Important note: Information in this article was accurate in 1998. The state of the art may have changed since the publication date.
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AIDS TREATMENT NEWS Issue #308, December 4, 1998
John S. James
ACTG 334 is a small, 16-week clinical trial using many laboratory measurements to study low-dose cyclosporin in persons with HIV. Cyclosporin suppresses some immune responses, and is used in higher doses in organ-transplant patients to help prevent rejection of the new organ. This study is important for several reasons:
* For many years there have been hints from anecdotal reports and small studies that cyclosporin or other immune- suppressive drugs may have a role in HIV treatment. But little prospective (planned in advance) research has been done--and most of the research on cyclosporin in persons with HIV was conducted over 10 years ago, when much less was known about the immune system, and when many modern laboratory tests of immune function were not available.
One theory of why immune-suppressive drugs could be useful is that AIDS is not really an immune deficiency, but rather immune dysregulation, with some parts of the system being over-active--including CD4 T-cells, which allow HIV to reproduce only when they are activated.
* Studies of cyclosporin in persons with HIV will help to address the widespread bias against allowing them to receive organ transplants. (Transplant recipients often need long- term cyclosporin treatment, so it is important to know if this drug could cause any problems unique to persons with HIV.)
* Cyclosporin also seems to have anti-HIV activity which is separate from its immune-suppressive effect (which could slow HIV replication by reducing the number of activated T-cells which can be infected). A cyclosporin variant, code-named NIM 811, has strong anti-HIV activity without the immune- suppressive effect of cyclosporin itself; unfortunately, in 1995 Sandoz Ltd. (which since merged with Ciba-Geigy Ltd. to form Novartis), stopped development of NIM 811, apparently because the company is focused on transplant drugs rather than anti-infectives.(1) A recent paper has suggested where to look for molecular targets which could be used to develop other drugs with the anti-HIV activity of cyclosporin but without its immune suppressive activity.(2)
ACTG 334 Entry Criteria
ACTG 334 is a phase II, placebo-controlled study of cyclosporin and immune activation in persons with HIV; its purpose is to advance knowledge of the disease, but there is no reason to expect that patients will benefit directly from the treatment. Some persons will want the extensive test results, many of which are not available commercially.
Volunteers must have a CD4 count greater than 500, and a viral load greater than 600. They may either be on no anti- HIV treatment, or be taking two nucleoside analog drugs (e.g. AZT plus 3TC, or d4T plus ddI). They cannot currently be using protease inhibitors, nor NNRTIs (such as efavirenz or nevirapine), although past use is allowed. They must not be planning to change their anti-HIV medications during the course of this 16-week study.
A total of 9 study visits (plus 5 additional short visits to have a skin test read) will be required; volunteers will be paid a small compensation for their time (the amount can vary by site). The following tests will be run: soluble IL-2 receptors, beta-2 microglobulin, neopterin, CD-25, CD-38, HLA-DR, lymphoproliferative assay, apoptosis, DTH (skin test of immune function), viral load, proviral DNA, and HIV microculture.
The cyclosporin dose in this trial is 2 mg/kg twice a day (a total of 4 mg/kg per day). Half of the volunteers will be assigned to a placebo group, and they will not receive any cyclosporin.
For More Information
For more information about ACTG 334, including how to contact a site near you, call the AIDS Clinical Trials Information Service, 800-TRIALS-A.
Note: ACTG 334 should not be confused with a separate cyclosporin study, being run by ViRx, Inc., in three California cities: Palm Springs, San Francisco, and San Jose. The ViRx study is for persons with somewhat more advanced HIV disease (CD-4 count between 300 and 600). For more information about this study, call the ViRx office, 415-474- 4440.
References
1. Loftus, R. Sandoz axes cyclosporine research. GMHC TREATMENT ISSUES December 12, 1995; volume 9, number 12.
2. Kinoshita S, Chen BK, Kaneshima H, and Nolan G. Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. CELL November 25, 1998; volume 95.
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