66   Effect of Recombinant Human Soluble Tumor Necrosis Factor Receptor (TNFR, Etanercept) on Interleukin-6 (IL- 6), TNF-α;, and Markers of Immune Activation in HIV- Infected Subjects Receiving Interleukin-2 (IL-2).

B. Sha*¹, H. Valdez², A. Landay¹, R. Gelman³, A. Namkung⁴, J. Agosti⁵, L. Bancroft⁶, D. Mildvan⁷, R. Mitsuyasu⁸, R Pollard⁹, D. Ogata-Arakaki¹⁰, P. Kilgo³, S. Estep¹¹, L. Fox¹¹, and M. Lederman²for the ACTG 928 Team.
¹Rush Med. Coll., Chicago, IL;²Case Western Reserve Univ., Cleveland, OH;³Harvard Univ., Boston, MA;⁴ACTG Operations, Rockville, MD;⁵Immunex, Seattle, WA; FSTRF, Amherst, NY;⁷Beth Israel Hosp., New York, NY;⁸Univ. of California,, Los Angeles;⁹Univ. of Texas, Galveston;¹⁰Univ. of Hawaii at Manoa, Honolulu; and¹¹NIH, Bethesda, MD.

Background:Neutralization of circulating TNF-α;may block IL-2 induced activation of proinflammatory cytokine expression.

Methods:A prospective, open-label, completed trial of HAART, HAART + SC IL-2 (7.5 MIU bid × 5d q8wks), or HAART + continuous IV (CIV) IL-2 (9 MIU qd × 5d q8wks). Plasma IL-6, IL-4, IL-10, IL-12, IFN-g, sTNFR I, sTNFR II, C-reactive protein (CRP), HIV-1 RNA levels; temperature; and CD4 counts were examined after IL- 2 cycle 2 and after cycle 3. Etanercept 10 mg IV was infused just prior to cycle 3.

Results:11 patients were evaluable: HAART (5), HAART + SC IL-2 (3), HAART + CIV IL-2 (3). Plasma IL-6 and CRP levels increased following IL-2 treatment. Etanercept pretreatment attenuated these increases. Median plasma IL-6 levels fell from 20 pg/ml 4 days after IL-2 to 8 pg/ml 4 days after etanercept and IL-2 (p = 0.22); CRP levels fell from 79 pg/ml to 46 pg/ml (p = 0.03). HAART controls had low levels of IL-6 and CRP unchanged by etanercept. An effect on TNF bioactivity could not be assessed as all measurements were below limits of detection. No change was seen in temperature or plasma levels of IL-4, IL-10, IL-12, or IFN-g. Baseline soluble TNFR levels were not associated with cytokine, CRP, or plasma HIV-1 RNA level or body temperature changes. Etanercept did not affect CD4⁺cell counts or plasma HIV-1 RNA levels. No grade 3 or higher toxicities attributable to etanercept were reported.

Conclusions:IL-2 treatment increases plasma levels of IL-6 and CRP; however, pretreatment with etanercept may blunt immune activation induced by IL-2 as measured by changes in IL-6 and CRP. Etanercept was well- tolerated.