Subject: Chinese Herbs; Drug Trials; Lab Prices Date: Sep 23 1988 (521 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. Articles by John S. James are from AIDS Treatment News unless otherwise indicated. John may be contacted by telephone at (415) XXX-XXX. AIDS TREATMENT NEWS issue #65, September 23, 1988 CONTENTS: [***** appears here at each new item] Chinese Herbs Show Early Result; Model for Community Trials? Scientific Justification for Community-Based Trials Drug-Trial Constipation Autopsy Study Pinpoints Diagnosis Failures Laboratory Testing: Saving Money with Package Prices California: "No on 102" Effort Needs Funds Women's AIDS Service Program Begins Deadline October 10 to Return Treatment Survey Questionnaires ***** Chinese Herbs Show Early Result; Model for Community-Based Trials? Keith Barton, M. D., C. A., a Berkeley, CA physician who is also a certified acupuncturist trained in Chinese herbal medi- cine, has prepared a combination of six traditional Chinese herbs, all of which have shown anti-HIV activity in laboratory tests. (See "Chinese Herbs Screened for Anti-HIV Activity", AIDS Treatment News issue #61, July 29, 1988, which reports on the laboratory testing.) The only patient so far to use the combina- tion went from P-24 antigen positive to zero in three weeks; he was using no other treatment during this time. One other patient started the herbs but had to stop after a potentially dangerous drop in white blood count which might have been caused by the herbs. His count recovered in three weeks. What's limiting further research now is lack of patients who are antigen positive and not using any other antiviral treat- ments -- for example, persons who could not tolerate AZT. Such patients or their physicians could contact Dr. Barton. No conclusions can be drawn from one patient, of course. But the facts that P-24 antigen become zero (unlikely with no treatment), that this therapy has good laboratory rationale as well as thousands of years of human experience with the component herbs, that the treatment if it works could be readily obtained and applied, and that further testing would be easy, rapid, and inexpensive, suggest that this approach is worth pursuing. Protocol Details The six herbs are Lonicera japonica, Lithospermum erythrorhizon, Prunella vulgaris, Viola yedoensis, Epimedium grandiflorum, and licorice root. The first five were from the eleven found to have antiviral activity (by R. Shihman Chang and H. W. Yeung, published in Antiviral Research 9 (1988), pages 163-176). Licorice root has shown anti-HIV activity in other research, in Japan. The herb mixture was provided in bags to be prepared as a tea according to written directions. Patients used one bag per day for the first two weeks, two bags a day on the third week, and four bags daily in the fourth week. After the fourth week, patients are taken off herbs for two weeks, while laboratory tests continue. Neither the patient who used the herbs successfully nor the one who had to stop had any obvious symptoms of side effects, except for some fatigue. But for safety, as well as good moni- toring of the results, extensive laboratory testing was done, including baseline (before treatment began) and weekly complete blood count (CBC), chem 16 blood chemistry panel, urinalysis, PT, PTT, platelet count, P-24 antigen, and beta-2 microglobulin. In addition, HIV cultures were done at baseline and every two weeks thereafter, and T-cell subsets at baseline and monthly. For more information send a self-addressed stamped envelope to: Keith Barton, M. D., 3099 Telegraph Avenue, Berke- ley, CA 94705. A Model for Community-Based Trials This test of certain Chinese herbs suggests a model for community-based trials in several important respects: * The treatment has a rationale. The herbs all showed anti-HIV activity in the laboratory; and all had been in human use for other purposes for many years. * The treatment is available, legal, easy to use in a physician's practice, and safe under medical supervision. * The trial has clear entry criteria (P-24 antigen posi- tive, overall health stable, not using other antivirals within the last month). * The trial has clear success criteria (P-24 antigen becoming negative within six weeks). An organization to support community-based trials will not have to start from scratch, but instead can develop and refine existing work. Such an organization could contribute in several ways: * A scientific review committee will select the best options to test, and the best ways to organize the trial -- how many subjects, what success criteria should be used, etc. * Many physicians will be involved, so it will be possi- ble to recruit eligible patients more quickly. * The consensus of a scientific review committee, an institutional review board, a number of participating physicians, and perhaps representatives of Federal agencies, will give each study more impact. Successful results will be disseminated, accepted, and used more rapidly than if only one physician were involved. ***** Scientific Justification for Community-Based Trials The kinds of studies which we believe are appropriate for community-based trials (such as the antiviral herb study above, or the kinds of trials proposed by Leland Traiman, interviewed in AIDS Treatment News #64, September 9, 1988) have sometimes been dismissed by establishment scientists, who have argued that only the much more elaborate studies such as those run by NIH can pro- duce valid data. Some AIDS organizers have been led to believe that there was no scientific support for the kind of research the AIDS community is coming to believe is needed. Those of us work- ing to develop community-based trials have so far heard from only one side of an ongoing debate. An important book which reviews both sides is Ethics and Regulation of Clinical Research, by Robert J. Levine, M. D., pub- lished by Yale University Press, New Haven, Connecticut, 1988. Dr. Levine is Professor of Medicine at Yale, and a well-known ethicist. A chapter on randomized clinical trials (RCTs) includes a four-page section titled "Excessive Reliance on RCTs", which reviews papers by scientists proposing other study designs. These scientists see randomized trials as a valuable tool -- but imposed excessively on U. S. medical research by the FDA and the National Cancer Institute of the NIH, "agencies which control the entry of new therapies into the practice of medicine", "through their refusal to accept data developed with other methods". Oth- ers have shown through statistical studies that randomized trials have often failed to prove what they claimed to have proved. One analyst described the conflict between "pragmatic" researchers (including most clinicians), and "fastidious" ones (including biostatisticians), with the fastidious school dominat- ing clinical trials. The result is "clean" study designs which do not reflect actual medical practice. And a larger problem, though barely hinted at in Dr. Levine's book, is that the practi- cal difficulties of meeting "fastidious" study requirements often cause grave delays, or even prevent important research from being done at all. The arguments we have heard against more practical designs are: * That each separate drug must first be tested by itself to show efficacy; it is not OK to test a treatment consisting of a combination of drugs not already tested and approved separately. (This argument supports the commercial needs of pharmaceutical companies, which want each of their products tested and approved by itself, not in combination with competi- tors' products.) * That new antivirals cannot be tested in doctors offices. Instead, such "phase I" trials often hospitalize patients in medical centers for the first weeks, for elaborate testing. (We agree with this procedure for new, high-tech drugs such as CD4 or DDI -- but not for herbs, foods, common chemicals already in human use, or prescription drugs -- which already have long records of human use, with toxicities either unimportant or known.) * The only good way to prove efficacy is with a random- ized clinical trial, meaning that patients who volunteer do not know which of two or more treatments they are going to get (one may be a placebo). (We agree that such trials have a major place -- but they involve great practical difficulties which have often delayed results for years. Most of the delays and difficulties can be avoided by tight, scientifically designed trials built around the kinds of medical intervention which patients would be receiving anyway.) The mainstream drug trials commonly take a year or much more before they even begin, to get approvals and funding. Many have such impractical entry criteria that it takes months to recruit even a single patient; these studies are doomed before they start, but they go through the motions anyway, giving the impression that something is being done. Other trials do collect potentially useful data, but keep it secret for a year or more until the slowest trial centers complete their last patients. Then results can take months to analyze, sometimes because the only people important enough to make decisions are too busy to find mutually acceptable times to meet. Finally the results must be kept quiet and unavailable to most physicians and patients for the months or more until publication. And even after publication there is no organized way to get the results to the attention of most of the physicians who could use them. This system usually takes years to test each interesting possibility -- if it ever does. This slow "turn-around time" has a disastrous effect of research results and productivity, because years are required for each full cycle of idea, test, and evalua- tion, and many such cycles may be needed to get practical results. These problems represent poor management, not good sci- ence. The research establishment is now coming to accept the concept of community-based trials -- a concept endorsed by the Presidential Commission on the HIV Epidemic. But we fear that this establishment wants to keep community-based trials in the same straightjacket as conventional studies. If community trials are required to repeat the unfeasible designs and procedures common in mainstream trials, they will be just a pale, underfunded imitation of the ineffectual system we already have. Dr. Levine's section on excessive reliance on randomized trials mentions an alternative design, called observational case control studies, which is practically identical to the drug-trial proposals developing in the AIDS community: "This design entails systematic observation of patients as they are treated by practicing physicians. Inclusion and exclusion criteria exactly like those used for RCTs are used to determine who will be observed. After the outcome has been esta- blished, patients are sorted by outcome, e.g., fatalities and survivors. Causes of the outcome are evaluated as in case-con- trol studies." Anyone organizing community-based trials should scan Eth- ics and regulation of Clinical Trials and the literature it cites (the book has over 700 references). The AIDS community does have authoritative scientific support for the kinds of studies which need to be done. ***** Drug-Trial Constipation One of our subscribers wrote to his Representative, Congresswoman Patricia Saiki of Hawaii, about delays in AIDS drug trials. Congresswoman Saiki forwarded the letter to NIH, and received a reply dated July 18, 1988 from James C. Hill, Ph.D., Deputy Director, National Institute of Allergy and Infectious Disease (NIAID). In the process of defending the system, Dr. Hill also illuminated what is wrong with it. We quote two para- graphs from his letter: "To help decide which drugs are the most promising, the NIAID established an AIDS Clinical Drug Development Committee (ACDDC), composed of Government and non-Government experts, to evaluate candidate drugs for entry into NIAID-sponsored clinical trials. The goal of this effort is to ensure than any drug show- ing scientific promise and receiving a high priority rating by the Committee will be evaluated in a clinical trial. Some concern has been expressed that there may have been undue delays from the point at which the ACDDC designates a drug as "high priority" to its being entered into a clinical trial and patient accrual begun. However, it is important to point out that the initiation of clinical trials with investigational new drugs is often com- plicated and requires extraordinary coordination among Govern- ment, research institutions, and pharmaceutical manufacturers. There are many issues that limit our ability to go rapidly from the designation of a drug as "high priority" to patient accrual into a clinical trial. "At either the stage of ACDDC review of a drug or the drug's subsequent referral to the AIDS Clinical Trials Group com- mittee, there are often a variety of issues that still may need to be resolved: recommendation for additional safety and effi- cacy studies in animals; extensive negotiations with the manufac- turer are often needed to ensure the production of sufficient quantities of clinical grade material prior to the further development of the protocol(s); all supporting preclinical infor- mation, manufacturing processes, and intended trial design must be approved by the Food and Drug Administration (FDA); the phar- maceutical manufacturer must agree to supply the drug required to conduct the study as well as agree to the design of the protocol; Institutional Review Boards at the individual medical centers must also review and approve the proposed protocol; case report forms must be designed and reviewed with statistical input to assure that the measurements taken throughout the study are being collected in a manner that will provide the necessary data to meet the predetermined objectives; and finally, patients must be screened in order to select the population that meets the intended protocol entrance criteria. The failure of any one or more of these elements to be accomplished in a timely fashion can cause unforeseen delays in the initiation of the clinical trial." ***** Autopsy Study Pinpoints Diagnosis Failures A study of autopsy records at two major New York hospi- tals found that half of the persons who died of AIDS had cytome- galovirus (CMV) infections not suspected while they were alive. Several other opportunistic conditions were also undiagnosed; three quarters of the patients who died were found to have unsuspected AIDS-related complications. This study, published July 9 in The Lancet by researchers at the New York University School of Medicine, New York City Department of Public Health, and New York Hospital-Cornell Medi- cal Center, can help physicians by letting them know which com- plications are most often missed, so that they can check care- fully for these, especially in patients with undiagnosed prob- lems. Of all AIDS death records between May 1981 and May 1987 at two large teaching hospitals, one public and one private, 101 adult patients had autopsy and all other records available. The major unsuspected AIDS-related conditions were: CMV infection, 49 percent (of all 101 cases); Systemic fungal infection, 20 percent; Systemic KS, 14 percent; MAI infection, 11 percent; Systemic herpes infection, 9 percent. Other problem diagnoses were fungal pneumonias (undiag- nosed despite bronchoscopy and even biopsy), tuberculosis, and central nervous system lymphomas (sometimes treated unsuccess- fully as toxoplasmosis). Bacterial pneumonias -- presumably treatable -- were important contributors to death in 30 percent of the patients. Successful diagnosis was found for pneumocystis (over 90 percent of cases), and cryptococcal infection and CMV retinitis (diagnosed correctly in all cases). Previous autopsy studies (when the cause of death was not AIDS related) have also found that many infectious diseases are missed. For more information, see Wilkes, MS and others, "Value of Necropsy in Acquired Immunodeficiency Syndrome", The Lancet, July 9, 1988, pages 85-88. ***** Laboratory Testing: Saving Money with Package Prices AIDS Treatment News talked with two physicians who nego- tiated large price reductions with testing laboratories by set- ting a price for panels of dozens of different tests. These examples may help other physicians make similar money-saving arrangements. (1) Positive Action HealthCare in San Francisco obtained a price of $168.40 from Roche Biomedical Laboratories for a panel including T- and B-cells with subsets (including T-helper cells of course), beta 2 microglobulin, P-24 antigen, sedimentation rate, CBC (complete blood count), a SMAC chemistry panel with about 20 different measurements, the RPR syphilis serology, and urinalysis. (2) Keith Barton, M. D., in Berkeley (see article on Chinese herbs above) obtained a similar package which in addition included an HIV culture, from another company for under $200. (Most laboratories may not offer so low a price for an HIV cul- ture; this company is developing its own tests, and may have sub- sidized the price to obtain blood samples in order to compare its tests with the standard ones.) Prices can be kept even lower by minimizing expensive tests. Even some of the research trials funded by major corpora- tions use only two or three T-cell subset tests, and avoid HIV cultures entirely. The other tests are much less expensive. Low prices on testing will facilitate community-based trials. Such trials can be integrated into the medical care the patient is receiving anyway, so they can cost very little in addition, and the cost of the tests can usually be paid by insurance. (The drugs likely to be tested in this way are seldom very expensive.) In other words, much community-based AIDS treatment research can be done with no external funding -- largely elim- inating the institutional delays which have made most existing research ineffectual. Community organizing, bringing together the knowledge and talents of persons with AIDS, physicians, and scientists, is the only limiting factor in how much can be accom- plished. ***** California: "No on 102" Effort Needs Funds A right-wing AIDS initiative on California's November ballot would close anonymous testing centers, require doctors and researchers to report the names of anyone they believe to be HIV positive, and allow employers and insurance companies access to HIV test results. The legislative analyst's official estimate of the cost of implementing this initiative is tens to hundreds of millions of dollars. This destructive initiative, called Propo- sition 102, even has a provision prohibiting the California Leg- islature from amending it without resubmission to the voters -- a time-consuming process which would prevent the State from adjust- ing public-health policy to changing conditions. While directly affecting only California, this initiative would impact public health everywhere by greatly impeding AIDS treatment research in California, since it would forbid research- ers from keeping the names of their subjects confidential. It would also end the anonymous testing and counseling programs which have proven successful in greatly reducing the spread of the virus. Two economics professors at the University of California at Berkeley recently estimated that other effects of this initia- tive, such as forcing the firing of over 30,000 teachers and food handlers found to be HIV positive, would cost California over three billion dollars a year in direct and indirect expenses. The normally conservative California Medical Association (CMA) went to court in an unsuccessful attempt to keep Proposi- tion 102 off the ballot. Many other groups such as the Califor- nia Nurses Association, California Association of Hospitals and Health Systems, and Health Officers Association of California officially oppose the initiative. An unusual development is that major corporations such as Levi Strauss, AT&T, and Apple Com- puter, which usually would not take a position on such an issue, are also opposing it. Others opposed include the California Chamber of Commerce, League of Women voters, California Taxpayers Association, California Federation of Labor, and both California Senators. But polls show that the initiative would pass if the election were held today, because people do not understand its provisions. The measure was designed to sound reasonable to the uninformed, and the California ballot is loaded with measures. Polls show that voters reject the initiative if they know that it would ban anonymous testing, and allow employers to require HIV tests and fire or refuse to hire anyone testing positive. It will cost hundreds of thousands of dollars for the media time needed to get this information to the voters before November. If you can help in any way, with money, volunteer time, contacts, publicity, etc., contact Californians Against Proposi- tion 102 at either 10 United Nations Plaza Suite 410, San Fran- cisco, CA 94102, (415) 621-4450, or at 7985 Santa Monica Blvd. Suite 109, West Hollywood, CA 90046, (213) 654-3757. ***** Women's AIDS Service Program Begins by Denny Smith The San Francisco AIDS Foundation has received special funding to serve women with AIDS and ARC, and their partners and children. This program, possibly the first of its kind in the nation, is already serving 80 women. Women with AIDS have faced unique, severe problems. For example, only five of the 80 clients in this program are now on AZT, and only five are on aerosol pentamidine. Only two of the 80 are now using an experimental treatment, such as dextran sul- fate or AL 721. Seventy of the 80 are low income; food and rent bills must compete with treatment costs. Many women are uninsured or underinsured. Women are often excluded from trials of experimen- tal drugs. Long waits in public clinics are often impractical for women with young children and no childcare. Women with AIDS seldom have the community support and institutions available to gay men. Because of these and other obstacles, women with HIV- related symptoms are often late to receive treatment. The new program runs ongoing discussion groups for shar- ing treatment and other resource information. With the help of Catholic Social Services and the Shanti Project, it hopes to open two houses for women with AIDS or ARC. For more information about this program, call Catherine Maier, its director, at the San Francisco AIDS Foundation, 415/864-5855. ***** Deadline October 10 To Return Treatment Survey Questionnaires Subscribers wo received our AIDS treatment survey ques- tionnaire in issue #63 must send them now to be counted. We have extended the deadline to include envelopes postmarked through October 10. If you have any useful information about treatments which did nor did not work, you can help. ***** [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display