting the LTR. The synergistic inhibition of viral production, using novel combinations of drugs at tolerable doses, is a here-and-now approach. In view of the urgent need for better treatments for AIDS, we must not overlook a potentially effective antiviral strategy that is possibly within reach today. Interview Dr. Pardee was interviewed by John S. James of AIDS TREATMENT NEWS, and by Charles Davidson, a graduate student with a strong interest in Tat and LTR inhibitors, who brought much of this information to our attention. James: Could you summarize the rationale for your work? Pardee: Our approach is a simple one. We look at the LTR of HIV-1, and see what substances respond. ItUs a quick, easy test, and you donUt need special safety precautions [which would be required for working with the live virus]. WeUre pretty much limited to that test [because of lack of funding to do the live-virus tests]. But weUve come up with pentoxifylline, and the other three compounds we reported a year ago. WeUve done other work on tenidap, which looks interesting, and we have more potential drugs in the pipeline. This approach has been productive. We have shown an effect on the LTR system; now itUs pretty much up to someone else to carry it forward. Bruce [Dr. Bruce Dezube] can carry it into the clinic if it looks good, but you need somebody in between [to do the preclinical development], and we do not have funds for that. Davidson: You found the topoisomerase inhibitor was quite effective? Pardee: Topotecan, the one we used in that work of a year ago, was by far the most potent drug. We think it has some promise. It was tested with the virus system very extensively, as we reported in our paper.(1) For reasons that arenUt too clear to me, Smith-Kline Beecham does not seem very interested in pursuing it further. ItUs the companyUs decision at this point; itUs pretty much out of our hands. We have largely shifted to some other camptothecin analogs; they look pretty effective, too. We are working mostly with camptothecin itself; there are analogs that are clinically preferable, but there are no patents on camptothecin; you run into problems when you work with companies. There are several ways a drug can inhibit the LTR, which is quite complicated. There are NF-kB motifs, and Tat-TAR motifs, and some others, SP-1 motifs, etc. The questions are what is the target for a particular compound, and how can we set up better assays for finding new compounds, by taking advantage of what weUve learned with the first generation. And of course curcumin [first discovered to have anti-HIV activity by PardeeUs group, using the test for LTR inhibitors] is another one which needs to be investigated. I understand there will be a clinical trial in the Boston area, also [to be conducted by the Community Research Initiative of New England -- in addition to the trial by SEARCH Alliance, in Los Angeles]. I have no further information on it. We are starting further work on curcumin. We hear stories about India, where they eat a lot of turmeric; some people say thereUs lots of AIDS in India. I understand there is a lot of HIV infection, but not very much AIDS, so it may slow down the disease. Dr. Biswas, my Indian colleague, is currently in India; he is in close contact with top leaders in their infectious-disease work, and they are interested. There are also some other Indian plant products which may be quite interesting; weUre hoping to look at them. Concerning curcumin, I have been told by another Indian scientist that there are other compounds in that plant which are more active than curcumin. There is much we can do if we get the time and resources. James: Two callers told me that they didnUt know where to get the more concentrated curcumin, so they used turmeric from a grocery store. Both said they had substantial improvement in blood work. This should be studied. Davidson: Curcumin is classified as an antioxidant? Pardee: Yes, but we donUt know what its real mechanism of action is against HIV. Somebody published an abstract at a recent meeting saying it may inhibit the HIV protease. They did a computer study of what the structure should be to block the specific HIV protease, and came up with a curcumin structure. Davidson: If you have several different mechanisms, and there is synergism, one should be able to use smaller doses of the drugs? Pardee: Right, you should be able to get more effectiveness with less side effects, we hope. But people are very complicated organisms; just because it works on some simple system in the laboratory does not mean there will be no toxicity or other problem. Pardee: I wish that what might be called the AIDS establishment was a little more open to innovative approaches. I have not been able to get a penny from the NIH to do any of our work, and we have come up with several new compounds [with potential use for AIDS], and we have several more in the pipeline. We will soon report on another class of compounds which is effective against the HIV LTR. But we canUt go on working without funds. We have to pay researchers to eat and pay rent. James: What study groups at NIH review your proposals? Pardee: It goes into some AIDS study groups. I must say that one of the reviews, on attempts to follow up on the topoisomerase inhibitors, was erroneous. It claimed that we did the work before we submitted the grant, which is absolutely untrue. We did all this work in the two years of the grant; we published two good papers, and they said we didnUt accomplish anything. And they also said we should be working on HIV-2 as well as HIV-1. Well, we are not a factory. If we discover something active against the HIV-1 LTR, it could be pursued with HIV-2 by someone else. ItUs pretty discouraging. James: Over the years I have seen that this is not a new problem. Pardee: The AIDS establishment has to produce something with all the money they are spending. They give us no encouragement or help at all [for innovative approaches]; and we get the same story from colleagues. The whole AIDS granting process has been dominated by the AZT types, and a few other interest areas. ItUs like molasses to get funded. This new panel [the National Task Force on Drug Development] is likely to have people who donUt rock the boat. A carefully worded article about how we need innovative approaches against AIDS, and need to support these innovative approaches, would hopefully do some good if it gets to the right people. We need to find out more about the mechanism of action, why these work. We are likely to find some new targets. When we know what the target is, and we get an assay for that target, we can test for other substances that work better. We published on several potential drugs already. Nobody has clinically tried topoisomerase I inhibitors on AIDS, and yet these compounds are pretty powerful, as we reported. We think we have a fairly clear understanding of pentoxifylline, how it blocks the LTR. ItUs through NF-kB, but there are additional details. ItUs part of another very interesting class of inhibitors of the LTR. ItUs not too hard to come up with possibilities. Hopefully some of them will work. Our approach is to use the LTR as a target, just like others use the protease as a target. I think itUs a very promising target. Davidson: How much do you think has been spent so far on LTR inhibitors? Pardee: I donUt know how much companies such as Roche spend. We get a small amount to do our work on pentoxifylline, from Hoechst-Roussel Pharmaceuticals, Inc. We luckily got an NIH grant to work on topoisomerase inhibitors, which I used to work on the AIDS problem; but that is terminating and wonUt be renewed, so this work will stop rather fast. We have never been funded to work on this project specifically; we havenUt gotten one cent. And very few people elsewhere are working on this approach. Virtually nothing has been spent on it. WeUll eke out what little we can. Davidson: Do you have any idea how the Roche Tat drug [Ro 24- 7429] works? Pardee: There are accessory proteins involved in the Tat-TAR interaction. WeUre trying to take these apart as fast as we can. [EditorUs note: Obstacles to the research on the Ro 24-7429, the Hoffmann-La Roche Tat inhibitor, have included not only lack of funding, but difficulty getting the drug to test, and lack of access to results from other researchers. Even though this substance failed to reduce viral activity in humans in a single-drug trial, it may be important because of the possibility that it might work in combination -- for example, with pentoxifylline, since that combination works very well in the laboratory. Also, it is worth investigating why Ro 24- 7429 did not work by itself in people; there are many possible reasons that a particular drug will not work in the body, and the failure of one compound does not invalidate the whole approach. (A recent paper suggests that Ro 24-7429 alone does not inhibit the Tat protein itself, but another protein which works with Tat.(4) This might help to explain the disappointing results of human tests.) While there are a number of ways to inhibit the LTR through the NF-kB mechanism, Tat inhibitors are still scarce. A very different Tat drug is being developed in Canada, by Allelix Biopharmaceuticals, but it is just beginning human tests (see AIDS TREATMENT NEWS #187, November 19, 1993). A prescription drug, d-penicillamine, was tested as a Tat inhibitor in Europe several years ago; it did not help patients in trials, but perhaps should be re-examined as a possible part of a combination. We believe that the most important work at this time is human trials of topotecan, curcumin, some other LTR inhibitors being tested by PardeeUs group, and the combination of Ro 24- 7429 with pentoxifylline. Equally important is the laboratory search for new LTR inhibitors, and especially for better combinations of LTR inhibitors, and combinations of these with other classes of AIDS treatments. This area could move quite rapidly, if it had support instead of roadblocks from corporations and from government research agencies.] References 1. Li CJ, Zhang LJ, Dezube BJ, Crumpacker CS, and Pardee AB. Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. March 1993; volume 90, pages 1839-1842. 2. Biswas DK, Ahlers CM, Dezube BJ, and Pardee AB. Cooperative inhibition of NF-kB and Tat-induced superactivation of human immunodeficiency virus type 1 long terminal repeat. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. December 1, 1993; volume 90, pages 11044- 11048. 3. Liu J, Perkins ND, Schmid RM, and Nabel GJ. Specific NF-kB subunits act in concert with Tat to stimulate human Immunodeficiency virus type 1 transcription. JOURNAL OF VIROLOGY. June 1992; volume 66, number 6, pages 3883-3887. 4. Braddock M, Cannon P, Muckenthaler M, Kingsman AJ, and Kingsman SM. Inhibition of human immunodeficiency virus type 1 Tat-dependent activation of translation in Xenopus oocytes by the benzodiazepine Ro 24-7429 requires trans-activation response element loop sequences. JOURNAL OF VIROLOGY. January 1994; volume 68, number 1, pages 25-33. ***** AIDS Research Databases Now Free to Community Organizations, Public Libraries, and Individuals by Tadd Tobias The worldUs largest library of health sciences, the National Library of Medicine (NLM, a unit of the National Institutes of Health), will no longer charge access fees for three AIDS- related research databases and an online directory of information sources. This means that AIDS organizations and public libraries can now offer their clients the ability to do a computer search of the medical literature to find extensive background information on almost any drug, condition, or other medical topic related to AIDS. Results are available immediately, allowing users to refine their searches again and again in order to get the information they need. AIDSLINE, the most important of these databases, includes 90,000 references (many with abstracts) to AIDS-related journal articles, conference presentations, government reports, books, and audiovisuals. It focuses on biomedical, epidemiological, health-care administration, and social and behavioral science AIDS literature. For example, AIDSLINE includes the several thousand abstracts from each yearUs International Conference on AIDS, as well as abstracts from other conferences, which otherwise are not readily available for computer searching. Arranging to Use the System Current users of AIDSLINE (and the other AIDS databases which have now been made free) will no longer be charged if they are accessed directly through the NLM (either by the RGrateful MedS software recommended by NLM, or by direct connection). New users must establish an account with the NLM to begin using the databases. There are two ways of doing this. Those organizations interested in using only the free databases may request a special password and user identification allowing free access. This option is good for libraries and service organizations which may want to let their clients use the databases without close supervision, since there is no danger that the client will accidentally get into a costly database and run up a bill. But organizations which also want to use other NLM databases (such as MEDLINE) must go through the standard registration process. They will have access to all the NLM databases, but will not be billed for using the AIDS-related ones. [Note: individuals are not eligible for the special free accounts, which are for community organizations and libraries. But individuals can get still get free access, by opening a regular account, and then using the AIDS databases, which will not be charged for.] In either case, users must have a computer and modem (or direct Internet access, usually through a local-area network at a university or other institution). The Grateful Med software, which makes the system easier to use, is available in IBM and Macintosh formats for $29.95. To order this software, contact the National Technical Information Service, U.S. Department of Commerce, 5285 Port Royal Rd., Springfield, VA 22161, 800/423-9255. For access to any of the databases, individuals and organizations must complete an application for a user identification and password. This application is included with the Grateful Med software package; alternatively, persons can obtain the application from MEDLARS (Medical Literature Analysis and Retrieval System), National Library of Medicine, Bethesda, MD, 20894, 800/638-8480, fax 301/496- 0822. There are no long-distance telephone charges to use this service, because local numbers are available in most cities, through several data-communication networks. If there is no local number in your area, other arrangements can be made. Overview of the Databases MEDLARS compiles technical and scientific information in about 30 different computer databases maintained by the National Library of Medicine. This system provides citations to peer-reviewed journals (with abstracts when available) but not full-text articles. Anyone can use a computer and modem to access this extensive information collection from their office or home. AIDSLINE (described above), AIDSTRIALS, AIDSDRUGS, and DIRLINE are four databases which are now being made available free. AIDSTRIALS is an online computer database of about 500 clinical trials which are testing agents for use in treating HIV disease, or for use as a vaccine. This database includes protocol design, patient inclusion/exclusion criteria, trial site, contact information, and a unique identifier which is cross-referenced for acquiring information about the specific agent being tested from its companion database, AIDSDRUGS. AIDSDRUGS describes approved and experimental treatments for HIV disease. [Note: The information in AIDSTRIALS and AIDSDRUGS is the same as that which is available by telephone from 800/TRIALS-A, the phone number of the AIDS Clinical Trials Information Service.] DIRLINE is a database of 15,000 organizations and projects that provide information or other services to the public on HIV/AIDS and other health topics. Alternative Access Note The HIV/AIDS Information BBS, modem phone 714/248-2836, provides free and anonymous access to all four of the NLM AIDS-related databases. (For more information about this system, see AIDS TREATMENT NEWS #191, January 21, 1994). Comment Online research databases such as AIDSLINE have been essential for AIDS TREATMENT NEWS; without them, this newsletter would not have been successful. When we started, AIDSLINE did not exist, and we used MEDLINE instead. Today we use many databases, but AIDSLINE accounts for about three quarters of our searches. We do not expect the new policy on free access to the AIDS information to result in a sudden spurt in use, since most people are unfamiliar with online databases; they do not know how to use them or why they are important. But what the new policy does is to remove a major barrier -- database cost, which used to start at about $18 per hour for AIDSLINE use -- which has prevented service organizations from considering this resource. There is still the expense of staff training to support this service, and of having a computer available. Community-based organizations and public libraries will now be able to provide clients access to these databases, so that individuals may research for themselves information about AIDS and possible therapies, without undue expense. The basic requirement is inexpensive software that can be used by anyone with a computer and modem. For now, we think that the key to organizational success, in using research databases for the first time, is having both high-level commitment -- that this is something management wants to do -- plus having at least one person (staff or volunteer) to RchampionS this project and make it happen. ***** HIV-Infected Health Care Workers: New Legal Guide Available by Tadd Tobias The American Association of Physicians for Human Rights (AAPHR) and the National Lawyers Guild AIDS Network have published a 47-page booklet, The Legal Rights and Obligations of HIV-Infected Health Care Workers, by Elise Gautier, J.D., M.A. This groundbreaking guide examines the many legal ramifications of being HIV positive and a health care provider. Written in a question-and-answer format which makes legal concepts understandable by non-lawyers, the publication provides information on laws prohibiting employment discrimination, state policies concerning HIV-infected health care workers, standards of care, informed consent law, employment issues, rights to privacy and confidentiality, and insurance issues. In addition to health care providers and attorneys, others may find this publication useful because it provides a thorough review of many legal issues. Specifically, information included about the American with Disabilities Act, insurance and employment considerations, and rights to privacy and confidentiality can be of value to AIDS service organizations, persons with HIV, and their advocates. The guide summarizes and provides legal references concerning the state of the law regarding the legal rights and obligations of HIV-positive health care workers as of mid- 1993. It also discusses major issues not yet resolved by the courts. RThe purpose of the guide, however, is to provide information; it does not provide legal advice. If you need legal advice, consult an attorney.S Copies of The Legal Rights and Obligations of HIV-Infected Health Care Workers are available from the American Association of Physicians for Human Rights, 273 Church St., San Francisco, CA 94114, phone 415/255-4547, fax 415/255- 4659. The cost is $10.00 for the general public and $5.00 for AAPHR members. ***** Prevention Funding: No New Dollars in PresidentUs Budget for 1995 by Rae Trewartha President ClintonUs budget plan for 1995 is due to be released February 7. Present indications are that it contains no new funding for HIV/AIDS prevention. What effect is this likely to have on prevention efforts in fiscal year 1995 (the year which begins October 1, 1994)? Mike Shriver, executive director of Mobilization Against AIDS, points out, Rwhile the presidentUs budget does not set figures, it does set floors and ceilings and thus shows where the president believes priorities should be. By not advocating any new money for prevention the president is basically giving the message that he does not believe HIV should be a priority.S Those working in the field, however, believe that prevention must be a major initiative Rif we are to slow down the occurrence of new cases and save lives.S In the last two years, Shriver explained, HIV/AIDS advocacy groups have worked intensely with the Centers for Disease Control (CDC) to reform the way the CDC organizes its prevention programs, both in the way these programs are funded and in the way they are delivered. He sees the CDC as now being committed to a community-planning process which would lead to much improved targeting of prevention money. It will, however, Rrequire new government funding of $95 millionS to bring these reforms to fruition; if there is no new money for prevention in 1995, Shriver believes that the work which has gone into reforming prevention strategies will have been wasted. Citing these reforms, Steve Morin, assistant on AIDS for Representative Nancy Pelosi (Democrat, California), agrees with Shriver, saying that under the circumstances it is Rironic that the administration would make prevention such a low priority.S Shriver is adamant, though, that despite the tight financial situation Congress is dealing with this year, Rfunding for prevention must not come at the expense of other HIV-funded programs such as research, care and housing.S This is echoed by Derek Hodel at AIDS Action Council who also believes it is vital that there is new funding for prevention but is concerned that such funding must not come out of other AIDS programs. John Gurrola, Kristine GebbieUs communicationsU director at the Office of the National AIDS Policy Coordinator, told us they have no comment to make on the budget recommendations at this point, but they Rknow prevention worksS and are Rheavily involved in advocating for new money in the budget.S What can our readers do to make sure the president and Congress realize how important it is that new funding for prevention is included in the final budget provisions? Mike Shriver described the development of the budget as a Rfour- step process.S Essentially planning for the budget begins a year and a half before the final version is voted into law by Congress. The first part of this process for fiscal 1995 will conclude when the president presents his budget intentions in February. Advocacy for this stage began in September 1993. The next stage -- the one in which our readers now need to be involved -- runs from April to September, when the subcommittee which writes the appropriations bill for the Departments of Labor - Health and Human Services - Education, makes actual dollar recommendations based on the presidentUs intentions i.e. Rthey carve out numbers.S This subcommittee reports back to the full committee, which takes the Labor - Health and Human Services - Education Appropriations Bill (which contains these numbers), to the floor of the House to be voted on. The Senate goes through a similar process and then the two Houses work together, in a Joint Conference, to come up with figures they can both live with. After the Labor - Health and Human Services - Education Appropriations Bill goes through the Joint Conference, it is then voted on again by Congress, and signed into law by the president. This bill will provide the appropriations for HIV/AIDS care, research, and prevention for fiscal 1995. It is urgent, Shriver says, that people Rlobby their Congresspersons intensely, either personally or by letter, to approach the members of the above-mentioned House appropriations subcommittee, to let them know it is vital that new funding is provided for prevention in 1995.S Nancy Pelosi is a particularly influential and concerned member of that subcommittee, but all members of the subcommittee need to be targeted. ***** New California Law Requires Off-Label Coverage by Dave Gilden In what could become model legislation for other states, a recent California law (effective since January 1993) requires insurance companies and health-care plans, if they cover prescription drugs, to include coverage for off-label use of approved drugs for life-threatening conditions, provided that, RTwo articles from major peer reviewed medical journals ... present data supporting the proposed off-label use or uses as generally safe and effective unless there is clear and convincing contradictory evidence presented in a major peer reviewed medical journal.S The drugs also have to be paid for if they are approved by the American Medical Association Drug Evaluations, the American Hospital Formulary Service Drug Information, or the United States Pharmacopoeia Dispensing Information, Volume 1, Drug Information for the Health Care Professional. (Off-label use means that a drug has been approved by the FDA, but is being used for a purpose not specifically approved by the FDA -- for example, a cancer drug approved for certain tumors but then used in treating other tumors.) Off-label use of approved drugs has become a continuing issue for people with AIDS. AIDS requires that many powerful antimicrobial therapies be administered under new, emergency conditions, although the manufacturers have been slow to do the research and paperwork needed for approval for AIDS indications. Many of these therapies are expensive, and health insurance companies are often reluctant to pay unless presented with irrefutable justification for the therapy. For example, the drug clarithromycin was only approved in December for mycobacterium avium complex (MAC) in people with AIDS, although it was approved over a year ago for certain respiratory infections in non-immune compromised individuals. Clarithromycin was the treatment of choice for MAC well before it was approved, due to promising results from early trials and experience with the drug. Even though clarithromycin was regarded as an essential life-saving weapon against MAC, many people with AIDS found that their insurance companies balked at the cost, which is several hundred dollars a month. Under the new California law, which added section 1367.21 to the Health and Safety Code and sections 10123.195 and 11512.182 to the Insurance Code, insurers can no longer refuse to pay. The law includes out-of-state companies which issue policies in California. There are some exemptions, especially contracts for delivery of Medicaid coverage. The San Francisco-based organization Project Inform has prepared an information packet to help people obtain insurance payment for intravenous immune globulin (IVIG) treatment. This therapy costs upwards of $1500 a month. It consists of administering antibodies collected from the blood of healthy individuals to those with low T-helper cell counts. IVIG, which has just been approved for use in children with AIDS but not adults, is a relatively nontoxic way to prevent recurring viral and bacterial infections. Those wishing to obtain the Project Inform packet on IVIG reimbursement may call the Project Inform hotline at 800/822- 7422, or 415/558-9051. If you know of other off-label treatments for an AIDS-related condition which should be covered, and know of two journal articles which support such a treatment, please contact Bill Thorne, ACT UP/Golden Gate, 519 Castro Street, Box #M-93, San Francisco, CA 94114, fax 415/252-9277. The HIV/AIDS Treatment and Resource Library of Healing Alternatives Foundation buyersU club in San Francisco will house the collection. The buyersU club/library is located at 1748 Market St., Suite 204, San Francisco, CA 94102, 415/626-4053, fax 415/626-0451. ***** California Drug Assistance Program Adds New Medications by Dave Gilden CaliforniaUs AIDS Drug Assistance Program (ADAP), which pays for AIDS drugs for uninsured persons with low or moderate income, has traveled a difficult road over the last several years, as the state tried to cut it back while the community demanded its expansion. A recent infusion of $3.4 million from the federal Ryan White CARE Act has allowed this little- known program to double the number of medications it pays for. The following 27 treatments for AIDS-related conditions are now included: acyclovir*, amphotericin B*, atovaquone*, azithromycin*, AZT, clarithromycin*, clindamycin, clofazimine*, clotrimazole, dapsone, ddC*, ddI, ethambutol*, 5-fluorouracil*, fluconazole, foscarnet*, ganciclovir, ketoconazole, nystatin, paromomycin*, pentamidine (aerosol), pentamidine (intravenous)*, pyrimethamine, rifabutin*, sulfadiazine, trimethoprim-sulfamethoxazole. The 13 medicines marked with an asterisk were added as a result of testimony at a December 1993 public CARE Act hearing by representatives of the Golden Gate, Los Angeles and Santa Barbara chapters of ACT UP. The ADAP program originally included only two drugs, AZT and aerosol pentamidine, and has been gradually extended over the last two years as a result of ACT UPUs efforts. CaliforniaUs program still has a long way to go. A similar New York state program covers 60 drugs for AIDS or opportunistic infections, including intravenous immune globulin. In addition, the California program has not been publicized, and has only 3500 enrollees at this time, despite its great value for those without insurance coverage for prescription drugs who are working or otherwise ineligible for Medicaid (Medi-Cal). (Substantial copayments are required for new enrollees making more than $28,000 per year.) The existence of ADAP has been virtually unadvertised in the past. Californians who want information about applying for the program should contact the AIDS programs at their county health departments or public hospitals, or an AIDS service organization which is knowledgeable about benefits programs. AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews.igc.apc.org Editor and Publisher: John S. James Reader Services and Business: David Keith Thom Fontaine Tadd Tobias Rae Trewartha Statement of Purpose: AIDS Treatment News reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1994 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.