A drug widely used to treat arthritis and other autoimmune disorders may significantly increase CD4 counts in people with HIV. The drug, sulfasalazine, also known by the trade name Azulfidine, is an anti-inflammatory agent originally approved to treat ulcerative colitis, but like many drugs its uses have expanded to include treatment of other illnesses. It has, in the process, been observed to have certain "immunoregulatory" properties.

Sulfasalazine's effect on CD4 cells was discovered incidentally by researchers at Cabrini Medical Center in New York who were treating HIV-infected patients with Reiter's syndrome. Reiter's is a chronic problem for some people with HIV, and it can produce a spectrum of seemingly disconnected symptoms, including joint inflammation, diarrhea, urethritis and conjunctivitis.

The patients at Cabrini had been given sulfasalazine as one of the standard treatments for inflamed synovia (the transparent fluid that lubricates the body's joints) and arthritic pain. Over time, the researchers happen to notice that CD4 counts in four patients rose substantially, by an average of 200, even though three of them were not using any anti-HIV medication that could be credited with the increase.

Last April, the researchers published their observations in THE JOURNAL OF RHEUMATOLOGY (volume 21, number 4). We recently discussed the potential of sulfasalazine with one of them, Hae Ran Rhim, M.D., who has since moved to San Francisco, where she has a rheumatology practice.

Elaborating on points made in the report, Dr. Rhim said that sulfasalazine had already been known to suppress certain inflammatory responses of the immune system, including the production of cytokines like tumor necrosis factor and interleukins 1 and 2. Tumor necrosis factor is strongly associated with HIV replication, as well as with wasting and perhaps the development of dementia. The role of interleukins is more equivocal, with some considered to inhibit HIV progression, and others seeming to enhance it.

Sulfasalazine is also known to be a scavenger of superoxide radicals, which are thought to provoke HIV by affecting the Long Terminal Repeat (LTR) of the virus. The LTR is at least one of the mechanisms responsible for regulating viral activity, and so it has been proposed that, theoretically, antioxidants could inhibit the LTR. (For more information on LTR inhibitors, see AIDS TREATMENT NEWS issues #192 and #196.) An increase in CD4 cells does not prove that a drug has had an impact on HIV replication. But if sulfasalazine lowers oxidative stress, or pacifies certain overactive components of the immune response, it would be consistent with some current directions in HIV research. Aspirin, curcumin, cyclosporin, NAC, pentoxifylline, thalidomide and vitamin C are other examples of agents that have been studied for their anti-inflammatory or antioxidant effects on HIV infection. And though they almost certainly will not replace drugs that are known to work directly against HIV, such as reverse transcriptase inhibitors or protease inhibitors, research suggests certain anti-inflammatories and antioxidants could complement antiretroviral treatments.

Dr. Rhim mentioned that there are some side effects associated with the drug, including a sulfa-like reaction in some patients, and bone marrow suppression with long-term use, and of course the immunosuppression of the cytokines, mentioned above, that are overproduced in HIV disease.

The allergic reaction might be avoided by starting with low doses and building up to the dose that is considered therapeutic for Reiter's syndrome, 2 grams a day. Bone marrow toxicity was not seen in the Cabrini patients, even in the one patient who was also taking AZT.

The patients treated at Cabrini were relatively unusual in that three of them were not on anti-HIV drugs despite low CD4 counts. Otherwise, presumably, the effect of sulfasalazine would have been diluted and less dramatic. Dr. Rhim said it has been difficult to design a larger, strictly controlled, clinical trial using sulfasalazine to treat individuals with low CD4 counts, since there are now four -- soon to be five -- antiretrovirals approved for that purpose.

Nonetheless, the Cabrini researchers, headed by Dr. Eddys Disla, have designed a controlled trial of sulfasalazine. The trial will begin recruiting March 1; interested persons in the New York area should call 212/995-6996. Dr. Disla told us that their original observations must be considered preliminary: it is not certain if or how sulfasalazine has a beneficial effect on HIV progression.

Both Drs. Rhim and Disla reiterated the widely-held feeling that CD4 counts are a poor marker for HIV activity. They are at best a very approximate, delayed effect of HIV progression and/or anti-HIV treatments. The same is probably true for other markers that were once sporadically monitored, like p24 antigen, beta 2 microglobulin and neopterin.

However, there are now tests to bypass these markers and to identify the impact of treatments like sulfasalazine on viral load. The quantitative polymerase chain reaction (PCR) RNA test and the branched DNA test can each measure the level of HIV in the blood quickly and accurately. The use of these tests, called HIV RNA assays, could make it possible to observe the effect of sulfasalazine on anyone with low CD4 counts and measurable HIV levels, even if they are also on other HIV treatments, and especially if they cannot join a clinical trial of the drug. [For extensive discussions of these tests, see AIDS TREATMENT NEWS issues #204, #210 and #211.] The new sulfasalazine study at Cabrini will monitor HIV RNA levels.

Anyone with anecdotal experience using sulfasalazine is encouraged to share it with Denny Smith or John James at 415/255-0588.

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