AIDS TREATMENT NEWS Issue #182, September 3, 1993 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Conocurvone: New Anti-HIV Chemical from Australian "Smoke Bush" DNCB Treatment Today Announcements: Vaccines: San Francisco Conference, Sept. 30 - October 2 Vaccines: Free Public Forum, San Francisco, October 1 National AIDS Update Conference, Oct. 19-23, San Francisco Lymph Node Study Still Open ***** Conocurvone: New Anti-HIV Chemical from Australian "Smoke Bush" by John S. James On August 31, as this issue went to press, the U.S. National Cancer Institute published a request for proposals (from pharmaceutical companies) to develop a new anti-HIV chemical which is generating more than usual interest among those familiar with it. Because of the urgency, applications must be received within two months. This article summarizes the information available so far. "Conocurvone" is the name given by scientists at the U.S. National Cancer Institute to a chemical found in the "smoke bush," a plant which grows only in Western Australia. The NCI collected the plant in 1981 for its program of screening for anti-cancer agents, but found that the plant was ineffective for cancer. The remainder of the sample stayed on the shelf, and was later screened for anti-HIV activity. The New Scientist(1) quoted one of the administrators of the screening program as calling conocurvone "extraordinarily exciting." (Conocurvone should not be confused with castanospermine, a different anti-HIV chemical which is found in another Australian plant.) The first technical information on conocurvone was published July 28, 1993, in the Journal of the American Chemical Society.(2) In laboratory tests, conocurvone was effective in concentrations of 0.02 micromolar in preventing HIV from killing cells. Synthetic and semi-synthetic versions (the latter made from other substances in the plant) worked as well as the natural extract. One chemical relative of conocurvone also appeared to work. It took about 2,500 times the effective anti-HIV concentration to be toxic to the cells in which the virus was being grown. The mechanism of action against HIV is currently unknown, although it is known that the drug does not inhibit either reverse transcriptase or protease, but works in some other way. An August 31, 1993 article in Bioworld Today, a daily biotechnology newsletter delivered by fax, quoted the researcher who collected the plant as estimating that there are 50 million of them in the Gairdner Mountains of Western Australia.(3) While conocurvone can be synthesized without the plant, only small quantities have been made so far; if there are enough plants, extracting the chemical from them would be the fastest way to make supplies available for development. The article quoted Dr. Michael Boyd of the NCI as noting that "news of this discovery is still very fresh," and that Australian scientists are studying the feasibility of harvesting the wild plants. A U.S.-Australia dispute over business arrangements for drug development was also described in the New Scientist article.(1) It reported that Australia refused to sign the standard NCI agreement when asked in 1990. Instead, a separate agreement was negotiated. Australia insisted that an agreement must "build in protection for plants in the wild, include Australian scientists in the research and development, and guarantee a 'fair and equitable' share of any commercial benefits from development of the plant." The agreement was reported in SCRIP World Pharmaceutical News.(4) (One side issue raised by this agreement is that if it becomes a precedent, there might be major delays if less- developed countries insist on building their own laboratories and training local scientists before drug-development proceeds. This is not a problem in Western Australia, which already has the world's leading scientific expertise on the smoke bush. The NCI screening program has also discovered potentially important anti-HIV chemicals in three other plants -- in Samoa, Sarawak, and Cameroon. Each of these countries appears to be willing to cooperate with the NCI in the development of these compounds.) The New Scientist article quoted a representative of the Western Australian government, who was worried about "poaching," as warning that components of the plant could be toxic. (It should also be emphasized that only laboratory anti-HIV activity has been demonstrated, and that no toxicological tests in animals have been conducted yet. Also, it is not certain which of the several species of smoke bush contains significant amounts of conocurvone, or which part of the plant contains the chemical.) The August 31 Federal Register published a detailed notice from the National Cancer Institute soliciting proposals for development of conocurvone(5); these must be received by November 1. Interested companies can get "a summary of conocurvone's anti-HIV activity, its pharmacological properties, and toxicological information" from the National Cancer Institute; the Federal Register notice tells how to do so. Also, companies can get the NCI patent application if they sign a confidentiality agreement. (The patent will be public after it is issued.) The U.S. government will grant an exclusive license to a company which shows that it can develop and commercialize the drug. The company will need to negotiate agreements with Australian and Western Australian government agencies concerning collection and use of the plant material, in order to comply "with all applicable Federal and Australian policies related to biodiversity." References 1. Miller SK and Dayton L. Australia takes tough line on 'HIV plant'. New Scientist. July 3, 1993; page 4. 2. Decosterd LA, Parsons IC, Gustafson KR, and others. Structure, absolute stereochemistry, and synthesis of conocurvone, a potent, novel HIV-inhibitory naphthoquinone trimer from a Conospermum sp. Journal of the American Chemical Society. July 28, 1993; volume 115, pages 6673-6679. 3. Leff DN. NCI offers to license 'intriguing' anti-HIV drug. BioWorld Today. August 31, 1993; volume 4, number 169, page 1. 4. W Australia/NCI 'HIV plant' deal. SCRIP World Pharmaceutical News. July 23, 1993; page 18(1). 5. Opportunity for a license for the preclinical and clinical development of conocurvone as an antiviral agent useful in the treatment of acquired immunodeficiency syndrome (AIDS). Federal Register. August 31, 1993; pages 45902-45903. ***** DNCB Treatment Today by Dave Gilden [Note: The following article is one of the longest to appear in AIDS TREATMENT NEWS. We publish it not because of any judgment about the value of DNCB in treatment of HIV disease, but because a number of people are now making decisions about whether or not to use this controversial treatment, and they need information. Seven years ago AIDS TREATMENT NEWS published an in-depth article on DNCB (chemical name dinitrochlorobenzene, a chemical which is painted on a small patch of skin and causes a reaction much like poison oak -- see issue #14, September 26, 1986). At that time the "guerrilla clinics" that dispensed DNCB were a national news story, and probably hundreds -- perhaps thousands -- of people with AIDS or HIV were using the treatment. Later, almost everyone abandoned it; for years there seem to have been no more than a few dozen people (and perhaps fewer) using it anywhere for HIV or related conditions. But during the period of early enthusiasm there were commendable efforts to get DNCB studied scientifically. These efforts were frustrated by the all-too-familiar obstacles and delays which have impeded everything that has happened in AIDS treatment development. But despite the obstacles, and after much hard work, a small, limited study did get off the ground. Recently, years later, its results were published. While scientists see this data as preliminary and suggestive at best, the published paper has provided a focus for a handful of activists, mostly in San Francisco, to promote DNCB with relentless enthusiasm, often suggesting that people stop other treatments which their physicians have recommended. Because of the gloom about treatment prevailing at this time, and because the DNCB advocates have media access and skills, and because few have put forward opposing views, these advocates are influencing the treatment decisions of an increasing number of people. Healing Alternatives Foundation (the San Francisco AIDS buyer's club) reports selling 55 DNCB starter kits a week, both directly and through mail order; some other groups also distribute DNCB, but we do not know how much. The following article is based on hundreds of pages of documentation, interviews with 15 users of DNCB, and additional interviews with researchers, activists, and physicians. AIDS writer Dave Gilden started with no preconceived conclusion about whether or not DNCB is useful. He finished with no final answer, but with a strong impression of how thin the evidence is. JSJ] * * * Since AIDS TREATMENT NEWS reported on DNCB seven years ago, public interest had largely disappeared, but now it is on the rise again. One man, who works in the office of a physician specializing in HIV and just obtained the substance for his lover, commented, "My lover's helper T-cells are down to seven. What we have right now has helped but isn't going anywhere. We have used everything out there, and we need more drugs." Because interest is now high in the community, and DNCB has a number of enthusiasts who promote it, AIDS TREATMENT NEWS undertook an extensive investigation to examine the existing evidence that it might or might not be beneficial. We started with an open mind and used several different approaches, interviewing researchers, practicing physicians, and people with HIV. Despite the reams of documentation issued by DNCB's supporters, in the end we could find little to substantiate this chemical's effect in HIV. But anecdotal reports of long-term stabilization in people using DNCB, especially in combination with other treatments, mean that this approach cannot be dismissed out of hand. And even if DNCB turns out to be ineffective in most people, it may point the way to other, more broadly beneficial compounds with similar modes of action. Background DNCB is a very powerful stimulator of a skin immune response known as delayed-type hypersensitivity. When dissolved in acetone and painted on a small area of the skin, it causes a rash that peaks a day or so after application. After penetrating the skin, DNCB combines with cell surface molecules, causing an immune response as if foreign cells were present. Virtually everyone with an intact immune system eventually can be sensitized to DNCB after repeated applications, and so can most people with AIDS. People react to DNCB in a very similar manner as they do to poison oak or poison ivy. Delayed-type hypersensitivity reactions involve the branch of the immune system known as cell-mediated immunity. Certain white blood cells called cytotoxic lymphocytes (as well as activated macrophages) are the main kinds of cells which produce this response. (Cytotoxic lymphocytes are among the cells with CD8 receptors on their surface, as distinguished from T-helper cells, which have CD4 receptors.) For the purposes of this article, there is no reason to go too deeply into the theory behind DNCB. Suffice it to say that it is used in hopes of increasing the body's systemic cell-mediated immune defense against HIV. DNCB's use as an AIDS treatment was first proposed by L. Bruce Mills, M.D., a dermatologist and researcher who learned of its use for treating certain warts in children, while he had been working at Stanford University. Treating just a small patch of skin could cause the warts to disappear all over the body -- clearly by provoking a systemic immune response, not only the local rash caused by DNCB in the area being treated. Dr. Mills published his experience treating 26 people with AIDS or ARC in 1986.(1) Ensuing articles in the Advocate and other publications helped spread the news. But after months of publicity and widespread use of DNCB, community interest almost disappeared for several years. The Revival, the Data, and the Doubts Interest in DNCB has revived this spring, largely due to the efforts of journalist Charles Caulfield; his articles in the gay newspaper San Francisco Sentinel and his presentations around the country described an apparent reversal in his disease progression after using DNCB since July 1992. Caulfield reports that his T-helper cell count continued to decline (after he started DNCB), then went back up within months from a low 140 to 490; and, correspondingly, his absolute CD8 count went from 400 to 1190 during the same period. Clinical symptoms, such as thrush and diarrhea, disappeared. Caulfield for years had been taking oral acemannan (an aloe vera plant extract that is a purported immune stimulant), which he credited with keeping him disease-free after seven major opportunistic illnesses five to ten years ago. For the first six months on DNCB, Caulfield also self-administered injectable acemannan; we will discuss combination therapies below. Although Caulfield has been quoted as saying that DNCB (plus acemannan) has virtually eliminated his AIDS,(2) in an interview with us he confined himself to terming DNCB, "a permanent general prophylaxis." Most of Caulfield's documentation of his personal success with DNCB comes from a lymph node removal performed last February, as part of the well-known series of biopsies to investigate HIV pathogenesis at NIH's Laboratory of Immunoregulation (directed by Anthony Fauci, M.D.).(3) Our examination of those biopsy results, which Caulfield has distributed, indicates a picture that is not so optimistic. It is clear that the lymph node architecture is seriously eroded, as is typical of people with lengthy HIV infection, and there continues to be a large number of HIV-infected cells in the nodes and bloodstream. On the other hand, the lymph nodes retain their ability to trap considerable amounts of HIV particles with their follicular dendritic cells, even though these cells no longer exist in an organized tissue. Cells that take part in cell-mediated immunity also still exist in large numbers, but their capacity to mount a response to foreign protein is diminished. At our press time, Caulfield had returned to the NIH for a second biopsy, which should give an indication of the trend in his disease process -- whether he is improving, worsening or stable. It will also indicate how representative the first lymph node was. The NIH has also examined a lymph node from two other DNCB users. Results are not yet available for the second of these biopsies, but the first reveals a picture similar to Caulfield's, although better. Immune cell counts were higher and HIV levels lower. Once again, a large number of follicular dendritic cells remained, although the structure of the node was considerably degenerated. This result came from one of the founders of the DNCB "guerrilla clinic" movement in the 1980s, who is once again active in distributing the chemical. He told us that his T- helper cell count had fallen to 70 three years ago. He then resumed using DNCB after several years hiatus during which he was on AZT. At the time of the lymph node biopsy his T-helper cell count was up to 779. "They told me at the NIH that this is the closest thing to a cure they've seen," he happily related. Dr. Fauci mentioned DNCB as a treatment strategy worth investigating at this June's International Conference on AIDS in Berlin. We talked on the telephone with him to get a better sense of his interest in DNCB as well as his appraisal of his lab's results so far. Dr. Fauci stated that he understood he was being misquoted in the community. Fauci, who also oversees AIDS research for the entire NIH, told AIDS TREATMENT NEWS, "We did lymph node biopsies on people without immune modulation, and now we want to study patients who are taking immune stimulants. DNCB is one among many such substances. One of our patients was on DNCB and said it turned him around. He told us about other people taking it, so now we're looking at them. When people have a positive experience, it makes a drug interesting, although such experiences happen with many drugs that ultimately don't pan out." On the subject of the lymph nodes, Fauci, as well as Giuseppe Pantaleo, M.D., another major figure at the Laboratory of Immunoregulation, were adamant that you cannot tell anything, good or bad, from one or two lymph node biopsies. Said Fauci about the results of the two biopsies, "I can't comment until I have a firm scientific finding, which may take another ten to thirty biopsies, depending on the magnitude of DNCB's effect. But I want to make it clear that I'm not damning DNCB, nor am I endorsing it." More new data on DNCB was published this spring by Raphael Stricker, M.D., and colleagues in three presentations(4,5,6). The first was a report on a 20-person "pilot study" sponsored by the California Pacific Medical Center (where Dr. Stricker was working), Project Inform, and the Elizabeth Reed Taylor Foundation.(4) One of the report's co-authors is William Epstein, M.D., an expert on contact dermatitis who has worked with DNCB since the nineteen fifties. Dr. Epstein advised the study investigators on safe, proper application of the chemical. Almost two years ago Dr. Epstein told this writer, "I can't say whether DNCB is having any effect in AIDS. If so, it's not an obvious effect." Now he thinks, "The study results look interesting. It looks like there is some value, and we know DNCB won't make the disease worse. But it is very hard to show an immune modulator's benefit. We need to follow up with many more subjects and more time." AIDS TREATMENT NEWS at this point has contacted five of the paper's co-authors. Strangely, only Drs. Stricker and Epstein wished to associate themselves with the results; two of the others refused to comment on the record at all. Dobri Kiprov, M.D., a co-author and Dr. Stricker's superior at California Pacific, told us, "I personally feel that the results do not justify any excitement or further workI The study was published against my judgment." (Project Inform, a principal sponsor of the study, states that it was not given the opportunity to review the data prior to publication.) A glance at the data shows good reason for doubt. Although 20 people started the trial, two do not appear in the published data for unstated reasons. Another two volunteers dropped out. Other than the fact that volunteers had not been diagnosed with AIDS, and had T-helper cell counts of from 100 to 500 (average: 347), no information is presented as to the study participants' health. There is no control population for comparison. Average values for "pre-DNCB" and "post-DNCB" data were presented for the sixteen continuing participants, who were observed for a period of three to twenty months. Since the two averages are calculated from measurements taken at greatly different points in treatment, they are even harder to interpret than usual. In any case, there was no noticeable increase in CD4 (T- helper) cells. While there was a modest 20 percent average gain in CD8 counts, none of that increase occurred among cytotoxic lymphocytes, which remained stable. (There was, though, no indication that DNCB negatively affected anyone's counts.) In the words of a statistician of our acquaintance, "You're down to the anecdotal level here. Unless there was a dramatic difference, you probably need more people to achieve anything that has real significance." As Dr. Epstein pointed out, trials of immune modulators for treating HIV/AIDS are notoriously hard to evaluate. Measuring subpopulations of immune system cells is difficult because the tests are inaccurate. And even if you can get accurate counts, their meaning is hard to analyze because they tell little about functional improvement in the immune system. Is any of the new activity aimed against HIV? Dr. Stricker tried to resolve this issue by using a new test, known as quantitative PCR, to measure how HIV levels in the blood changed after DNCB treatment began. Unfortunately, the company doing the testing, which was using its own private version of quantitative PCR, pulled out of the project after analyzing only a few early samples from just 11 of the volunteers, including the two dropouts. The paucity in the PCR data was not mentioned in the published article. The company involved, HRI Research of Concord, California, would not even let its name be associated with the data. When contacted, an official of the company refused to comment on the reasons for this rupture, except to say that the company had other, more pressing work to do and that the DNCB situation had become intensely "political." Quantitative PCR data right now is still more controversial than cell subset measurements. There is first of all the question of whether the test is accurate; even if it is, the reason for fluctuations in viral load is hard to understand. And even if you tested many subjects many times, it is not clear how much of a change in viral load is needed to make a difference in symptoms. On the surface, the published PCR data looked at least promising: The overall average viral load decreased by 38 percent among the nine in the study who both continued on DNCB and had blood samples tested. But because of all the questions surrounding these figures, AIDS TREATMENT NEWS obtained the charts for all the individual study participants in whom virus load was measured by PCR. It turns out that the figures for two people, whose initial PCR results showed exceptionally high blood levels of HIV, seriously skewed the published overall averages. These two were only evaluated once by PCR after the original, pre-treatment measurement. The only post-treatment measurements were carried out on samples taken just two months after the original ones, and the results were two- and four-fold less than the first time around. Without more data points to establish a trend, the reasons for these two larger drops can only be speculated. The observed declines could merely reflect faulty test results, or something else in the volunteer's lives besides DNCB. Whatever the reason for the two anomalous cases, eliminating them from the DNCB data seriously weakens the quantitative PCR results. Dr. Stricker admits that the study data is weak. "We have lots of frozen samples waiting for PCR testing," he lamented, "This was just a pilot study with no controls, but the data looks good, especially when you compare the compliant and noncompliant participants. DNCB is an attempt to boost the immune system to control HIV. It is a very crude technique, but it is the only thing we have." In a poster at the Berlin AIDS Conference,(5) Dr. Stricker presented "follow-up" data on 24 volunteers (some of them apparently new people) involved in the DNCB trial. The average length of observation is longer, but the results are similar to the original paper in Immunology Letters. So are the problems. This time there is no quantitative PCR data to sort out. On the other hand, seven "noncompliant" subjects, really those who chose to drop out of the study, were sorted out and contrasted with the volunteers continuing with DNCB. The problem here is the classic one of self-selection. Those who happen to do worse tend to quit a therapy, while those who are doing better, for whatever reason, tend to continue. One indicative sign is that the "noncompliants" started the trial with considerably fewer cytotoxic lymphocytes than the continuing participants. Considering the noncompliants apart from the compliants is not a fair way to judge a therapy's efficacy. (Note that the published abstract of the poster presentation -- the poster was presented at the Berlin conference, but has not yet been published -- does not separate the compliant and non-compliant. It shows that the average CD4 count dropped from 353 to 251 -- hardly a positive result for DNCB.) More Personal Experience Billi Goldberg, a San Francisco DNCB treatment activist who assisted in analyzing the trial results, replies to criticisms of Dr. Stricker's study by saying, "We ran the trial on a shoestring and we got published. I just want to know whether people on DNCB lived, and I let other people argue about trials." Dr. Stricker himself says, "The study participants are all doing very well after three years. [Actually, the average follow up time at this point is only about 18 months, Stricker later conceded.] The poster at Berlin received a lot of attention from NIH scientists like Fauci and Pantaleo as well as from Jonas Salk. I would like to continue the study for five years." Unfortunately, Dr. Stricker and California Pacific Medical Center recently came to a parting of ways, reportedly at least partly due to the DNCB trial, and the study is in limbo. Be that as it may, Stricker continues, "I know 30 people around the country who have used DNCB for up to seven years and are doing very well. Some of them were diagnosed with AIDS four years ago." To be fair, other groups also have had trouble demonstrating the efficacy of their proposed immune modulators (see, for example, AIDS TREATMENT NEWS #168 on thymopentin, a thymus hormone derivative). Given the lack of any accepted way of proving such substances, perhaps, for the present, we can only look at personal experiences with DNCB to see how individuals are faring on the treatment. If some people feel DNCB has helped them, then DNCB may be promising for at least a certain subgroup. Indeed, Dr. Stricker followed this method last spring, in a brief article(6) which presented a table on "clinical and laboratory features of ten long-time DNCB users." Six of the ten became infected with HIV in 1984 and 1985, and three in 1982; one was reportedly infected in 1979. (Several of these dates were established by testing frozen blood samples.) The ten started on DNCB between 1986 and 1989. Using DNCB or not, there are a large number of people who survive HIV, even with an AIDS diagnosis. This writer has met dozens of people who have been stable for three years or more with low T-helper cell counts, and hardly any are on DNCB. As for statistics, Susan Buchbinder, M.D., who is Chief of Research at the AIDS Office of the San Francisco Health Department, reports that in an HIV-positive group she is following (the San Francisco City Clinic Cohort), eight percent of the members have lived for ten years or more with HIV while retaining normal or near normal T-helper counts.(7) And only half the group members experience an AIDS-defining illness in their first decade with HIV. (See AIDS TREATMENT NEWS # 178, "Berlin: Long-Term Survival Studies Suggest New Treatment Strategies," for background on possible reasons for long-term survival.) With this in mind, the table presented by Dr. Stricker shows a group of remarkable but not exceptional people. Seven of the ten have low T-helper (CD4) counts, ranging from 30 to 350. For nine of the ten, CD8 counts were within the usual range for people with HIV (1,000 or somewhat above except in late-stage disease.) Of the three stellar performers, one is listed as also taking isoprinosine and another is on compound Q. But one table showing undated post-DNCB immune cell counts does not say much one way or the other. Perhaps these people experienced dramatic improvements in their health after starting DNCB. Maybe their physical condition is much better than their helper-T cell numbers indicate. Because of these lingering questions, AIDS TREATMENT NEWS interviewed 15 people currently using DNCB. Eight have been applying the substance for six months or less, but seven were long-time users of up to seven years. At least four of these seven were among the ten included in Dr. Stricker's published note. Since these were committed users by and large, it was to be expected that negative impressions would be few. Typical of these people's sentiment was the statement of one man: "The further I go from western medicine, the better I feel." Several people mentioned how empowering the weekly act of applying DNCB was. A common comment was that DNCB increased energy levels. Also, many people felt that their symptoms cleared up faster after starting DNCB, especially those involving the skin, mouth and vagina. The most frequent negative effect was scarring and persistent rashes from the DNCB application. One person said he has constant welts on all the recent patches of skin where he painted DNCB. This person further suspected that DNCB was making him "hyperallergic" to other things as well, such as chlorinated pools and antibiotics, both of which now give him hive-like rashes, although they never did before. This person, who was using DNCB for six months until he recently stopped, also saw his CD4 and CD8 cell counts, low to begin with, drop by 60 percent. Most of the newer users haven't yet seen much change in blood counts, except for one man whose CD8 count went up from 700 to 1100. The long-time DNCB users we contacted claimed they were able to minimize DNCB rashes by learning the concentration and amount to apply that produced only a small, temporary red spot. Other than that, their reports were mixed. Four of the seven have gone for years without severe symptoms, but one is now seriously ill with cryptosporidium, an intestinal parasite; and in another, blood counts are dropping. A fifth man came down with lymphoma in 1990 while on DNCB, but is generally healthy now. He believes an improved method of applying DNCB has helped to preserve his health since this episode. However, he also had a course of chemotherapy and then was treated with acupuncture for three years. He also takes megadoses of various vitamins. This use of multiple treatment strategies is typical. Only four of those interviewed (two short-time and two long-time users) are at present on an exclusive DNCB regimen. Chinese herbs are popular among this group, as are antioxidants (such as NAC, beta carotene, and vitamin C), megavitamins, and coenzyme Q. In addition, many are taking co-trimoxazole (Bactrim, Septra) to prevent pneumocystis pneumonia, plus a variety of antibiotics to treat lesser infections. One person who has adopted a multifaceted approach is long- time DNCB user Thomas Avena. He said, "When I work with my health, my cell counts go up. I confront my level of fear, meditate, take walks, and concentrate on my diet. Meditation is work, but it gives me tremendous benefit. Every illness I have seems activated by frustration and stress." Larry Janssen, who started DNCB last winter, commented, "I'm saying that DNCB is part of the portfolio of options, it's not the answer. Everybody wants to be told what to do, but you have to figure out what works for you." This seemed to us to be as succinct a summary of our interviewees' experience as anything we could say. DNCB in Real Life Talk of combination therapies bothers Billi Goldberg, a retired civil engineer who at the moment is the main popular theorist of DNCB. (Several of the DNCB users we interviewed said that they were convinced to start on the chemical because they were impressed by the writings of Goldberg on the science behind DNCB.) Goldberg has based a case for DNCB on the work of Drs. Mario Clerici and Gene Shearer at the National Cancer Institute and others on the "Th1-Th2 switch" -- a possible suppression of cell-mediated immunity-- as an indicator progression to AIDS.(8) They argue that the decline in cell-mediated immunity, orchestrated by the Th1 subset of T-helper cells, results from an increase in antibody production, which is governed by the activity of Th2 T-helper cells. These two T-helper cell subsets tend to suppress each other, and a predominantly Th2 defense against HIV seems less effective than a predominantly Th1, cell-mediated response. According to Goldberg, "DNCB is not the answer, but a step in the right direction. It will boost cell-mediated immunity and control intracellular infections, which are most AIDS opportunistic infections. The people it works best in are those who get off all drugs except PCP prophylaxis. They must be treated for the other diseases should they appear. People who are asymptomatic and get off herbs, which increase antibodies, and high-dose vitamin C, which suppresses lymphocyte proliferation, they do well." Although DNCB is supposed to counter the immune-suppressing effects of HIV and help control opportunistic infections, Goldberg thinks that most major medications used in AIDS have white blood cell toxicity that can interfere with DNCB's effect -- either by impeding the cell-mediated immune response directly or by promoting the Th2 immune mode that discourages cell-mediated immunity. The only exception, in his view, is temporary use of acemannan as a complementary salvage therapy in people whose absolute CD8 counts have fallen below 400. (Isoprinosine is another possibility.) DNCB, meanwhile, is to be taken for life. There is mounting evidence from long-term survivor studies, and elsewhere, that some kind of cell-mediated immunity is crucial to maintaining health during HIV infection (again, see AIDS TREATMENT NEWS # 178 on long-term survivors). But nearly everybody with HIV (including people with high CD8 counts) also produces anti-HIV antibodies -- that is why they test positive on the HIV blood test. Shearer and Clerici are not nearly as rigid on the subject as Goldberg. Dr. Shearer explained over the telephone, "All we're certain about is that cell-mediated immunity is important. It's possible to have both cell-mediated and antibody immunity in HIV. The distinctions are fuzzy. The question is how to optimize the immune balance, and we don't know how to extrapolate from our experiments with in vitro cell clones." One of the pioneers of lymph node studies in HIV is Cecil Fox, Ph.D., who is president of Molecular Histology Laboratories. Dr. Fox is collaborating with the NIH team in the current lymph node study. Dr. Fox told AIDS TREATMENT NEWS, "People who think they are going to meet the challenges of this disease with one drug are fooling themselves. This is a multifactorial disease going on for a decade or two of a human's life. One drug is not going to be effective for all that time. In the future there will be an HIV treatment armamentarium. Different treatment combinations for different phases will be appropriate, with therapy changing from year to year depending on the person's needs." Fox predicted that an effective regimen would be available within the next several years. He did not exclude DNCB as a possible candidate for his "armamentarium." A Physician's Experience The physician today with probably the broadest on-going experience with DNCB is David Payne, D.O., of Mesa, Arizona. Dr. Payne started recommending DNCB a year ago and now has 150 HIV patients on it. Echoing Dr. Fox, Dr. Payne is trying DNCB as part of a combination of medications that evolves according to disease stage. Among the other treatments Dr. Payne suggests are hypericin and curcumin as antivirals, and blood root (sanguinaria), which may work as an immune stimulant. Some of his patients also are taking nucleoside analogs such as AZT. About DNCB, Dr. Payne observes, "The feeling I have is that it stabilizes patients a lot and increases the effectiveness of other things. I have seen some improvements, but I certainly have seen patients whose illness has continued to progress. But judging by DNCB's effect on warts and molluscum contagiosum [both viral infections of the skin], something is happening. After a few months on DNCB, these clear up dramatically. For molluscum, we had tried everything under the sun in some patients without success." Dr. Payne is careful about the danger of long-lasting welts from DNCB, which, he says, can last for weeks if you are not careful about the amount you apply. Payne says, "You have to fiddle around with the dose. I tell my patients to check every few hours after applying and wash off the spot if blistering occurs." Another, more conservative, physician with a few patients on DNCB was not so sure that harmful eruptions can be prevented. He says, "I see people getting horrible welts. One had them all over his body. He had a separate itchy rash, perhaps indicating DNCB triggered a hyperactivity to something else." Plans for Trials As Dr. Payne noted, it is difficult to separate out DNCB's effect from other elements of a combined regimen. But if it is to be used with any assurance, it has to be tested in the ways it is used in real life, where the chemical will interact with countless physical and chemical factors. One attempt to do this is shaping up in Portland, Oregon, where Bruce Bradley, a volunteer at the Institute for Traditional Medicine and Preventive Health Care, is working with Mark Loveless, M.D., of Oregon Health Sciences University, to develop a year-long trial of DNCB. The 60 participants will come from ITM's Wellness Program, which administers herbs and acupuncture to people with HIV. ITM's clients also take a variety of popular treatments, such as antioxidants, on their own. They will not be expected to give up any of these during the trial, although an attempt will be made to standardize dosages. Thirty people will start on DNCB at the beginning of the trial, and 30 people six months later, to provide a means for assessing DNCB's influence within the context of the other treatments. Only the investigators will not know who are in early and late groups. "Blinding" the researchers will help ensure an objective evaluation of the data, most of which will be collected during normal clinic visits. In addition, Dr. Fauci's lab plans to perform lymph node biopsies on members of the early- and delayed-DNCB groups, as part of its continuing study of node deterioration on HIV/AIDS. Ten or more biopsies will be performed at the start of the DNCB trial to provide baseline data, and at six months to document disease progression in the people on DNCB and in those not applying it. The final results probably will not be ready for two years. In San Francisco and San Diego, small community groups are collecting data on DNCB plus acemannan in a more informal, observational basis. Another trial is slowly taking shape in Toronto. Plans are to involve 150 people recruited through the Community Research Initiative of Toronto. Until there is some solid information on effectiveness, people should know that, reports of DNCB's enthusiasts aside, there is little to indicate who might benefit from DNCB and under what circumstances. The treatment is cheap and appears largely safe, at least if used under expert supervision, but you take it at your own risk. It would be foolhardy to give up other treatments and put all your hopes in this one. References 1. Mills LB. Stimulation of T-cellular immunity by cutaneous application of dinitrochlorobenzene. Journal of the American Academy of Dermatology. June 1986; volume 14 number 6, pages 1089-1090. 2. Antoine, R. AIDS researcher says treatment has cured him. Texas Triangle. August 4, 1993. 3. Panteleo G, Graziosi C, Demarest JF, and others. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. March 25 1993; volume 362, pages 355-358. 4. Stricker RB, Zhu YS, Elswood BF, and others. Pilot study of topical dinitrochlorobenzene (DNCB) in human immunodeficiency virus infection. Immunology Letters. April 1993; volume 36 number 1, pages 1-6. 5. Stricker RB, Elswood BF, Goldberg B, and others. Analysis of lymphocyte subsets in HIV-infected patients treated with topical dinitrochlorobenzene (DNCB). IXth International Conference on AIDS, Berlin, June 6P11, 1993 [abstract PO-B28- 2140]. 6. Stricker RB and Elswood BF. Topical dinitrochlorobenzene in HIV disease. Journal of the American Academy of Dermatology. May 1993; volume 28, number 5, part 1, pages 796-797. 7. Buchbinder S, Mann D, Louie L, and others. Healthy long- term positives: Genetic cofactors for delayed HIV disease progression. IXth International Conference on AIDS, Berlin, June 6P11, 1993 [abstract WS-B03-2]. 8. Clerici M and Shearer G. A Th1.Th2 switch is a critical step in the etiology of HIV infection. Immunology Today. March 1993; volume 14, number 2, pages 107-111. ***** Announcements ** Vaccines: San Francisco Conference, Sept. 30 - October 2 The First International Conference on Engineered Vaccines for Cancer and AIDS will be held September 30 - October 2, 1993, at The Fairmont Hotel, San Francisco. It is sponsored by the Clinical Research Program at Saint Francis Memorial Hospital. (Also see note below on free public forum, October 1.) Ten sessions are scheduled: Vaccinology; Vectors; Cancer Antigens; AIDS Antigens; Correlates of HIV Immunity; Adjuvants; Animal Models, Cancer Vaccines; Animal Models, AIDS Vaccines; Clinical Trials, Cancer; and Issues in AIDS Vaccine Clinical Trial Design and Implementation. Many of the nation's leading vaccine experts will be speaking. The registration fee is $450. For more information, call Vaccines Conference, 619/565-9921. ** Vaccines: Free Public Forum, San Francisco, October 1 A community forum on AIDS vaccines will be held Friday, October 1, 7:00 p.m., at the UCSF Laurel Heights Conference Room, 3333 California Street, San Francisco. Scheduled speakers include David Chernoff, M.D., Associate Director, Biocine Clinical Research, Chiron Corporation; Patricia Fast, M.D., Ph.D., Chief, Clinical Development, VRDB/Division of AIDS/NIAID; Don Francis, M.D, Medical Monitor for gp120 prophylaxis vaccine program, Genentech; Bonnie Mathieson, Ph.D., Chief, Basic Research Section, Division of AIDS/NIAID; and Robert Schooley, M.D., Head of Division of Infectious Diseases, University of Colorado Health Science Center. Most of them will be in town for the vaccine conference (see announcement above). Brenda Lein of Project Inform, and Mark Bowers of HIVCare (of St. Francis Hospital in San Francisco) and of ACT UP/Golden Gate Treatment Issues Committee, will also participate. This forum is sponsored by HIVCare, Project Inform, ACT UP/Golden Gate, and AIDS TREATMENT NEWS. ** National AIDS Update Conference, Oct. 19-23, San Francisco The 6th National AIDS Update Conference will be held October 19-23, at the San Francisco Civic Center. This is not primarily a research conference (although some new information is usually presented), but a continuing-education training conference for health-care professionals (including physicians, nurses, dentists, pharmacists, program administrators, government and community leaders, hospital service and planning managers, etc.) and persons with HIV/AIDS. It is sponsored by more than 20 organizations, including the American Foundation for AIDS Research, the American Medical Association, the National Association of People with AIDS, and the U.S. Public Health Service. The registration fee is $100 for a person with HIV ($75 before September 10), or $254 general ($195 before September 10). For a preliminary program, or to register, contact KREBS Convention Management Services, San Francisco, phone 415/255- 1297, fax 415/255-8496. ** Lymph Node Study Still Open by David Gilden The U.S. National Institutes of Health lymph node pathogenesis study referred to in the DNCB article in this issue has two parts. One part, which has been filled, is looking at the effect of antiretroviral drugs (AZT and/or ddI) by examining lymph tissue before and after treatment begins. The second branch of the study is focusing on healthy nonprogressors, people who have lived for eight years or more with HIV and retained near-normal T-helper counts. The Immunopathogenesis Section of Dr. Anthony Fauci's Laboratory of Immunoregulation, which is conducting the study, is still looking for about six more such people. The study hopes to identify the correlates of health, to try to define strategies that maintain health. Participants are flown free to the NIH hospital in Bethesda, Maryland, where they will stay for several days. A lymph node will be removed from under the skin in what is described as a "relatively minor" procedure. The operation is performed under local anesthesia. Losing one lymph node is not considered dangerous because each individual has thousands of nodes. Some people may be asked to come back later for a second node removal. Lymph nodes are one of the centers of immune system activity. Earlier parts of the NIH study have revealed previously unsuspected disease processes occurring in the nodes, including a continuously spreading HIV infection (with no period of latency), and the gradual disintegration of the node structure. Tests carried out on the excised node include microscopic examination, quantitative PCR, in-situ hybridization, and other high-tech tests to check the presence of various cell subsets and estimate their rate of infection with HIV. Investigators want to know, for example, whether long-term asymptomatic people with HIV have lymph nodes that resemble those of early-stage or late-stage disease. Entry criteria are not rigid; in fact, the NIH team has recently examined several long-term survivors with very low T-helper counts. Interested volunteers or their physicians can call Oren Cohen, M.D., at 301/496-5509 to see if they qualify, and to make arrangements to enter the study. ***** 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 415/255-4659 fax Editor and Publisher: John S. James Medical Reporters: Jason Heyman John S. James Nancy Solomon 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 1993 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.