AIDS TREATMENT NEWS No. 109 - August 17, 1990
John S. James

For several years a number of physicians have used aspirin or other anti-inflammatory drugs to help patients with AIDS feel better -- especially to relieve fever or diarrhea when these symptoms are unexplained, and in some other cases such as fevers caused by MAI. While aspirin works for these purposes, until recently the treatment of choice was usually indomethacin, a nonsteroidal anti-inflammatory drug (NSAID); the reason for preferring indomethacin is that published information was available, since most of the early research was done with that drug. But new research is now suggesting that aspirin might be better than indomethacin or other NSAIDs. Both provide symptomatic relief from fever and diarrhea, and both reduce synthesis of a certain prostaglandin (see explanation below), which appears to be excessive in persons with AIDS and may make the disease worse. But aspirin might also have an anti-HIV effect which indomethacin does not.

Aside from a small study recruiting now, we know of no clinical trials to find out whether aspirin or similar drugs might have use in AIDS treatment. Without trials, the possibility remains theoretical; it is not known what dose, if any, might be useful.

It may seem impossible that if something as simple as aspirin might have value in treating AIDS, it could have been overlooked. But in fact, that outcome would be most likely. Aspirin is a generic drug, so there is no commercial incentive to run trials. Governments would have incentive to learn about an inexpensive treatment, but Federal research is based on letting scientists decide what they want to study. Usually this is a good policy, but in AIDS it has led to control of most funds by small groups of scientists, whose research interests have been narrowly focused and have been influenced by the availability of funding from pharmaceutical companies. Few private physicians conduct their own research without funding, or use treatments not already accepted as standard of practice and not proven in clinical trials. The essence of the problem here is that no person or office has, or ever has had, overall responsibility for managing government or public-policy response to the epidemic. Therefore when there are hints that a safe and readily available treatment may be useful, it is nobody's job to make sure that those hints are followed up.

Background and Literature Review

Aspirin is considered the prototype of the nonsteroidal anti-inflammatory drugs. These agents work by reducing the synthesis of certain prostaglandins (especially prostaglandin E2), which are part of the inflammatory response. Other drugs which may be similar to aspirin as potential HIV treatments are indomethacin (a prescription drug) and ibuprofen (e.g., Advil), but not acetaminophen (e.g., Tylenol), which is not believed to have the same effect.

Early in the AIDS epidemic, before the discovery of HIV, a number of scientists interested in the pathogenesis (origin and development) of AIDS saw certain inflammatory reactions as part of the disease process. This approach led to a number of laboratory studies, which were later published. Most of these early studies used indomethacin instead of aspirin, probably because the former was a proprietary drug until 1984 (when it became generic). After the announcement of HIV, also in 1984, most research interest focused on it and on nucleoside analogs like AZT; pathogenesis was neglected. Some indomethacin studies were published after 1984, mostly in 1985 or 1986 -- probably reflecting the time required to complete and publish work which was conceived in the earlier era. (But one study published in 1985(1) was funded by the Gay Men's Health Crisis, which would be open to funding research on non-proprietary drugs.)

We have only found one abstract on anti-inflammatory drugs and AIDS or HIV published since 1987. Recent research seems to be preferring aspirin to indomethacin. A small clinical trial of a proprietary aspirin derivative, now recruiting at St. Luke's/Roosevelt Hospital in New York, may provide the first scientific test in humans of whether or not aspirin can reduce HIV activity. (See additional information, below, on this trial.)

A literature search using the Medline computer database found only nine articles or letters about acetylsalicylic acid (aspirin) or indomethacin, that were also about AIDS. The earliest article, in 1984, reported that indomethacin enhanced the proliferation of lymphocytes from gay men with lymphadenopathy(2). (Research on immunological effects of indomethacin, especially in the context of cancer, goes back to the 1970s.) A 1985 article(1) found that the enhanced proliferation of lymphocytes applied only to cells from persons with AIDS or ARC, not to those of normal volunteers; the article suggested that indomethacin might have therapeutic use in treating these diseases. A 1986 paper(3) found two separate immunological impairments in cells of patients with KS and AIDS; both were improved with indomethacin. But a 1987 laboratory study(4) found no difference between the cells of persons with AIDS or ARC vs. controls, in the effect of indomethacin; however, this study only measured production of IL2, a T-cell growth factor, in the indomethacin test.

Letters from two different groups in Spain concerned indomethacin for relief of AIDS symptoms. The first, published in 1986(5), reported experience with six patients with HIV. The first patient had been treated with indomethacin in 1983, due to a wrong diagnosis. This patient had generalized lymphadenopathy, malaise, fever, and severely reduced lymphocyte count; when treated with 150 mg of indomethacin daily, all symptoms disappeared, and they had not returned after three years, during which the treatment was continued. Because of that case, the physicians tried indomethacin in five persons with AIDS; they found no toxicity, and four of the five showed "considerable clinical improvement" after four weeks of indomethacin (the other patient died of pneumocystis). Two of the four successful patients needed doses raised to 75 mg every eight hours for the best results.

The other letter(6) was published in Barcelona in Spanish in 1988. It reported on three patients with AIDS or HIV who were treated with indomethacin. While all three seemed to be helped by the drug, two of them had died, one from a recurrence of pneumocystis, and the other from a recurrence of an unspecified infection.

Also from Spain, a different research group reported to the III International Conference on AIDS in Washington, D. C. in 1987(7) that they found increased levels of prostaglandin E2 (PGE2, believed to inhibit immunological functions and possibly stimulate replication of HIV) in persons with HIV. In HIV positive patients with depressed cell-mediated immunity, the level of PGE2 was ten times higher than normal; high levels of PGE2 correlated significantly with low lymphocyte count, low T- helper count, and impaired response to mitogens; it was also observed to correlate with clinical deterioration. (These observations are significant because both aspirin and indomethacin are known to reduce PGE2 levels in patients.)

In a computer search of tens of thousands of newspaper and wire-service stories, we found only one story mentioning a possible use of aspirin in treating AIDS. An Associated Press report in 1986(8) quoted researchers from the George Washington University Medical Center as suggesting that aspirin might be useful in AIDS and other immunological disorders. Preliminary trials had found that "one to two aspirin tablets daily can triple interferon production and double interleukin output." None of these volunteers were HIV positive, however. (See "Current Research," below, for more information about this work.)

Two earlier studies, in the 1970s, had found antiviral effects of aspirin in tests in animals and in plants(9,10).

Current Research

A laboratory study published this May reported a difference between aspirin and indomethacin in their effect on HIV(11). The same research group had already reported that intestinal mucosal cells from persons with AIDS or HIV, taken by rectal biopsy, would produce p24, a protein of the AIDS virus, during incubation for 48 hours in the laboratory. The new report found that indomethacin failed to change the p24 level, while an aspirin derivative reduced it by half. The researchers speculated that this effect of aspirin might be related to inhibition of the enzyme lipoxygenase.

Based on this result, a small clinical trial now recruiting in New York is testing the aspirin derivative (aminosalicylic acid, brand name Asacol, an experimental drug now in phase III trials) as a treatment for non-specific colonic inflammation in persons with HIV. This aspirin derivative is designed to be poorly absorbed, and formulated to pass through the stomach unchanged, so that it can deliver a very large aspirin dose directly to the intestines. This special form of aspirin is being used in the research in order to allow a clean study design, but it is suspected that ordinary aspirin would work, too.

Perhaps the most interesting result of this study will come later, when the p24 tests are run on the frozen samples. (These tests are usually run together as one batch, to reduce random variation caused by laboratory errors.) This data may provide the first scientific hint on whether aspirin can reduce HIV activity in patients. Later in this article we suggest other trials which could be carried out by community-based research organizations, to answer the question directly, using ordinary aspirin.

For information about a completely different project, we spoke with Dr. Judith Hsia at George Washington University to follow up on the 1986 report on aspirin research, mentioned above. She told us that researchers there are still actively looking at aspirin as an immune modulator; however, none of the volunteers so far have been HIV positive. (One of the scientists in this study, Dr. Allan Goldstein, is also the developer of the HGP-30 AIDS vaccine.)

A 1989 publication from the George Washington group(12) documented large increases in levels of gamma interferon and IL2 in normal volunteers after aspirin treatment. The dose was surprisingly small; 325 mg (one ordinary aspirin tablet) every other day worked much better than one tablet every day, during the one week of the study. Later, volunteers were deliberately infected with a common-cold virus; not surprisingly, the small aspirin dose did not protect them.

In a current study by the same research team, aspirin is being given to elderly mice (elderly so that they would be immune deficient) in order to see if it would make flu vaccine work better. No results are available yet.

Practical Experience: Interviews with Physicians

Joseph Sonnabend, M.D., is a well-known AIDS physician in New York and one of the founders of the Community Research Initiative (CRI), a leading organization in community-based research. Dr. Sonnabend has long been critical of the overemphasis on HIV as the cause of AIDS to the virtual exclusion of other promising research areas such as pathogenesis. He has used anti-inflammatory drugs for years in treating AIDS and related conditions.

In our recent interview, Dr. Sonnabend made the following points:

* He had used indomethacin, because of the experience with it reflected in published literature (reviewed above). Now he uses aspirin instead.

* He has used anti-inflammatory drugs when patients are seriously ill, with recurring fevers not due to opportunistic infections. (Dr. Sonnabend is notably aggressive about prompt diagnosis and treatment of opportunistic diseases; anti-inflammatory drugs must not be used instead of such medical care.) These patients usually take one gram of aspirin (two 500 mg tablets) four times a day.

Continuous use of this high dose is likely to cause stomach ulcers, unless another drug is used to protect the stomach. Dr. Sonnabend uses misoprostol (brand name Cytotec). Another physician we spoke with preferred sucralfate (brand name Carafate) to protect the stomach; he was concerned that misoprostol would reduce stomach acidity so much that the antifungal Nizoral (used by some AIDS patients) would not work. Also, Cytotec is expensive. And it is an abortifaciant, so it cannot be used during pregnancy.

* While there is no scientific proof that aspirin can or cannot slow the progression of AIDS, it is clear that many patients feel much better while on the treatment.

* Enteric-coated aspirin -- and also aspirin suppositories -- are available, and they might be better than the tablets because they avoid direct irritation of the stomach. (They would not eliminate the need for a drug to protect the stomach, however, because high-dose aspirin can cause ulcers through systemic effects, even without direct contact with the stomach.)

For another view, we called James Campbell, M.D., in San Francisco. He was aware of the research interest in anti-inflammatory drugs as immune modulators, but added that they have been used most extensively to help patients feel better: to suppress fevers caused by MAI, for example, or to reduce diarrhea when it is unexplained. With large doses there can be toxicity to the kidney and to the stomach.

Anecdotal Reports

We have heard four anecdotal reports relevant to aspirin as a component of AIDS or HIV treatment.

One person with AIDS had fever most of the time, and noticed that he felt dramatically better when using aspirin. His physician warned that he should stop, because of the danger of stomach ulcers. We lost touch with this person over a year ago, and do not know what treatment he used, or with what result.

Two other people had taken aspirin daily for years, for reasons unrelated to AIDS, and both had done unexpectedly well in remaining alive and healthy. One takes two aspirin tablets every night; we do not know what dose the other uses.

One physician with AIDS told us he tried anti-inflammatory drugs, without apparent value. He had used both NSAIDs and aspirin.

Precautions

Continuous use of large doses of aspirin can be dangerous, and it is important to discuss the risks of this treatment possibility with one's physician.

Here is a partial list of some of the concerns which have come to our attention:

* Precautions against stomach ulcers were discussed above. In addition, aspirin should be taken with "food, milk, antacid, or large glass of water"(13) to reduce stomach irritation. Effervescent preparations may be helpful. Alcohol makes the stomach problems worse, and should be avoided by persons using long-term aspirin therapy.

* Aspirin delays blood clotting. Persons with hemophilia or other blood-clotting disorders, or who are taking medications which affect clotting, must get medical advice before using aspirin.

* One case of Reye's syndrome in an adult with AIDS who was using aspirin was recently reported(14). This rare but serious disease is usually found in children, and aspirin is believed to increase the risk. The authors had not heard of any other case in an adult with AIDS.

* Large doses of vitamin C can cause aspirin to be excreted more slowly, increasing its concentration in the body.

* Aspirin can interact with other drugs.

For these and other reasons, persons should consult their physician before using large doses of aspirin.

Suggestions for Trials

Community-based research organizations could easily conduct trials of aspirin in the treatment of AIDS or HIV, and could make an important contribution by doing so. Here are some of the trials that we think most need to be done. The goal is to obtain objective evidence relevant to the usefulness of aspirin in AIDS treatment.

* Can aspirin reduce HIV replication or activity? One way to find out would be a randomized trial with p24-positive volunteers assigned to take aspirin or not to take it. Volunteers could continue AZT and other medications they were using.

How long would this trial have to run, and how many patients would be necessary? To find out, an initial pilot study would watch changes in p24 levels in several patients treated with aspirin. This pilot data may already be available in existing medical records.

* Could aspirin have a role in early HIV treatment? Here most patients would be p24 negative, so p24 could not be used as a marker of viral activity.

One physician suggested that a good time to try aspirin might be at around 300 T-helper cells, when the first symptoms of HIV, such as inflammation in the mouth, were beginning to develop. He thought that large doses, such as used by persons with arthritis, would be necessary.

To test this theory, a study could look at T-helper counts, in patients with starting counts in a range of about 200 to 500. In this range, the T-cell count appears to be a sensitive indicator of whether a treatment is working. Different doses should be tried, to obtain information about dose-response. If a low dose can be helpful, it would be important to know that.

A pilot study could suggest how much of an effect to expect, and how long to wait for it. Again, this pilot data may already be available.

* What is the long-term effect of aspirin on health and survival? The problem here is to design a study which is feasible to carry out.

Nobody knows for sure that p24 and T-cell improvements necessarily predict improved long-range outcome. But to get statistical proof that a treatment affects "hard" clinical endpoints like death or disease progression requires a huge study with hundreds of patients, some randomly assigned to a control group. For aspirin, no such study will happen.

The alternative of "historical controls" -- comparing treated patients with others who were not treated in the past -- presents problems because of the changes in the epidemic. Treatments have changed, and the virus has changed. Patients are different, too; for example, those now becoming ill were often infected in the early 1980s, before safe-sex campaigns, so they are patients in whom the disease has progressed relatively slowly. But those who became ill in the early 1980s clearly had a more rapid progression, since the virus had not been prevalent until shortly before that time; perhaps they were more susceptible to it. With historical controls, such changes in the patient population might make a treatment look like it is working even if it is not.

One approach to this problem might be called a computer-model control; we believe it was first suggested by San Francisco AIDS activist Michelle Roland, who occasionally writes for AIDS TREATMENT NEWS. A computer model would be prepared based on the best statistical data available about predictors of disease progression -- the relative importance of T-helper count, other blood tests, clinical symptoms, use of treatments such as AZT and OI prophylaxis, information such as age, sex, and race, etc. Whenever epidemiologists, clinicians, or other experts find errors in the model, they could correct them, building cumulative improvements. When they found trends in how the epidemic was changing over time, they could have the computer mathematically project the known trends to the present time. Eventually the model would contain information from thousands of patients, organized with the ideas of dozens of leading experts.

Then when a clinical trial is designed, the model could substitute for a placebo control group. All the study volunteers could be treated; and from their baseline blood work and other information, the model could predict how many deaths, infections, or other outcomes would statistically be expected at any given time in the future, in the absence of any new treatment. (The methods for making such calculations are well known, as they are routinely used for actuarial purposes in the insurance industry.) The group receiving the new drug could then be compared with the prediction, to see if the drug was working. These trials would be much easier to organize than those which require a no-treatment comparison, since patients who would want the treatment anyway would enroll in the trial to receive consistent followup. This approach to trial design might be called "smart" (computerized) historical controls.

Ms. Roland is preparing a proposal for initial development of such a computer model. Anyone interested can write to her c/o AIDS TREATMENT NEWS, P.O. Box 411256, San Francisco, CA 94141.

Comment

Until more trials are conducted, it is not possible to be sure that aspirin can be helpful in treating AIDS or HIV. We are concerned that as a result of this article, many people will start taking aspirin. But we are also concerned that a promising treatment lead is being dropped by default, because of lack of commercial incentive.

People should be cautious, and tell their physicians about this or any treatment they plan to use. We also hope that community- based or other research organizations will organize trials to obtain definitive information on whether or not aspirin can help to slow the progression of AIDS or HIV. This treatment possibility, until now almost unknown in the AIDS community, deserves serious attention.

Please Send Us Information

If you have any experience with aspirin and AIDS or HIV, either as a physician or as a patient, please let us know. Contact John S. James, AIDS TREATMENT NEWS, P.O. Box 411256, San Francisco, CA 94141, 415/255-0588. We are especially interested in experience with long-term use, and/or with high doses.

References

1. Reddy MM, Manvar D, Ahuja KK, Moriarty ML, Grieco MH. Augmentation of mitogen-induced proliferative responses by in vitro indomethacin in patients with acquired immune deficiency syndrome and AIDS-related complex. International Journal of Immuno- pharmacology. June 1985; volume 7 number 6, pages 917-921.

2. Valone FH, Payan DG, Abrams DI, Dohlman JG, Goetzl EJ. Indomethacin enhances the proliferation of mitogen-stimulated T lymphocytes of homosexual males with persistent generalized lymphadenopathy. Journal of Clinical Immunology. September 1984; volume 4 number 5, pages 383-387.

3. Braun DP, Harris JE. Abnormal monocyte function in patients with Kaposi's sarcoma. Cancer. April 15, 1986; volume 57 number 8, pages 1501-1506.

4. Hofmann B, Fugger L, Ryder LP, and others. Immunological studies in acquired immunodeficiency syndrome: effects of TCGF and indomethacin on the in vitro lymphocyte response. Cancer Detection and Prevention Supplement. 1987; number 1, pages 619- 626.

5. Ramirez J, Alcami J, Arnaiz-Villena A, and others. Indomethacin in the relief of AIDS symptoms [letter]. Lancet. September 6, 1986; 2 (8506), page 570.

6. Salinas Argenta R, Sans-Sabrafen J, Martin E, Zaragoza J. Indomethacin as symptomatic medication in patients with advanced HIV infection [letter]. (English translation of title.) Med. Clin. (Barcelona). April 2, 1988; volume 90 number 13, pages 556-557.

7. Fernando-Cruz E, Fernandez A, Gutierrez C, Garcia Montes M, Rodriguez M, Zabay JM. Increased levels in plasma of Prostaglandin E2 (PGE2) could account for the abnormalities of cellular immune function in drug addicts with HIV infection [abstract]. III International Conference on AIDS, abstract number WP. 120.

8. Associated Press. Aspirin may be useful in battling cancer, AIDS, pregnancy problems. December 3, 1986.

9. Seifter E, Rettura G, Levenson SM, Appleman M, Seifter J. Aspirin inhibits a murine viral infection. Life Sci. 1975; 16, page 629.

10. White RF. Acetylsalicylic acid (aspirin) induces resistance to tobacco mosaic virus in tobacco. Virology. 1979; 99, page 410.

11. Kotler DP, Reka S. Modulation of HIV production by rectal mucosa in vitro [abstract]. Gastroenterology. May 1990; volume 98 number 5 part 2, page A-457.

12. Hsia J, Simon GL, Higgins N, Goldstein AL, Hayden FG. Immune modulation by aspirin during experimental rhinovirus colds. Bulletin of the New York Academy of Medicine. January 1989; volume 65 number 1, pages 45-56.

13. Nursing89 Drug Handbook. Springhouse Corporation, Springhouse, Pennsylvania.

14. Jolliet P, Widmann JJ. Reye's syndrome in adult with AIDS [letter]. Lancet. June 16, 1990; volume 335 number 8703, page 1457.

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