Subject: AIDS Treatment News #198 Date: May 06 1994 (763 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1994 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS #198, May 6, 1994 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Curcumin Trial Results: Antiviral Effect Reported Resource Articles: ** Protease Inhibitors; ** Interview with Roy Vagelos of Merck & Co d4T Approval: FDA Advisory Committee Meeting, May 20 Acyclovir Over the Counter? FDA Hearing, May 19 AIDS TREATMENT NEWS Volume III Now Available (May 1991 Through December 1993) ***** Curcumin Trial Results: Antiviral Effect Reported by John S. James The first human trial of curcumin -- an "alternative" treatment in use in the AIDS community, and the first of a potentially new class of anti-HIV treatments which target the LTR (long terminal repeat) of the AIDS virus -- found a modest antiviral effect, according to SEARCH Alliance, a community-based research organization in Los Angeles. This was only a pilot study, however; and the effect appeared to be temporary, as it had partially faded by 20 weeks when this study ended. More research is needed -- such as the new curcumin trial, about to begin in Boston, which will be conducted by the Community Research Initiative of New England. The antiviral effect was seen in measurements of HIV RNA, using an experimental test (quantitative PCR) which is very sensitive, but also highly sensitive to laboratory errors and variations. P24 antigen tests, which are much less sensitive, failed to confirm an antiviral effect; also, there was no improvement in average T-helper count. The only toxicity seen at the dose tested (which is the most popular dose in use in the community), was upper gastrointestinal discomfort in some of the volunteers; it was severe enough to cause two of the 19 to drop out of the trial. Curcumin is found in the spice turmeric; it is the substance which gives curry its yellow color. It first came to the attention of the AIDS community after laboratory studies at the Dana-Farber Cancer Institute, and follow-up viral tests at Beth Israel Hospital in Boston, showed anti-HIV activity in the laboratory. Despite publication of these laboratory findings more than a year ago in the Proceedings of the National Academy of Sciences, USA (March 1993; volume 90, pages 1839-1842), no company or government agency is studying curcumin as a possible treatment, nor funding anyone else to do so. SEARCH Alliance, which specializes in fast-track development of the earliest pilot studies of potential AIDS treatments, found private funding for its small trial, and reported the results on May 3. Curcumin is the weakest known agent in its class (of substances found to inhibit the HIV LTR); it was chosen for the trial because more powerful LTR inhibitors were not available for this research. All information suggests that this treatment technology could be developed much further. We hope the SEARCH Alliance results will bring more attention to a very important research area which has been neglected by the mainstream. But it is also important to remember that the results so far are limited and sometimes ambiguous; they do not yet prove that curcumin is beneficial. [Note: This writer is a member of the medical/scientific advisory board of SEARCH Alliance; however, this article represents only our views, not necessarily those of the organization. We originally suggested a curcumin trial to SEARCH Alliance; however, we were not involved in designing or conducting the study, and we first saw the data on May 2, a week before this issue went to press. [This article is based on "Curcumin As an Antiretroviral in HIV-1 Positive Patients," an unpublished manuscript by Robert E. Winters, M. D., Michael J. Slattery, Charles V. Chesson II, Ph.D., and Natalie L. Sanders, M. D. -- and on additional information provided by SEARCH Alliance. Our analysis differs from that of the SEARCH team -- we used median values, instead of mean values, to summarize the data, as explained below -- but while the numbers are different, our conclusions are the same.] Notes on Interpretation of the Data This was a small pilot study with a total of 19 patients enrolled, and 11 completing the trial. There was no placebo or other control group. As a result, this trial will not provide hard conclusions; it cannot prove that one treatment is better than another. What it can do is to give us early, suggestive information about a new kind of potential treatment in human use -- a more complete and accurate view than can be obtained from collecting anecdotal reports. Therefore, this article will not focus on conclusions, but rather walk through the key data, pointing out what we find interesting and important. In both the scientific and activist AIDS communities at this time, there is a widespread conservative view that trial results must only be analyzed according to procedures specified in advance. The purpose of this limitation is to prevent errors which can occur when researchers look at the data and then concoct theories to fit it; if dozens of different theories are considered, some are likely to fit just by chance alone, when no real discovery has been made. We believe that this conservative view is correct for certain large trials which are seeking definitive proof of the value of a treatment. But it should not apply to initial pilot studies, which aim to help researchers find out what is going on, not to test or prove a preconceived idea. All too often, researchers blindfold themselves, creating theories and designing trials abstractly, without looking at enough real data; usually these theories are wrong, and then the resulting trials are not useful, except as miscellaneous negative results. The consequence is inefficient, unproductive research. A better way is to run a pilot study first, and look at all of its data in various ways, asking what the data is trying to tell us; then use that information to design a more formal, definitive trial. In the curcumin study, a related issue concerns analyzing subsets of the data. This study sought volunteers with advanced HIV disease; the median T-helper count at entry was 100. Several participants dropped out of the trial, usually because of opportunistic infections; and any infection or other immune activation is likely to cause a substantial rise in HIV RNA, the principal viral measure used in this study, making the treatment look less active than it otherwise would. As a result, when all the patients who entered the trial are analyzed together, the antiviral effect observed is small; but when those who completed the trial without an OI are analyzed -- or those who entered it with a higher than average T-helper count -- the effect is much more clear. We present the data both ways. Also, in this article we have summarized the data using median values, instead of mean (average) values. The median of a set of numbers is the 50-percent point -- the value such that half of the numbers are above it and half are below it. We decided to use the median instead of the average, because the most important data (the measurement of HIV RNA) are highly variable, with a number of extremely high and low values which may be due to laboratory errors. The median is often used for looking at ill-behaved data, since a few extreme values can only cause a limited error in the median, no matter how high or low those values may be -- while a few extreme values can completely distort an average. Study Design Overview The purpose of the SEARCH Alliance curcumin trial was to look for any signs of toxicity of the treatment, at the dose commonly used in the AIDS community -- and also to record any indications of antiviral activity. For this pilot study, all patients were enrolled in a single treatment arm; there was no control group. To check for toxicity, the study included "a complete blood count with differential, chemistry panel, amylase, and a self- evaluation questionnaire at baseline and at the end of week 1, 2, 4, 6, 8, 12, 16, and 20." (Quotations are from the SEARCH Alliance manuscript, "Curcumin As an Antiretroviral in HIV-1 Positive Patients," unless otherwise stated.) To look for anti-HIV activity, "Viral load was monitored by serum RNA-PCR at baseline and at week 2, 4, 8, 12, 16, and 20." (The manuscript includes a technical overview of the PCR test used, and of procedures for quality control.) Also, three different kinds of p24 antigen tests were used, in an effort to find one which gave enough positive values at baseline to allow useful comparisons. The study was initially designed to last eight weeks. However, the data at week four was encouraging enough that the trial was extended to 20 weeks. All study volunteers received the same dose of curcumin. "Patients were instructed to take three capsules of concentrated curcumin, three times a day, one hour before or two hours after meals. Each capsule, supplied by Nature's Herbs, weighed 445 mg. and contained approximately 285 mg. of curcumin concentrate in a ground turmeric base. The total amount of curcumin ingested per day was 2.56 grams." (The volunteers were judged "very compliant as determined by counting the number of returned capsules," meaning that they actually took the intended study dose.) In case stomach upset became a problem, the curcumin could be taken with meals. A total of 19 volunteers entered the study. One dropped out after two days, however, and therefore was not included in the analysis of antiretroviral data below, since only a baseline test was done, so there is no data on changes in viral tests. Inclusion/Exclusion Criteria Study volunteers could have any T-helper count; however, an effort was made to enroll persons with a low count, so that they would be more likely to have p24 antigen values which could be measured. For the 18 patients, the T-helper count at baseline ranged from 10 to 391, with a median of 100.5. Of the total of 19 who enrolled, 11 finished all 20 weeks of the study without an opportunistic infection. (A 12th has 20 weeks of data, but was not included with the other 11 due to an OI.) Volunteers could use AZT or other antiretrovirals during the trial, provided they were on a stable treatment regimen for 60 days preceding enrollment (so that changes in antiviral treatments, such as starting or stopping AZT or ddI, would not interfere with the viral measurements in the trial.) All of the 11 patients who finished the trial were using antiretrovirals; we do not have information on the others. Only one started an antiretroviral treatment during the trial -- patient number 02, who started d4T. Use of vitamins, minerals, and herbs during the study was strongly discouraged. Inclusion criteria also included hemoglobin, white blood count, granulocytes, platelets, bilirubin, ALT, AST, SGPT, alkaline phosphatase, and creatinine. The 19 participants included 15 men and 4 women. There were two Mexican-Americans, two African-Americans, and 15 Caucasians. Their ages ranged from 29 to 59 years old. Results [Note: The data discussed in this article is reproduced in Table I, below. The charts (Figure I through Figure III) could not be reproduced here. But the data used to create the charts -- the median values, and the counts on which those medians are based -- are shown, below Table I. Even without the charts, you can use this data to follow the discussion. [For a copy of the original article including Figure I through Figure III, send a self-addressed stamped envelope to: AIDS Treatment News, P. O. Box 411256, San Francisco, CA 94141, or call 415/255-0588.] One of the 19 volunteers who entered the study, who had a history of peptic ulcer disease, withdrew after two days due to gastrointestinal irritability. This person is not included in the 18 patients analyzed below, since only the baseline tests were given, so there are no data on changes in HIV RNA. One other patient also withdrew due to gastrointestinal irritability, after eight weeks. Four others withdrew due to opportunistic infections, and two others left for non-medical reasons. No patient was lost to analysis. Aside from the gastrointestinal irritability, no indications of toxicity were found. The study measured HIV RNA by polymerase chain reaction (PCR). It also measured p24 antigen, an older test of viral activity. In addition, T-helper count and percent, CD8 count and percent, complete blood count with differential, and some blood- chemistry values, were recorded throughout the trial. The primary indicator of viral load -- HIV RNA in the blood, as measured by quantitative PCR -- is presented in the tables and charts below. Table 1 shows the raw data on HIV RNA for all of the patients in this study (except for the one who dropped out after two days). Also, the baseline T-helper count for each patient is shown. Even a casual look at this table suggests that those with high T-helper counts appear to be responding better than others to the treatment. Note that the charts below (Figure 1 through Figure 3) can all be reproduced from Table I, with no additional information required. Figure 1 shows the HIV RNA data graphically. Also, for each time point, the median RNA value at that time, and the number of patients in that median, are shown below the chart. Notice that there is a substantial spread of HIV RNA values at baseline (week 0) and at week 2. But later (with the possible exception of week 8, which is discussed separately), the pattern is that the most of the values are clustered at the low end of the scale -- often clustered so tightly that the separate lines cannot be distinguished on the graph. Besides these low values, there are a few "outliers," very high values which are entirely different from the rest. We do not know what these high values represent; some could be laboratory errors. [Note: In these graphs (Figure 1 through Figure 3), a point by itself only means that the data points adjacent to it are missing, so there is no line connecting them.] At week 8, the median is high, about where it was at baseline. But, as one can verify from the data in Table 1, a change of a single value would have made the median more than six times lower. The data at week 8 shows a very unusual distribution, with six values under 1,000, two values which are both 3900, and the other nine values beginning at 25,000. If laboratory error accounts for a single one of these high values at week 8, the medians would show a clear antiviral effect; even as it is, the medians still suggest an antiviral effect. And this is with all data included, even from those patients who had opportunistic infections, which are likely to greatly raise the level of HIV RNA. Note that no one dropped out of the study until the week 8 data (there is one missing value at week 4, but this person did not drop out at that time). Only one participant had dropped out by week 8; and three more dropped out by week 12. A low dropout rate is important, because those who are doing poorly in a trial are the most likely to leave; this creates a selection bias, which can make a drug look good even if it really does nothing. With this study, a close look at the data shows that the dropouts could not have affected the medians very much, even through week 20, no matter how high their HIV RNA values might have been. Figure 2 shows the HIV RNA for patients who completed the trial without an opportunistic infection. Here the antiviral effect looks very clear, with the median viral load showing a drop of 20-fold or more between weeks four and 12. At weeks 16 and 20 the medians have climbed, but they are still several times lower than when the trial began. This suggests that the antiviral effect may be temporary, with viral load rising again by sixteen weeks. Figure 2 must be viewed with caution, however, because of the likelihood of selection bias. Those who stayed with the study to the end (and therefore were counted in Figure 2) would be likely to be those who were doing well. Therefore, the results shown in Figure 2 are likely to be too optimistic. Figure 3 shows that patients with less advanced HIV infection seem to respond better to the treatment (by having a larger drop in viral load) than the group as a whole. It shows the changes in HIV RNA for those patients whose T-helper count at entry to the study was in the upper half of the group. This turns out to be those with a T-helper count over 100. The medians do show a good antiviral response in this group. Each median is based on a small number of data points; but there is a clear pattern, with the medians being much higher at baseline and at week 2 than later. Figure 3 is important because it has less opportunity for selection bias than Figure 2. We deliberately selected the most healthy patients (at enrollment) for Figure 3; this is a legitimate choice, as the trial could have made the same selection through its inclusion criteria, and Figure 3 shows what would have happened if it did. But (except for a few dropouts near the end of the trial), Figure 3 avoids the major potential bias of Figure 2 -- the retrospective elimination of some patients who turned out to do poorly (a choice which could not possibly have been made at the time the trial began). The fact that Figure 3 shows a substantial drop in HIV RNA after week 4 provides reassurance that the antiviral effect is real. Figure 3 is also reassuring in that it is hard to imagine any laboratory bias that could cause those with higher T-helper counts at study entry to show more improvement than those with lower counts. Figure 3 also suggests that future curcumin trials might find better results in persons with higher T-helper counts. Discussion and Commentary The results of this trial could be interpreted differently. Because of the wide variability in the data, and the lack of confirmation of antiviral activity by p24 antigen tests, one could conclude that the possible anti-HIV effect of curcumin in people has not been shown. The absence of p24 antigen reduction is surprising, since it was anecdotal reports of just such an effect, completely unexpected and unlikely to have been due to chance, that led to the curcumin trial in the first place. Some uncertainty will remain until other studies confirm or contradict these results. Meanwhile, we note that the HIV RNA reduction was seen despite the fact that a number of circumstances probably made the response lower than it otherwise would have been. First, this trial deliberately recruited persons with more advanced HIV disease, in order to get enough viral load for the p24 antigen test to measure. The data suggests that those with less advanced HIV infection might have responded better. (See discussion on viral suppression, below.) Also, four of the 18 volunteers in this trial had opportunistic infections -- which can greatly increase the HIV viral load, by causing immune activation, which leads to the growth of HIV. In addition, ten of the 18 volunteers received their flu shots during the trial. This probably affected the data; at least two research groups have reported that the immune activation caused by flu shots can temporarily raise the level of HIV RNA. Four patients received flu shots within three weeks of a measurement of HIV RNA, and all of them showed large increases -- about 10-fold for two of the four. This probably made the antiviral response to the treatment appear less than it really was. (Patient 7 received a flu shot one week before the blood draw which showed a very high value at week 8, contributing to the unusual data for week 8, which was discussed above.) How do these results compare to what is known about other antivirals? Definitive figures are hard to obtain, since testing for HIV RNA is still experimental and fairly new; there is much variation within each test, and between the different tests. But it is generally believed that AZT will produce about a one log reduction (10-fold reduction) of viral load as measured by HIV RNA. The best viral suppression so far has been with some of the new protease inhibitors, which can temporarily produce a reduction of viral load by two to three logs (about 100-fold to 1000-fold). New information is suggesting that even persons with very advanced HIV disease (for example, with a T-helper count under 10) do show immune recovery and clinical benefit, if the virus can be suppressed enough. (At this time, unfortunately, that result can only be achieved temporarily, since HIV develops resistance to the drugs. This is why it is so important to test new drug combinations, such as one or more protease inhibitors together with other drugs; in other diseases, such as tuberculosis and certain cancers, combinations of several drugs with different mechanisms of action have been successful in overcoming major problems of drug resistance. For the same reason, it is also important to test LTR inhibitors -- an approach not accepted at this time, nor even widely understood, in the AIDS research mainstream. If this kind of treatment works, it could become an important part of drug combinations.) It might not matter how the virus is suppressed, as long as it is kept low enough. This is why it is also critically important that better tests for viral load or activity become available for clinical practice. Then physicians will be able to tell quickly if a treatment regimen is working, or if it needs to be changed. The SEARCH Alliance trial fits into this picture by showing the potential for developing an entirely new class of treatments -- drugs which target the LTR of HIV, not to kill the virus but to keep it inactive. Remember that curcumin is the weakest known agent of this class; it is attractive because it is widely available and relatively nontoxic, since it has long been used in food. But it may not be strong enough to help much by itself, especially when HIV disease is already advanced. SEARCH Alliance is currently developing plans to test more powerful LTR inhibitors, such as beta lapachone, CPT-11, or topotecan. Better HIV treatments are urgently needed. And a new kind of treatment would be especially important, by contributing to drug combinations which attack multiple targets of the virus. The SEARCH Alliance curcumin trial has provided the first human data on a new approach to AIDS drug development -- screening for compounds which inhibit the HIV LTR. While much more research is necessary, this trial has already suggested that the approach does work in people. For More Information For more information, contact SEARCH Alliance, 7461 Beverly Blvd., Suite 304, Los Angeles, California, 90036, 213/930-8820. Table I: HIV RNA Data Patient# week2 week4 week8 week12 week16 week20 CD4 baseline (baseline) p01 180 4,000 1 70 5 10 10 344 p02 31,800 120,000 24,000 3,900 40 8,700 137,000 107 p03 86,300 20,800 400 120,000 7,800 27,600 2,700 133 p04 100 450 1 200 80 5 320 181 p05 28,500 13,300 12,400 25,000 530 6,000 3,700 78 p06 31,900 34,600 6,400 3,900 910 3,900 5,800 219 p07 15,000 41,000 14,000 150,000 900 7,000 3,700 15 p08 58,500 12,000 500 960 4,500 2,800 2,600 94 p09 38,400 18,000 200 88 890 9,100 5,000 46 p10 20,600 10,000 500 400 80 8,000 710 116 p11 1,854 61,500 1 270 800 3,000 850 391 p12 55,000 20,000 1 95,600 25,000 68,100 49,000 56 p13 78,400 46,900 16,000 25,200 1,400 88 p14 2,500 15,400 10,000 130,000 8,000 33 p15 13,700 25,000 1,000 83,900 142 p16 21,800 52,100missing 180,000 127 p17 16,000 100,000 11,800 76,100 32 p18 100,000 45,590 25,000 10 ** Figure I Data: [Note: Figure I to Figure III not included] baseline week2 week4 week8 week12 week16 week20 Median 25150 22900 1000 25000 895 6500 3200 Count 18 18 17 17 14 12 12 ** Figure II Data: baseline week2 week4 week8 week12 week16 week20 Median 28500 18000 500 960 800 6000 2700 Count 11 11 11 11 11 11 11 ** Figure III Data: baseline week2 week4 week8 week12 week16 week20 Median 20600 25000 450 3900 80 3900 850 Count 9 9 8 9 7 7 7 ***** Resources: Important Articles *** Protease Inhibitors: Current Status "Protease Inhibitors: Overview and Analysis," by Dave Gilden, with assistance from Ben Cheng, Rick Loftus, and others, which appears in the March 1994 GMHC Treatment Issues, uses both published articles and unpublished information from within companies to provide an authoritative status report on the protease inhibitors now in human trials. This class of potential anti-HIV drugs is perhaps the most important group of experimental treatments at the present time, although the current candidates still face major problems -- including the development of resistant strains of HIV, poor oral absorption, and expense and difficulty of manufacture. The article reviews the drugs of Hoffmann-La Roche, Merck, Abbot, Searle (Monsanto), Vertex/Burroughs Wellcome, and Agouron; it also names a number of other companies which are developing protease inhibitors that are not yet in human trials. To obtain a free copy of the March 1994 issue, write to: GMHC, Medical Information, 129 West 20th St., New York, NY 10011. [GMHC Treatment Issues is published 12 times a year; annual subscriptions are available for a suggested donation of $30 individual, $50 physicians and institutions, and $60 foreign; persons with AIDS or HIV can contribute on a sliding scale or obtain a free subscription. You can ask to have your subscription start at the beginning of 1994, and include the special winter 1993/1994 issue on alternative treatments.] Note: Dave Gilden, formerly a San Francisco-based freelance writer who often appeared in AIDS TREATMENT NEWS, recently moved to New York to become editor of GMHC Treatment Issues. *** Drug Development: Interview with Roy Vagelos, Chairman of Merck & Co. "Roy Vagelos on AIDS Research and Drug Development," in the March 1994 GMHC Treatment Issues, examines a number of important areas from the viewpoint of perhaps the most influential person in the pharmaceutical industry. Dr. Vagelos is the chairman of Merck & Co., Inc., and the principal organizer of the Inter- Company Collaboration for AIDS Drug Development. Some quotes: ** "My opinion is that the cure, the real cure of any disease will come from an observation that may be totally unrelated to a focused applied program. And so the best thing that the government could do is to continue to stimulate the off-the-wall types of research that come from people who are not told what do to. And people who develop real insight into following their own leads and their own hunches and are allowed to dream." ** "With AIDS, I am convinced that with persistence and probably a combination of drugs aimed at the enzymes that are now known we will be able to put together something that will control the infection." ** "What concerns me the most is that the Clinton health care reform proposal really puts our kind of work in great jeopardy. What they essentially would like to do is to have us invest and then at the end tell us what the price should be [and] determine what is reasonable. I just cannot see companies investing that kind of resources for that kind of time [with] the government at the end." Dr. Vagelos also discusses how he would focus a national AIDS research program, and what kind of person he would put in charge. He expresses great confidence in Dr. Harold Varmus, the new director of the U.S. National Institutes of Health. He explains the difference between the kinds of focused drug development that pharmaceutical companies can do well, and the basic research and insight which is more likely to come from government-supported science. The interview appears in the same issue as the protease inhibitor article, reviewed above. To obtain a copy, see the information above. ***** d4T Approval: FDA Advisory Committee Meeting, May 20 The Antiviral Drug Products Advisory Committee, a panel of outside experts convened by the U.S. Food and Drug Administration, will hold a public hearing on whether d4T (generic name stavudine, brand name Zerit) should be given accelerated approval on the basis of currently available data. The hearing, which includes times for public participation, is scheduled for 7:30 a.m. to 4 p.m. on May 20, at the Parklawn Building, conference rooms D and E, 5600 Fishers Lane, Rockville, Maryland. This committee will not make the final decision, but will make a recommendation which is almost always followed by the FDA. The committee is likely to vote on its recommendation at the end of the meeting that day. Our understanding is that the developer, Bristol-Myers Squibb, will be asking for accelerated approval -- approval based mainly on the results of T-helper and viral tests, and given on the condition that additional research continues in order to obtain statistical proof of clinical benefit. Comment We have not seen the data which will be presented at the hearing, and therefore cannot take a position on whether the drug should be approved. Some activists are concerned that the drug may be rejected even if the data is good, due to a more conservative make-up of the committee, and also due to general disappointment with the followup research after accelerated approval of ddC -- even though ddC was developed by a different company. If this happens, the fear is that, in effect, there will be no accelerated-approval mechanism left. Other activists believe that certain possible side effects of d4T, such as sleep disturbances and depression, have not been adequately recorded. They are likely to ask that neuropsychiatric studies of any such effects be required as a condition for accelerated approval. ***** Acyclovir Over the Counter? FDA Hearing, May 19 The Antiviral Drug Products Advisory Committee will hold a public hearing on whether acyclovir should be switched from prescription to over-the-counter status. The hearing is scheduled for May 19 from 8 a.m. to 3 p.m., at the Parklawn Building, conference rooms D and E, 5600 Fishers Lane, Rockville, Maryland. Comment A major concern is that over-the-counter status will allow private and public insurers to refuse to pay for acyclovir, even when it is prescribed by a physician, making access difficult or impossible or some people. The price of the drug is expected to remain high, regardless of its prescription status, until rights to it expire in 1995. ***** AIDS TREATMENT NEWS Volume III Now Available The new bound volume of AIDS TREATMENT NEWS is now available through our office, and will be in bookstores shortly. Unlike our previous two volumes, Volume III is organized by subject, not chronologically. Therefore you can find all the articles on a major topic in one place. There is also a detailed table of contents, and an extensive, professionally compiled 23- page index. And throughout the book there are "January 1994" notes, to inform readers of new information available when the book went to press. (Volume III includes about 80 percent of the material published in AIDS TREATMENT NEWS from May 1991 through December 1993.) Volume III also has a 42-page Resources section, much of which has never been published before in this newsletter or elsewhere. For example, it includes annotated lists of AIDS hotlines for general information, AIDS hotlines for treatment information, other specialized hotlines, AIDS newsletters, medical and healthcare books, how to obtain AIDS treatment information by computer, and lists of organizations; all phone numbers and other information was recently checked. A cross- reference lists AIDS information sources in Cambodian, Cantonese, Creole (Haiti), Dutch, French, German, Japanese, Korean, Laotian, Mandarin, Portuguese, Samoan, Spanish, Tagalog/Filipino, and Vietnamese. The book is likely to be on the shelf in gay/lesbian bookstores, or in other bookstores which have a gay/lesbian shelf; the bookstore price is $14.95. Any bookstore can order the book through its distributor. You can also obtain Volume III from AIDS TREATMENT NEWS; we have it in stock, available immediately. Send $21. (which includes first-class postage and handling) to: AIDS Treatment News, P. O. Box 411256, San Francisco, CA 94141; or you can order by phone, 800/TREAT-1-2, or 415/255-0588. (California residents add $1.08 tax. Orders outside of North America add $14 for air parcel post.) Note: Volume III is now included when you order back issues. For back issues since April 1989, send $95 (California residents add $6.90 tax). This includes volume II, volume III, and all loose issues since volume III. (Volume I, April 1986 through March 1989 and now mostly for historical interest and in limited supply, is available separately for $18, which includes postage and handling.) Also, effective May 5, a copy of volume III will be included with any new subscription at the business/professional-office rate. ***** 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. 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