From: "John S. James" Date: 02 Apr 94 01:26 PST Subject: AIDS TREATMENT NEWS #196 AIDS TREATMENT NEWS Issue #196, April 2, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: National Task Force Meets April 14-15 More on LTR Inhibitors: No Drug Resistance to a Tat Inhibitor New Nation-Wide Trial Tests Timing of Switch from AZT Kaposi's Sarcoma, Genistein, and Soybeans AIDS Hotlines: Selected List ***** National Task Force Meets April 14-15 The National Task Force on AIDS Drug Development will hold its first meeting on April 14 and 15, at the Sheraton National Hotel in Arlington, Virginia. The meeting is open to the public, and there will be time for public testimony. Those wishing to speak should notify the contact person (below) in advance, by April 7 if possible. Perhaps more importantly, information can also be submitted in writing. The National Task Force "identifies any barriers and provides creative options for the rapid development and evaluation of treatments for HIV infections and its sequelae. It also advises on issues related to such barriers and provides options for the elimination of these barriers." The contact person for this meeting is Jean H. McKay, Office of AIDS and Special Health Issues (HF-12), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, phone 301/443-0104, fax 301/443-4555. Comment This task force, meeting occasionally for two days in an auditorium, cannot automatically fix the problems of AIDS research -- any more than the election of a sympathetic U.S. president could automatically do so. What the National Task Force can do is to enable those who are working in the laboratories and clinics to explain their practical problems and their suggestions -- and hopefully get results. But principal investigators, research nurses, lab assistants, etc. will need to approach the task force and tell what they know. Often this is difficult, because of the politics of funding, or of the workplace; perhaps we need an organization called Speak Up to encourage people to give the task force the depth of information it needs. You can write to the National Task Force on AIDS Drug Development, c/o Jean McKay at the address above, at any time, before or after the upcoming meeting, and your information will be forwarded to the members. Incidentally, AIDS TREATMENT NEWS is always interested in such information; we read everything you send. You can write or call us at any time, anonymously if you want. ***** More on LTR Inhibitors: No Drug Resistance to a Tat Inhibitor by Charles Davidson The rapid development of drug resistance by HIV continues to be a major obstacle in finding better treatments. Resistance to AZT and similar drugs is well known; resistance to protease inhibitors, a new class of experimental drugs, is now also being found. A number of different strategies may help to deal with the problem, however. This article looks at what can be learned from one drug (Ro 24-7429, the Hoffmann-La Roche Tat inhibitor) to which HIV developed no resistance at all, in two years of laboratory studies which attempted to create such resistance.(1) We will also examine the class of drugs to which Ro 24-7429 belongs -- the LTR inhibitors. A look at how LTR inhibitors work suggests that they will need to be used in well- designed combinations in order to work most effectively. [Editor's note: Ro 24-7429 was tested alone, and rejected by Hoffmann-La Roche for further development, after it failed to reduce the level of p24 antigen in people in a small clinical trial; this data was presented at the Ninth International Conference on AIDS, in Berlin, in June 1993. Since that time, laboratory tests have shown that the drug works many times better when combined with pentoxifylline, a readily available prescription drug. Unfortunately the company had been trying to kill the project for several years, for business reasons, and had only kept it alive because of pressure from scientists, who understood the importance of this unique drug; AIDS TREATMENT NEWS has covered these events over the years. The negative result presented in Berlin provided the necessary excuse to stop development; and as a result of this drug's political history, there is virtually no chance that the company will run combination tests, which it could have done long ago. Ro 24-7429 remains important, not only in itself, but also for the doors it opens for developing better treatments. These possibilities urgently need more attention. JSJ] Note: This article is the second in a series, which began with "LTR Inhibitors, a New Kind of Potential AIDS Treatment: Interview with Arthur B. Pardee, Ph.D.," published in AIDS TREATMENT NEWS #192, February 4, 1994. Parts of this article are more technical than what usually appears in AIDS TREATMENT NEWS; for those who do not have a background in this area, we suggest reading the previous article first. If you do not already have a copy, you can obtain one by sending a self-addressed stamped envelope to: AIDS TREATMENT NEWS, P.O. Box 411256, San Francisco, CA 94141; be sure to mention "LTR" (or "issue #192") so that we will know which issue to send. HIV and Drug Resistance Nucleoside analog drugs (such as AZT or ddI) and protease inhibitors invite drug resistance because they are directed against viral proteins, which are highly prone to mutations (genetic changes) when HIV reproduces. Frequent mutations occur because reverse transcriptase (RT), the viral enzyme that produces copies of viral genes, is a thousand times more error-prone than the human enzyme that cells use when copying their own genes. Altered genes result in altered proteins. Therefore, while most essential human proteins are fairly accurately and consistently produced by human cells, viral proteins mutate at a rate hundreds of times faster. When mutations accumulate, the altered viral proteins are less able to bind to the drugs, so the drugs become less effective. Background: The HIV Life Cycle HIV is a retrovirus; and in retroviruses, the genetic information is in the form of RNA, not DNA as with most living things. After HIV infects a cell, the information in RNA is copied to DNA by reverse transcriptase (which is the enzyme inhibited by AZT). This DNA becomes incorporated into the DNA of the infected cell, whereupon it may either lie dormant or become active. If this "integrated" DNA is activated, more viral RNA is produced; some of it is "translated" into viral proteins, and some is encapsulated directly into new viral particles. While some viral proteins are used in constructing the viral coat, others regulate the production and processing of viral RNA from its (integrated) DNA "template". The most important of these regulatory proteins is Tat. Tat activates high levels of viral RNA production -- the first step in viral replication in an HIV-infected cell. About five percent of the viral DNA does not code for proteins at all, but instead acts as a binding site for a class of proteins known as activators. This portion of viral DNA is called the Long Terminal Repeat (or LTR); it functions as the "on" switch for the production of viral RNA. A number of proteins bind onto the LTR to activate it; the two most important are Tat (produced by HIV) and NF-kB (NF-kappa B, which is a normal and necessary human protein, but one which often becomes overactive in HIV disease and certain other chronic illnesses). Drugs which reduce activation of the virus by the LTR are called LTR inhibitors. Three potential treatments (topotecan, beta lapachone, and curcumin) have been found through a test to screen for LTR inhibitors (see AIDS TREATMENT NEWS issue #174, May 7, 1993). Antioxidants -- such as vitamins C and E, or curcumin (from the spice turmeric), or the amino acid N-acetyl cysteine.(2,3) (NAC), or the drug pentoxifylline -- are examples of one type of LTR inhibitor. These compounds work by preventing the binding of NF-kB to its DNA binding site, and those which have been tested have been observed in the laboratory to partially inhibit the production of HIV. Normal immune responses, inflammation, opportunistic infections and co-infection with other viruses all increase NF-kB binding and subsequent production of viral RNA. Individuals with HIV have impaired antioxidant defenses -- for example, they have abnormally low levels of cysteine. Conversely, a high cysteine level inside the cells (which provides for greater DNA-protective, antioxidant activity) is required for the DNA synthesis preceding T-cell division.(4) Therefore, not only does "oxidative stress" activate the LTR, it also inhibits the functioning of T-cells.(2) No Resistance with Tat Inhibitor Ro 24-7429 Unlike other activators, Tat binds onto recently formed RNA instead of onto DNA. Its binding site is a small region of the LTR known as TAR. There are only about 15 proteins coded for by the virus; therefore, HIV uses certain cellular (i.e., human) proteins to assist in its own replication. The Tat inhibitor, Ro 24-7429, however, prevents LTR activation by binding onto a cellular protein instead of onto Tat itself. Because this target is a human protein, not a viral one, resistance is unlikely to occur. Furthermore, when researchers flooded cells with the Tat protein in a 25-fold excess over that required for maximal activation, there was no decrease in the effectiveness of Ro 24-7429. This suggests that it does not bind to Tat, since if it did, the large excess of Tat would have overwhelmed the drug.(1) Recent work by Alan Kingsman and colleagues at Oxford has now formally proven that Ro 24-7429 does not bind onto Tat at all, but rather to a cellular "loop binding protein." This protein, in turn, binds onto a small loop adjacent to the Tat binding site. Kingsman and colleagues suggest that the loop binding protein cooperates with Tat, and that Ro 24-7429 inhibits this interaction.(5) The hope from this research is that once the loop binding protein is physically isolated, its 3-dimensional structure will be determined. Knowing the structure could lead to the development of second-generation drugs with greater binding activity, smaller effective doses, and fewer side effects. In recently infected cell cultures exposed to very low doses of Ro 24-7429 alone, viral production is suppressed for a while, then it returns to higher levels. The lower the dose, the less the inhibition and the shorter the interval before viral production rebounds to higher levels. Low-dose monotherapy may result in only a partial suppression. This effect is probably not due to HIV resistance, but to increasing numbers of infected cells and accumulating amounts of viral proteins. Infected cells respond to these proteins by secreting inflammatory substances that increase NF-kB activity, thereby driving viral production higher. This result also suggests the importance of combination therapy, to prevent viral activation by Tat, while also preventing excessive activation by NF-kB. Synergy in LTR Activation and Inhibition The interrelationship of NF-kB and Tat in LTR activation (and hence viral production) is far more than additive. A modified LTR, in which the Tat activation pathway has been disabled, is activated by NF-kB alone to 15-fold above unstimulated (or basal) levels. An LTR without NF-kB (but with an intact Tat activation pathway) can be activated by Tat alone to 80-fold above basal levels. But HIV LTR with both NF-kB and Tat pathways intact can be activated 388- to 760-fold above basal levels by the combination of Tat and NF-kB (depending on the amount of Tat added).(6) And when both pathways are disabled, the virus cannot replicate at all. Such experiments indicate that NF-kB and Tat are required for replication and that they function synergistically. [Definition: "synergism" is defined by Steadman's Medical Dictionary as "coordinated or correlated action of two or more structures, agents, or physiologic processes so that the combined action is greater than that of each acting separately."] It is exactly this type of synergism that Debajit K. Biswas and colleagues (at Harvard University's Dana-Farber Cancer Institute) built upon when they analyzed the effects of an NF-kB inhibitor (pentoxifylline) combined with a Tat-inhibitor (Ro 24-7429). They showed that when pentoxifylline and Ro 24-7429 were used together, instead of separately, only one-tenth as much of each compound was needed to produce the same LTR inhibition.(7) These results are important for two reasons. First, the synergism of Ro 24-7429 with other LTR inhibitors would allow the use of lower doses, and might therefore eliminate the side effects of the drugs. Second, lower doses of pentoxifylline would lead to less marked inhibition of NF-kB and leave unhindered certain important immune functions still dependent on NF-kB. More laboratory work is needed to determine the most effective and least toxic combination of LTR inhibitors. These would simultaneously reduce viral production and oxidative stress. Ro 24- 7429 should certainly be tested as a candidate for such a combination, as should the other recently developed Tat inhibitor from Allelix, Alx40-4C, which is presently in early clinical trials. LTR inhibitors with good toxicity profiles might sometimes show low efficacy as a monotherapy, but combinations would be expected to work much better. LTR combination therapy is definitely a here-and-now possibility that should go into clinical trials immediately. This new approach to treatment might become a valuable therapy in itself. And also, by reducing viral replication, it might help to delay the development of resistance to other classes of drugs, such as nucleoside analogs or protease inhibitors. References 1. Hsu MC, Dhingra U, Earley JV, and others. Inhibition of type 1 human immunodeficiency virus replication by a Tat antagonist to which the virus remains sensitive after prolonged exposure in vitro. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. July 1993; volume 90, pages 6395-6399. 2. Roederer M, Staal FJT, Ela SW, Herzenberg LA, and Herzenberg LA. N-Acetylcysteine: Potential for AIDS Therapy. PHARMACOLOGY. 1993; volume 46, pages 121-129. 3. Mihm S, Ennen J, Pessara U, Kurth R, and Droge W. Inhibition of HIV-1 replication and NF-kB activity by cysteine and cysteine derivatives. AIDS. 1991; volume 5, number 5, pages 497-503. 4. Gmnder H, Roth S, Eck H-P, Gallas H, Mihm S, Droge W. Interleukin-2 mRNA Expression, Lymphokine Production and DNA Synthesis in Glutathione-Depleted T Cells. CELLULAR IMMUNOLOGY. 1990; volume 24, pages 520-528. 5. Braddock M, Cannon P, Muckenthaler M, Kingsman AJ, and Kingsman SM. Inhibition of human immunodeficiency virus type 1 Tat-dependent activation of translation of Xenopus oocytes by the benzodiazepine Ro 24-7429 requires trans-activation response element loop sequences. JOURNAL OF VIROLOGY. January 1994; pages 25-33. 6. 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. 7. 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 1993; volume 90, pages 11044-11048. ***** New Nation-Wide Trial Tests Timing of Switch from AZT by John S. James A new clinical trial -- the first conducted jointly by the Federally- sponsored AIDS Clinical Trials Group and military institutions -- will study whether an advanced blood test can show the best time to switch from AZT alone to other treatments. This trial is seeking 300 volunteers, 150 from civilian and 150 from military sites, and will last for up to four years. This is the first time an AIDS clinical trial has used a virological test to change the treatment regimen at the first sign of viral resistance to the original treatment. All volunteers will begin this trial taking only AZT as the active drug. They will also take placebos for ddI, and for nevirapine, an experimental drug proposed for the "convergent combination" approach to triple-drug therapy. As the trial proceeds, their blood will be tested for the presence of a particular mutation of HIV, at "codon 215" (position 215 in the viral gene which codes for reverse transcriptase, the enzyme which is targeted by AZT, and also by ddI and nevirapine). At least five different mutations are known to cause AZT resistance; however, the one at position 215 is the most serious. When the mutation is detected (which can be at any time in the course of the trial, or never), the patient will be secretly assigned to one of three treatment groups: continuation of AZT, switch to AZT plus ddI, or switch to the triple combination of AZT plus ddI plus nevirapine. Neither the patient nor the research nurses, physicians, or study administrators will know if or when the switch occurs. Instead, one or more of the placebos will be changed to active drug, without their knowledge. This will make the pill-taking somewhat complex. All patients, throughout the trial, will take AZT every eight hours, ddI placebo (or real ddI) every 12 hours, and nevirapine placebo (or real nevirapine) once per day. And when they take the nevirapine, they will always take one pill from each of two different bottles. The reason for this is the protocol calls for starting nevirapine at half dose for the first eight weeks it is administered; the half dose is given by changing only one of the bottles from placebo to real drug. Eight weeks later, the other bottle also will be switched from placebo to drug. Once the mutation has been detected and randomization has occurred, the assigned treatment will be maintained throughout the trial, unless side effects or other problems force it to be discontinued. Note that this trial is designed to look for changes in blood measurements, not the development of clinical disease. It's main objective is "to validate that (the '215' mutation) precedes the increase in viral burden ... and decline in CD4 count which been observed in association with clinical failure" on AZT, and to see if adding the other drugs will prevent the increase in viral burden and decline in T-helper count. (The importance of the '215' mutation has been suggested by a small retrospective study of stored specimens. Seventeen patients with the mutation had a mean 50 percent decrease in T-helper count, during treatment of approximately three years; the other 21 patients had a mean increase of 11 percent. See Kozal MJ, Shafer RW, Winters MA, Katzenstein DA, and Merigan TC, Mutation in HIV Reverse Transcriptase and Decline in CD4 Lymphocyte Numbers in Long Term Zidovudine Recipients, Journal of Infectious Diseases 1993; pages 526-532.) The protocol chair for this study is Thomas C. Merigan, M.D., Stanford University Center for AIDS Research. The co-chair is Douglas L. Mayers, M.D., Walter Reed Army Institute of Research and Naval Medical Research Institute. Switch to Non-Blinded Therapies What about those who do poorly on the study, who may be randomly assigned to continue AZT after the resistance mutation has developed? The protocol calls for taking the volunteer off the study medication if (1) dose-limiting toxicity has developed, (2) an AIDS- defining condition develops (using the 1977 definition, as amended for this study), or (3) the patient's T-helper count has declined by more than 50 percent, as shown by two consecutive measurements at least 72 hours apart. If any of these occur, the patient's physician can begin any other treatment; the patient may continue to be enrolled in the trial for followup. However, the study will not pay for AZT or ddI once the patient is off the study medication; whether nevirapine (which is not commercially available) can be provided is being negotiated as this article goes to press. Also, the blind will not be broken until the study is finished and the data analyzed, so the volunteer who is taken off study medication will not be told whether it was AZT alone or something else that did not work for them. Eligibility, How to Enroll To be eligible for the study, volunteers must be asymptomatic, with T-helper count between 300 and 600. They must have had AZT for at least one month, uninterrupted, before being screened for the study, but must not have had more than two years of AZT. They must be at least 13 years old (at least 18 for the military sites). They must not have a history of pancreatitis, and must not currently be alcohol or drug abusers. Women are encouraged to enroll in this trial, but they will be excluded if they are pregnant, or intend to breast feed during the study. During the screening, they will be tested for the '215' mutation, and be excluded if it has already developed. There are a number of other medical and laboratory entry criteria. [One possible advantage of being screened for the study is finding out if one has the '215' mutation already; about half of those with T- helper count between 300 and 600 who have been tested do have it, and therefore they are not eligible to enroll in the study. They might want to start treatment with something other than AZT, for example, with ddI; however, there is no professional consensus yet about the clinical meaning of this mutation, which is why the study is being run. Unfortunately for some volunteers, the T-helper count is tested first; both samples are drawn on the same day, to avoid an extra visit, but if the T-helper test shows that the volunteer is ineligible, the virology test for the '215' mutation is not run. As far as we know, this test is not commercially available; it could become available, however, well before the trial ends.] The civilian trial sites are located in: Baltimore, Cleveland, Galveston, Los Angeles, Minneapolis, New York City, Philadelphia, Stanford (Palo Alto), Rochester, and Washington D.C. For the contact number to call for information at a site near you, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. Ask for information about study ACTG 244. The military study slots are open to those who have an ID card which shows that they are eligible to receive care at a Department of Defense medical treatment facility. They can be a veteran, on active duty, or a dependent (age 18 or older). The DoD will fly them to a participating center, which will usually be either Wilfert Hall USAF Medical Center, San Antonio, Texas, or Walter Reed Army Medical Center, Washington, D.C., or National Naval Medical Center, Bethesda, Maryland. (Those not on active duty can choose whether to enroll at a military or a civilian site.) To enroll at a military site, call Douglas L. Mayers, M.D., at Walter Reed Army Institute of Research, 301/217- 9410, or Kenneth Wagner, D.O., at National Naval Medical Center, HIV Research Unit, 301/897-3290; they will refer you to a protocol nurse. Comment This study is expected to take four to six years to affect the standard of care -- two to four years of treatment time (depending on how many of the volunteers develop the '215' mutation), and additional time for recruiting, getting all centers started, data analysis, and publication, dissemination, and use of the results. And then the results will apply directly only to AZT (and probably indirectly to other drugs in the same class, such as ddI -- although a different test would be used, as different mutations cause HIV to become resistant to ddI). Our concern is not with this trial itself, but with the broader questions of research planning. Does a major study now to fine-tune the use of AZT several years down the road reflect a successful strategy for dealing with the epidemic? In treating bacterial infection, it has long been common to test for resistance, in order to avoid using antibiotics which will not work for a particular patient. HIV is different from bacteria, but a case could be made for using the '215' test now, at physicians' discretion, to switch from AZT to ddI or some other drug as soon as AZT resistance is indicated. Meanwhile, use clinical trials to test truly important leads, such as topotecan or conocurvone, which have been neglected because of the happenstance of politics. The fundamental problem is that for over ten years, a research effort which could not possibly save most people's lives has been acceptable to the general consensus -- almost casually accepted as scientifically inevitable. Little serious effort has been made to think through the consequences and change direction. We wonder if this basic root of the failure of AIDS research can be changed today. ***** Kaposi's Sarcoma, Genistein, and Soybeans by John S. James A paper published a year ago, in the Proceedings of the National Academy of Sciences, USA, suggested that substances found in a plant-based diet, especially one high in soy products, such as the traditional Japanese diet, may help control abnormal angiogenesis (growth of blood vessels).(1) Angiogenesis is centrally important in Kaposi's sarcoma, and is important in solid tumors (which cannot grow beyond a small size unless they can force the growth of new blood vessels to nourish the tumor), and in a number of other diseases. The authors, at universities in Heidelberg, Geneva, and Helsinki, chemically fractionated the urine of volunteers who were eating a soy-rich vegetarian diet. They found one substance, genistein, which had a strong anti-angiogenesis effect in laboratory tests, and which is 30 times more concentrated in the urine of those eating traditional Japanese diets vs. those eating typical Western diets. (Soy contains genistein precursors.) The higher urine concentrations were enough to affect angiogenesis in laboratory tests. This paper did not mention KS, or anything AIDS related. Therefore it is not included on AIDS computer databases, and is largely unknown to the AIDS community. However, abnormal angiogenesis is central to KS. (Two reference on the AIDSLINE database do mention genistein; one of them noted that it suppressed KS cell growth.(2)) The urine of the volunteers was chemically fractionated into six fractions. Four of them had anti-angiogenesis activity. The two most active fractions were NOT analyzed in this study, however; genistein came from one of the less active fractions. (This suggests that plant- based diets may supply other substances which may be better than genistein in anti-angiogenesis activity.) The paper cited other published studies which suggested that the traditional Japanese diet may inhibit breast and prostate cancer. Incidentally -- though not cited in the paper -- there are popular "alternative" cancer treatments (for example, the Gerson diet) which emphasize large quantities of juices, etc. Comment: The Next Step "Macrobiotic" and other plant-based diets have long had advocates in the AIDS community. Unfortunately, these diets have often ignored the known nutritional needs of people with AIDS, as well as food- safety requirements for avoiding infection. Diets not properly designed for persons with HIV disease can do much more harm than good. We see little hope that enough money can be found for clinical trials to scientifically test diets, or nutritional products, for KS or other AIDS-related conditions. Mainstream research is unlikely to develop this area for years. Instead of waiting for trials that may never come, let's take what knowledge does exist and see if something useful can be done with it. What is needed now is for a team, including an HIV-experienced dietitian, to prepare recommendations which meet the nutritional and food-safety needs of persons with AIDS, but also are formulated to have anti-angiogenesis effects, based on what is known at this time. Persons with KS might want to try such a diet to see if it seemed to help. References 1. Fotsis T, Pepper M, Adlercreutz H, and others. Genistein, a dietary- derived inhibitor of in vitro angiogenesis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. April 1993; volume 90, pages 2690-2694. 2. Amaral MC, Miles S, Kumar G, and Nel AE. Oncostatin-M stimulates tyrosine protein phosphorylation in parallel with the activation of p42MAPK/ERK-2 in Kaposi's cells. Evidence that this pathway is important in Kaposi cell growth. JOURNAL OF CLINICAL INVESTIGATION. August 1993; volume 92 (2), pages 848-857. ***** AIDS Hotlines: Selected List The following listings are from AIDS TREATMENT NEWS Volume 3, which is now in press (publisher, Alyson Publications, Boston) and should be in the bookstores in late May or early June. We did not include all hotlines, but those we think will be most useful for our readers. You may want to keep this reference handy, for help with your own questions, or for referring other people. General AIDS Hotlines ** National AIDS Hotline: 800/342-AIDS (800/342-2437), 24 hours; Spanish, 800/344-SIDA (800/344-7432), 8:00 a.m. - 2:00 a.m.; TDD for the deaf, 800/243-7889, 10:00 a.m. - 10:00 p.m. This service, operated by the U.S. Centers for Disease Control, provides confidential information, referrals, and educational materials to callers in the United States, its territories, and Puerto Rico. Its information specialists use a database of over 10,000 service organizations to find appropriate local referrals, for example financial assistance, legal assistance, support groups, buddy programs, housing services, and medical referrals. They can also answer many kinds of general questions about AIDS. We have found that it is usually possible to reach an operator with little or no wait on the phone. But the treatment information from government hotlines is limited at best. The reason is that there are many different ideas about AIDS treatment, and no official body to decide which ones are OK for a government agency to disseminate. For treatment information, you need to check with private organizations; some are listed in this directory, below. [Note: Any '800' telephone number can only offer confidentiality -- not true anonymity -- because the recipient is paying for the call, and therefore receives the telephone number of all callers with its phone bills. We think it is unlikely that this will be a problem for callers. But those who are especially concerned about confidentiality may want to call '800' numbers from a public phone.] ** PWA Coalition of New York Hotline: National, 800/828-3280; local, 212/647-1420. Monday - Friday, 10:00 a.m. - 6:00 p.m. Eastern Time. This toll-free hotline is staffed entirely by volunteers living with AIDS or HIV. Callers receive peer counseling, medical and treatment information, and referrals. Also available without charge is the monthly magazine, Newsline, and the Spanish language publication, SIDAhora. Mothers of people with AIDS or HIV volunteer on the hotline, Monday, Wednesday, and Friday, 2:00 p.m. - 6:00 p.m. Eastern Time. ** HIV Nightline, San Francisco: 415/668-AIDS; Northern California outside San Francisco, 800/273-AIDS. Monday - Friday, 9:00 p.m. - 5:00 a.m. Saturdays and Sundays, 5:00 p.m. - 5:00 a.m. Pacific Time. Sponsored by the Suicide Prevention Project, the AIDS/HIV Nightline is the only service of its kind in the U.S. It receives calls from around the country, and is staffed by volunteers who are trained to speak compassionately and knowledgeably about a range of issues related to HIV infection and crisis intervention. Volunteers and donations for the Nightline are welcomed. ** AIDS Project Los Angeles AIDS Hotline: 213/876-2437; in Southern California, 800/922-2437; Spanish language in Southern California, 800/400-SIDA; TDD in Southern California, 800/553-2437; multilanguage communicator in Southern California, 800/922-2438. Monday - Friday, 9:00 a.m. - 9:00 p.m. Saturday, Sunday, and Holidays, 9:00 a.m. - 5:00 p.m. Pacific Time. ** AIDS Hotline of Gay Men's Health Crisis (GMHC): 212/807-6655; TDD/TTY, 212/645-7470. Monday - Friday, 10:00 a.m. - 9:00 p.m. Saturday, noon - 3:00 p.m. Eastern Time. ** San Francisco AIDS Foundation Hotline (English, Spanish, Filipino), 415/863-2437; in Northern California 800/367-2437; Filipino-only in Northern California 800/345-2437. Monday - Friday, 9:00 a.m. - 9:00 p.m. Saturday and Sunday, 11:00 a.m. - 5:00 p.m. Pacific Time. AIDS Hotlines for Treatment Information ** Project Inform: 800/822-7422; 415/558-9051. Monday - Friday, 10:00 a.m. - 4:00 p.m. Pacific Time. Provides information on experimental treatments for AIDS or HIV -- including government and industry treatment trials, AIDS vaccines, standards of care, and treatment and prophylaxis of opportunistic infections. ** Seattle Treatment Education Project (STEP), Treatment Information Hotline: 800/869-7837. Monday - Friday, 1:00 p.m. - 5:00 p.m. Pacific Time. Provides information on experimental and alternative treatments for AIDS or HIV -- including nutrition, vitamins, herbs, etc. ** Critical Path AIDS Project: 215/545-2212, 24-hours. This hotline offers in-depth and specific AIDS treatment information. It is not a general AIDS information hotline. Callers get individualized attention to treatment questions for conventional, alternative, and complimentary therapies. Additionally, literature searches from a CD-ROM AIDS library can be conducted while you wait. ** AIDS Clinical Trials Information Service: 1/800-TRIALS-A (1/800- 874-2572); TDD for the deaf, 800/243-7012. Monday - Friday, 9:00 a.m. - 7:00 p.m. Eastern Time. The AIDS Clinical Trial Information Service (ACTIS) provides current information about federally and privately sponsored clinical trials of experimental drugs and other therapies for adults and children who have AIDS or HIV infection. Both health professionals and the general public can call to learn about clinical trials which are open for volunteers in their area. Information usually includes a brief description of the study and of the investigational drug, entry and exclusion criteria for volunteers, sites where the study is being conducted, and whom to call at your local site for more information about the study, or to volunteer. ACTIS is jointly sponsored by the Centers for Disease Control, Food and Drug Administration, National Institute of Allergy and Infectious Disease, and the National Library of Medicine. ** Canadian HIV Trials Network: 604/631-5327; or fax requests to 604/631-5210. Monday - Friday, 7:30 a.m. - 4:30 p.m. Pacific Time. This registry for Canadian AIDS trials includes a brief description of each trial, centers running the trial, inclusion/exclusion criteria, and where to phone locally for more information. Information can be given over the phone, or mailed if requested, in English or French. ** HIV Telephone Consultation Service (for physicians, nurses, and other health-care providers only): 800/933-3413; or 415/476-7969. Every day, 7:30 a.m. - 5:00 p.m. Pacific Time; 24 hour voice mail. Sponsored by Health Resources and Services Administration's (HRSA), Community Provider AIDS Training Project at San Francisco General Hospital, and American Academy of Family Physicians. Under the direction of Ronald Goldschmidt, M.D. in the University of California San Francisco Department of Family and Community Medicine, this is a telephone consultation service for health care providers who treat patients with HIV disease. Urgent questions are answered but it is not a substitute for emergency care or specialty consultation. The phone is answered by a clinical pharmacist, physician or nurse practitioner. Patient-specific information is requested (CD4 cell count, current medications, previous manifestations of HIV disease, sex, age, and transmission category) for case consultation, as well as demographic information about the caller (address, phone number, type of practice, number of HIV+ patients in the practice, field of medicine). Whenever possible, questions are answered immediately. Most calls are answered within 2 hours, and almost all calls are answered within a day. Information available to primary health care providers includes case consultation, medications, infection control, clinical trials, and literature searches. Referrals to local clinical consultants and community resources are made through the national network of HRSA regional AIDS Education and Training Centers. This service is free, but restricted to health care providers. ** Information Line for AIDS Studies: 800/AIDS-NIH (800/243- 7644). Monday - Friday, 12:00 p.m. - 3:00 p.m. Eastern Time. Provides information (English or Spanish) about AIDS trials being conducted at the National Institutes of Health Clinical Center. Specialized Hotlines ** CDC National AIDS Clearinghouse: 800/458-5231; TDD for the deaf, 800/243-7012. Monday - Friday, 9 a.m. - 7 p.m. Eastern Time. This service works closely with the National AIDS Hotline, but it focuses on providing printed and audiovisual material used in AIDS education efforts, often to organizations -- while the National AIDS Hotline usually provides information and referral during the call. The National AIDS Clearinghouse has many kinds of specialized information, including funding opportunities for AIDS programs, and a database of national, state, and local HIV-related meetings, seminars, and workshops. There is often a wait on the phone to reach an information specialist at this number. ** CDC Fax Information Service: 404/332-4565. 24 hours. This automated service, which gives information by fax, includes a variety of AIDS information (statistics, transmission, education/prevention, anti-body testing, universal precautions, approved treatments, clinical trials, vaccines, etc.), health advice for international travelers (not AIDS specific), and other health topics. This service is a useful example of a "fax back" system, which organizations can use to provide detailed information by request to the public. ** CDC AIDS Statistical Information: 404/332-4570. 24 hours. This automated service, which gives information from the HIV/AIDS Quarterly Surveillance Report, either by voicemail or by fax, includes statistics for journalists and organizations. ** Indian AIDS Information Hotline: 800/283-2437. Monday - Friday, 8:30 a.m. - 12:00 noon. Pacific Time. Operated by the National Native American AIDS Prevention Center to promote health in American Indians and Alaska Natives through empowerment and self-determination. This group serves as a resource to Native communities and to support community efforts by providing education and information services, thereby enhancing the physical, spiritual, and economic health of Native people. ** Consumer Nutrition Hotline: 800/366-1655. Monday - Friday, 8:00 a.m. - 8:00 p.m. Central Time. Sponsored by the American Dietetic Association, callers can speak with a registered dietitian about HIV/AIDS and nutrition, or ask for a referral to a registered dietitian. ** Body Positive Hotline: 212/721-1346. 10:00 a.m. - 6:00 p.m. Eastern Time. This hotline offers information and referral, emotional and practical support, and treatment information for persons infected or affected by HIV. Hotline volunteers may be individuals with HIV who can provide peer support. If a person with HIV has not answered the phone, a caller may specifically request to speak with someone living with HIV and it can be facilitated (English, Spanish). ** National Hearing Impaired Hotline: 800/243-7889 (TDD). ** HANDI (Hemophilia and AIDS/HIV Network for the Dissemination of Information): 800/424-2634 (English, extension 3051; Spanish, extension 3054). Sponsored by the National Hemophilia Foundation, this national hotline provides information about hemophilia and HIV/AIDS through a variety of publications, brochures, and articles. They also provide referrals to local service providers. ***** 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.