Subject: AIDS Treatment News #94 Date: Jan 12 1990 (615 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1990 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS issue #94, Jan. 5, 1990 CONTENTS: [items are separated by "*****" for this display] Plans for 1990 New Viral Measurement for Rapid Drug Testing CMV/Herpes Therapies; Scanning the News Congressional Hearings on Treatment Funding: San Francisco Jan. 16, Los Angeles Jan. 17 Please Return Survey on What to Use after AZT; Deadline Jan. 20 In Memoriam: Nathaniel Pier, 1952-1989 ***** PLANS FOR 1990 A year ago, AIDS TREATMENT NEWS published a list of treatments to watch in 1989 (see "Last Year's Predictions," below). This year we are less confident about which treatments may be important -- although there are some clear candidates, including ddI, ddC, AzdU, compound Q, and hypericin, among the antivirals. We are less confident than last year about predicting for the year ahead, because so much is happening that it is impossible to follow all relevant developments. We did select three developments which, in addition to the resource problems we outlined in our last issue, we believe will be important in 1990: (1) Viral Tests for Rapid Drug Trials Existing clinical trials for antivirals (ddI, ddC, and others to follow) are typically planned to run for two years, but may take much longer because they must recruit hundreds of people before the two-year timer begins. These study designs are highly inefficient because they rely on body counts -- deaths or other serious events -- in those not being treated. Therefore the pace is set by the slow progression of AIDS, regardless of how well the new drug works. We are now on the verge of having better blood tests which will allow researchers to get the same level of statistical proof (of antiviral efficacy in humans) in weeks instead of years, and with far fewer subjects -- probably less than a tenth as many as needed today. Such trials could be done now. The tests required are somewhat difficult and expensive; better ones should become available in the future. The AIDS community must follow this development closely, because the normal forces of inertia which slow the acceptance of any new way of doing things could in this case cost many lives. Federal officials or others may insist that body counts are still necessary to be absolutely sure that the drug, combination or other treatment improves survival, even after safety and antiviral efficacy in patients are well established. No proper weighing of costs and benefits could justify delaying all new antivirals for years because of the small chance that one of them might not save lives even after it shows clear antiviral activity in humans. For more information about new viral tests for rapid drug trials, see the article below. (2) Affordable Treatments for the Third World Almost no research anywhere in the world is developing treatment options for Africa or elsewhere (including the Third World nation of poverty within the United States) where people cannot afford AZT-scale drug prices. Most of the world is being written off. But occasionally an affordable treatment possibility accidentally appears. The most important example today is ddC (2',3'-dideoxycytidine -- see "ddC: The Low-Cost Antiviral," in AIDS TREATMENT NEWS #89, October 20, 1989). Now in major U. S. trials in very low doses, ddC may be at least as valuable as AZT or ddI -- but it costs pennies a day, is widely available from chemical supply houses throughout the world, and can be taken by mouth with little or no medical technology needed. The drug is dangerous if misused, but traditional healers in any culture could be trained to use it properly, whether or not Western medical infrastructure is available. No organization in the world is developing ddC as a Third World treatment possibility. Therefore AIDS TREATMENT NEWS will help interested people find each other. To keep informed, write to: ddC Project, AIDS TREATMENT NEWS, P. O. Box 411256, San Francisco, CA 94141. ddC is only one example. What is needed is an ongoing organization to find and develop the best possible treatment options for those who are otherwise excluded from AIDS/HIV treatment for economic reasons. (3) The Sixth International Conference on AIDS, June 20-24 in San Francisco Each year many if not most of the scientific papers on AIDS are presented at a giant international conference in June. Each January scientists rush to finish work and submit abstracts before the deadline (January 20 this year). The 1990 meeting is in San Francisco; previous meetings were in Montreal, Stockholm, Washington, Paris, and Atlanta. In San Francisco there may also be a meeting of NGOs (non-governmental organizations) before the conference, as there was last year in Montreal. To avoid overcrowding, the international conference will only admit 12,000 paid registrants; to be sure to get in, persons should register early. This year's international conference differs from the previous ones in that it is not co-sponsored by the government of the host country. The School of Medicine of the University of California San Francisco is responsible for planning, funding, and conducting the event. This year's conference also differs from all previous ones in that it is threatened by U. S. government rules which make it difficult and possibly dangerous for persons with HIV to enter the United States, even for a few days for a scientific conference. They must apply for a special waiver, a difficult procedure as there are no clear standards of what constitutes an acceptable application, and therefore no clear end to the work needed to gather supporting evidence. In addition, persons will have their passport stamped with a code which identifies them as HIV-positive, and may subject them to discrimination in their own countries or elsewhere. Organizations which have withdrawn from the conference as a result of this policy include the European AIDS Service Organizations, the League of Red Cross and Red Crescent Societies, the Scandinavian AIDS and HIV organizations, British Hemophilia Society, Canadian Hemophilia Society, British Frontliners, British Red Cross, Norwegian Red Cross, several member organizations of the UK NGO AIDS Consortium, and in the U. S., the National Association of People With AIDS. It is commonly believed that the travel restrictions which already are disrupting planning for the conference were imposed by an act of Congress in 1987. But according to Steve Morin, legislative assistant to Congresswoman Nancy Pelosi (Democrat, San Francisco), the documentary history clearly shows that the intent of Congress was to restrict only permanent or long-term residents, not short-term visitors. Apparently the law passed by Congress was misinterpreted by Federal officials who wrote the regulations. Last Year's Treatment Predictions A year ago, AIDS TREATMENT NEWS #72 (January 13, 1989) listed the following nine treatments to watch in 1989: * ddI * passive immunotherapy * hypericin * compound Q * Chinese anti-infection herbs * FLT (fluorodeoxythymidine) * AzdU * D4T * Soluble CD4 To evaluate our predictions in detail would require researching the current status of all these treatments -- research effort which we would rather spend on other matters. Two of the treatments -- ddI and compound Q, both largely unknown a year ago -- did receive major attention during 1989 and are still promising. We do not know of any of the nine which has been eliminated from consideration. But overall, we may have been too optimistic in expecting more in 1989 than would be accomplished. In 1990 we hope that new methods of quantifying virus in the blood will allow rapid determination of whether proposed antivirals do or do not work -- and if so, how well they work -- during actual use by patients. ***** NEW VIRAL MEASUREMENT FOR RAPID DRUG TESTING On December 14, 1989, The New England Journal of Medicine published an editorial and two articles on measuring the amount of HIV in blood. Since then we have heard that many AIDS experts consider this work among the most important of the year. At first it was not clear to us why a new blood test should be so important, when what we need are treatments. The new tests are important because they tell researchers quickly and accurately which antivirals are working in actual human use -- and how well they are working. It should now take weeks, instead of two years or more, to obtain statistical proof that a treatment does have efficacy in patients. The new tests could break the logjam of promising drugs waiting for clinical trials. Also, they should make it possible to find the best doses quickly, to develop drug combinations rationally, and even to tell individuals whether a particular treatment regimen is working for them, and when it has stopped working and should be changed. In the past, the only rapid test for antiviral activity was in a laboratory dish. Even if the drug worked and was known to be safe, many questions remained. Would enough of the drug be absorbed? Would it get to the virus in the body? Could high enough concentrations be achieved? Would the drug remain in the body long enough to have the desired effect? The new tests bypass these questions by directly measuring whether or not patients' viral levels have decreased. They quickly measure antiviral effectiveness of treatments in actual use, not of chemicals in test tubes. The biggest bottleneck to making new drugs available is the time taken by very slow, cumbersome, and expensive clinical trials. For example, since hundreds of volunteers are needed to prove that each antiviral works, each trial must run at many different sites, requiring time-consuming coordination among institutions in distant cities; for example, dozens of different IRBs (institutional review boards) must approve any change in the protocol of a major trial. By contrast, the new tests can show a clear, unambiguous antiviral effect in a handful of patients in a few weeks. There are several different approaches to quantifying HIV levels in blood plasma or blood cells. The ones described last month in The New England Journal of Medicine have the most visibility and professional momentum at this time; they are the ones ready for use now. We will focus on them in this article, but also mention alternative approaches. Background: Viral Cultures Most (although not all) methods for quantifying HIV in blood use viral cultures; in other words, they determine if the virus is present by attempting to grow it in the laboratory. HIV cultures have been used for several years, but until now they have not proved very useful for measuring the effects of antivirals. The fundamental problem is that cultures remained positive even after treatment, and therefore they did not show how well the treatment worked. No drug yet known can kill all the AIDS virus in patients; therefore, to evaluate a drug today, we need a quantitative test -- one that shows how much virus is present, not just whether or not any is there. In addition, there are practical difficulties with using viral cultures -- and these remain today. The tests are more expensive than routine blood work like T-cell counts, and they require special laboratory facilities to protect lab workers from exposure to virus. Also, it is difficult to get consistent results with viral cultures -- partly because the tests must use human blood cells as "food" for HIV, and since everyone's cells are different, it is difficult or impossible to reproduce a test exactly. Fortunately the ACTG (AIDS Clinical Trials Group) of the U. S. National Institute of Allergy and Infectious Diseases has certified certain labs as able to perform viral cultures competently. At this time, because of the difficulty of doing viral cultures, the best way to get them done for clinical trials is probably by collaboration between researchers doing the trials and those developing testing methods. The latter usually need more blood samples for their research -- especially samples collected under the controlled, well-documented conditions of clinical trials. Measuring AIDS Virus in the Blood The most important new development for faster testing of new treatments was the publication last month of a means for measuring the amount of HIV in blood (Ho and others, 1989). Two different tests were reported: one for blood plasma, and the other for certain blood cells. The basic idea of the new tests is so simple that it is surprising no one tried it before. The sample of blood plasma (or blood cells) is successively diluted to lower and lower concentrations, until finally the solution is so dilute that usually there is no virus left in the small amount of the solution which is tested. Ordinary viral cultures are run at all the different dilutions, and the researchers merely note the amount of dilution beyond which the cultures stop being positive. From this information, the amount of virus in the original blood serum or cell sample can be estimated. Since it is not known how many viral particles may be needed to make a culture become positive, the test does not estimate the actual number of particles, but rather gives results in units called "tissue-culture-infective doses" (TCID) per milliliter of blood. For example, patients with asymptomatic HIV infection were found to have 30 TCID per milliliter of blood plasma -- meaning that one thirtieth of a milliliter was enough to infect a viral culture and make it positive, while less than that amount was not enough. Dr. Ho and his team found virus in the plasma and blood cells of every one of 54 HIV-positive persons who were not receiving antiviral treatment -- and from none of 22 HIV-negative subjects used as controls. While persons who were asymptomatic had only 30 TCID per millimeter of plasma, persons with AIDS and ARC had over 100 times as much virus, 3500 and 3200 TCID respectively. Blood cells from persons with AIDS or ARC were also found to be more than 100 times as infective as cells from asymptomatic seropositives (20 TCID per million cells for asymptomatic patients, 2200 for AIDS, and 2700 for ARC). How well do these tests show whether a treatment is working? Seven patients were tested before and after four weeks of AZT; the amount of virus in plasma dropped 94 percent, although unfortunately the level of virus in blood cells did not change greatly. In contrast, in four persons with ARC who were not receiving antiviral treatment, the viral levels in plasma remained stable during the 12 to 20 weeks they were tested. These results clearly showed antiviral effectiveness of AZT in human use, in a four-week test with only seven patients. In six of the seven, plasma viral levels decreased more than ten times; in the seventh, they decreased almost ten times. But in clinically stable, untreated patients, the levels stayed the same. This complete separation between treated patients and controls suggests that statistical proof of antiviral efficacy could be obtained with a small number of volunteers; and the short time required (four weeks to prove efficacy of AZT, for example) might allow placebo trials to be ethically conducted in clinically stable patients who agreed to risk being untreated for that time (some patients cannot tolerate standard treatment anyway). Placebo trials can usually get results much faster than trials which use an active control such as AZT. A well-designed, focused program of small, rapid clinical trials could screen the most attractive of the many safe, available, but so far unproven treatment possibilities, and provide numerical measures showing which ones do or do not work to reduce the AIDS virus in actual use by patients. Such a program could quickly and inexpensively test ddI, ddC, compound Q, hypericin, very low doses of AZT, etc., as well as drug combinations, or even proposed diet or lifestyle changes. Some immune modulators might also be found to reduce viral levels indirectly, by helping the body control HIV, even if there is no direct antiviral effect. Such a testing program could give much better guidance for making treatment decisions than any information now available, and greatly reduce the time now taken for clinical trials and new-drug approval. (Note: Part II of this article will examine other new evidence that plasma viral level is the best marker available to show the stage of HIV infection. It will also discuss other approaches to measuring HIV in the blood, including R-HEV and quantitative PCR.) References Ho, DD and others. Quantitation of Human Immunodeficiency Virus Type 1 in the Blood of Infected Persons. The New England Journal of Medicine, volume 321, number 24, pages 1621-1625, December 14, 1989. ***** CMV/HERPES THERAPIES; SCANNING THE NEWS By Denny Smith The story of treatments for cytomegalovirus (CMV) infection contains more than its share of chapters on intrigue and neglect. When CMV was first recognized as an AIDS opportunistic infection, no drug was yet available to treat it effectively. Slowly the AIDS community became aware of ganciclovir (see DHPG, AIDS TREATMENT NEWS #44) and then of Foscarnet (AIDS TREATMENT NEWS #71), as effective but limited therapies for CMV retinitis or colitis. Ganciclovir was begrudgingly approved last year by the FDA; but Foscarnet, which could save the eyesight of many PWAs who cannot continue with ganciclovir, remains unapproved and generally unavailable. CMV belongs to a viral family which includes the cause of cold sores and genital lesions (herpes simplex 1 and 2, or HSV), the cause of chicken pox and shingles (varicella-zoster virus, or VZV), and one source of mononucleosis and certain lymphomas (Epstein-Barr virus, or EBV). These viruses are commonly latent in the general population, but can re-emerge as an active infection for people who are HIV-positive or who must take immunosuppressive drugs to protect transplanted organs. Fortunately, the "herpesvirus" family is well-studied and some FDA-approved drugs, as well as several investigational agents, appear to have overlapping activity against more than one herpesvirus. Acyclovir (Zovirax), can be administered orally for mild herpes simplex flareups, or intravenously for severe episodes. Acyclovir is relatively non-toxic, and may suppress latent CMV as well as HSV, and is often prescribed in conjunction with AZT (AIDS TREATMENT NEWS #86). Unfortunately, certain toxicities may pose limits on the duration of other drugs, or their safety in combination with AZT and other treatments. Prolonged treatment with ganciclovir often results in neutropenia (low neutrophil counts), and Foscarnet can be toxic to the kidneys. Vidarabine as well as Foscarnet has been used successfully to treat herpes simplex which will not respond to acyclovir, but vidarabine can suppress bone marrow, making it a questionable choice to replace ganciclovir for treating CMV. Since ganciclovir and Foscarnet pose different toxicities, people who cannot tolerate ganciclovir should have unqualified access to Foscarnet, in our opinion. In terms of therapeutic value against CMV, however, Foscarnet is not considered to be superior to ganciclovir. We spoke to Shelley M. Gordon, M. D., an infectious disease specialist who said early trial results indicate that granulocyte macrophage-colony stimulating factor (GM-CSF) can counter the neutropenia of ganciclovir, allowing extended use of that treatment. Dr. Gordon also described laser treatments as a successful way to correct retinal detachment caused by CMV, although they would be a complementary treatment and not a replacement for anti-viral drug maintenance therapy. Laser therapy is available already for many other indications, but GM- CSF is accessible only through participation in clinical trials. In September AIDS TREATMENT NEWS #87 reported the early success with GM-CSF for controlling the toxicity of AZT and alpha interferon, a combination approved to treat KS and which may also prove synergistic against HIV. Dr. Gordon mentioned that interferon has been discussed as a possible agent for treating CMV as well. Ganciclovir is presently administered intravenously, but studies are under way testing the effectiveness of an oral formulation, as well as intraocular injections. In vitro studies suggest that DFMO (Eflornithine) has a synergistic effect with ganciclovir, implying that lower, less toxic doses might be possible in the future to control retinitis. We spoke to Danny King, a researcher who has studied a drug called FIAC at Oclassen Pharmaceuticals in San Rafael, California. He said that FIAC is active against all the herpesviruses, as well as the hepatitis B virus. Although FIAC is a nucleoside analog like AZT and ddI, it has no effect on HIV. One early advantage seen with FIAC is its ability to be administered in an oral form. FIAC was first studied in the early 1980s at Memorial Sloan- Kettering Hospital in New York for treating severe VZV and CMV infections, and demonstrated some bone-marrow toxicity and gastrointestinal upsets. FIAC is now entering additional phase one (toxicity) trials at four sites: the University of Alabama, the University of Washington in Seattle, the University of California in San Diego and the National Institute of Health in Bethesda. For information about local clinical trials involving FIAC, GM-CSF, and Foscarnet, interested persons can call 800/TRIALS-A. In the interest of renewing the discussion of CMV treatments and questions of promising but neglected options, we want to bring attention to a list of possibilities for treating CMV or herpes infections which are still in laboratory or animal studies or known to us anecdotally: aphidicolin (APH); BHT (see AIDS TREATMENT NEWS #10); capsaicin; decyclovir; dextran sulfate; HPMPA and HPMPC (see AIDS TREATMENT NEWS #76); hypericin; pentosan polysulfate; SQ 32,829 and SQ 33,054; and tumor necrosis factor. Many of these were discussed at the Interscience Conference on Antimicrobial Agents and Chemotherapy last September in Houston. Some of them were discussed a year earlier at the same annual conference. At least five CMV possibilities have demonstrated in vitro activity against HIV as well as against the herpesviruses: APH, dextran sulfate, pentosan polysulfate, foscarnet, and hypericin. The question now is how long these possibilities will remain on the drawing board, and why Foscarnet, GM-CSF and FIAC are usually not available to many people who need them. Compassionate use or parallel track access does not seem too much to ask for people who stand to lose first their sight and then their lives. ***** CONGRESSIONAL HEARINGS ON TREATMENT FUNDING: SAN FRANCISCO JAN. 16, LOS ANGELES JAN. 17 Next week Congresswoman Barbara Boxer, Chair of the Human Resources Task Force of the House Budget Committee, will hold public hearings in San Francisco and Los Angeles on the Federal fiscal 1990 AIDS budget. The hearings will focus on impact aid/disaster relief to cities and regions with high incidence of AIDS, and on Federal support to make early intervention available when medically indicated. The San Francisco hearing is at 9 a.m. on January 16 in the 19th Floor Ceremonial Courtroom of the Federal Building, 450 Golden Gate Avenue. Witnesses include Art Agnos, Pat Christen, George Rutherford, and Phil R. Lee. In Los Angeles the hearing will be at 9 a.m. on January 17 in the Brentwood Theater (next to bldg. 258) at the VA Medical Center Campus, Wilshire and Sautelle Blvd. Witnesses in Los Angeles include Mervyn Silverman, Charles Forrester, David Johnson, and Stephen Bennett. For more information, call Mark Cloutier in Congresswoman Boxer's office, 415/626-6943. ***** PLEASE RETURN SURVEY ON WHAT TO USE AFTER AZT; DEADLINE JAN. 20 If you have used AZT for a year or more, you could help others by returning the survey in issue number 92 of AIDS TREATMENT NEWS. We are extending the deadline to January 20; surveys mailed after that date may be too late for inclusion in our report of the results, which will be published in AIDS TREATMENT NEWS. ***** IN MEMORIAM: NATHANIEL PIER, 1952-1989 Nathaniel Pier, M. D., one of the strongest advocates for faster development of AIDS treatments, died of AIDS complications on December 27, 1989. We first spoke with Dr. Pier in 1986, while researching lentinan. He had long urged trials for this drug, an immune modulator derived from the shiitake mushroom and widely used in Japan in treating cancer. In February 1988 Dr. Pier presented the history of his four-year efforts to spark research on lentinan to the Presidential Commission on the HIV Epidemic. (Recently clinical trials of lentinan were conducted at San Francisco General Hospital, and at New York's Community Research Initiative.) Dr. Pier, who had a large AIDS practice in New York, was also a founder of the Community Research Initiative, a model organization for conducting clinical trials outside of the usual research centers, through the help of practicing physicians. Dr. Pier and the other founders carried the organization through the first difficult year before it was popular, and stayed with it afterwards. AIDS TREATMENT NEWS published interviews with Dr. Pier on January 1, 1988 and August 12, 1988. The conclusion of the August interview suggested the "parallel track" later proposed by NIAID director Anthony Fauci, M. D., as well as the criticism of mainstream clinical AIDS research which is now becoming more common: "The current system simply has not produced the goods. And if Dr. Frank Young's prediction (of few new drugs approved by 1991) is any indication, it will not produce the goods for a long time to come. This consigns large numbers of people to death without giving them a dignified chance to fight back. It is not an acceptable human or reasonable approach to doing research in this epidemic. "After five years of being on the front lines, my heartfelt feeling is that the top priority for people with AIDS and people who care about AIDS is to demand access to experimental therapies to try to save their lives. "I appeal to people to organize this effort immediately, to bring it forward in their local groups, then present the case to their political people, and to the people who are running the present medical system of testing drugs. It's time we told them that the emperor has no clothes, that the current system is not working. It's time to insist on wider access to promising therapies, and rapid testing of existing drugs to develop better treatment options." In our last conversation, shortly before his death, Dr. Pier told us that hypericin herbal extracts appeared disappointing to him and other New York physicians -- they were not seeing the results that had been hoped. Earlier, Dr. Pier had been the first to tell us that AL 721, and later dextran sulfate, appeared disappointing. Dr. Pier graduated summa cum laude from the University of California at Berkeley in 1974, and received his M. D. from the Albert Einstein College of Medicine in 1977. He is survived by his lover, Michael Hannaway. ***** STATEMENT OF PURPOSE AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists, physicians, and other health practitioners, and persons with AIDS or ARC. 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. We also examine the ethical and public-policy issues around AIDS treatment research and treatment access. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display