Title:  Cytokine Profiles of Antiretroviral-Naïve HIV+ Patients Treated with Lopinavir/ritonovir (Kaletra) Based Therapy for Three Years.

 

A.Landay^1*, D Tokimoto¹¹, M King¹¹, R Murphy², C Hicks³, J Eron⁴,

R Gulick⁵, M Glesby⁵, P Wolfe⁶, M Thompson⁷, C White⁸, C Benson⁹, M Albrecht¹⁰, H Kessler¹, S Brun¹¹ for the M97-720 Study Group

 

¹Rush Med. Coll., ²Northwestern, ³Duke, ⁴UNC at Chapel Hill, ⁵Cornell, ⁶Pacific Oaks Research, ⁷AIDS Research Consortium of Atlanta, ⁸Baylor, ⁹U. of Colorado, ¹⁰Harvard, and ¹¹Abbott Laboratories.

 

Background: Kaletra is a co-formulation of lopinavir (LPV), an HIV protease inhibitor, and ritonovir (r), which inhibits CYP3A. On therapy, plasma cytokine levels associated with immune activity were quantitatively measured in the patient cohort treated with LPV/r for the longest duration (Study 720).

Methods: One hundred (100) antiretroviral-naïve patients (pts) were treated with d4T/3TC and one of 3 doses of LPV/r. After 48 weeks (wks), pts began open-label treatment with LPV/r 400/100 mg BID with continued NRTI use and follow-up quarterly. Viral load (VL), CD4, and CD8 counts were obtained at each visit. MIP (macrophage inflammatory protein)-1a, MIP-1b, RANTES, IFN-g, IL-2 levels, IL-10, MCP-1 (monocyte chemotactic protein), and sTNFR2 (soluble tumor necrosis factor receptor) were assayed at baseline (BL) and wk 156 or final visit for 83 pts.

Results: Mean BL VL was 4.9 log₁₀ copies/mL and mean BL CD4 count was 338 cells/mm³. By intent-to-treat (non-completer = failure) analysis, 71% (70%) of pts had VL < 400 (< 50) copies/mL at wk 204. Mean CD4 cell count increased by 440 cells/mm³ from BL; response was consistent regardless of BL CD4 count. Seven (7) pts stopped therapy due to LPV/r-related adverse events; 0/7 pts with detectable VL through 204 wks and available genotype demonstrated resistance. A significant change from BL was observed in the following: MIP-1b (mean increase of 11.5 pg/mL from BL mean of 33.1 pg/mL), sTNFR2 (mean decrease of 2.6 ng/mL from BL mean of 8.7 ng/mL), and MCP-1 (mean decrease of 42 pg/mL from BL mean of 211 pg/mL). Overall, mean RANTES and IL-2 levels tended to increase from BL while mean MIP-1b IFN-g, and IL-10 levels tended to decrease from BL. Pts with BL CD4 counts < 350 cells/mm³ had higher BL levels of sTNFR2, IL-10, and MCP-1 vs pts with BL CD4 > 350 cells/mm³ and had significantly larger mean decreases from baseline.

Conclusions: ARV-naïve pts treated with LPV/r-based therapy have demonstrated sustained virologic responses through yr 4. At 3 yrs, a trend towards normalization of several cytokine profiles was observed with evidence of reduced immune activation and increases in chemokines capable of decreasing viral replication. This finding of significantly reduced levels of serum markers of immune activation at 3 yrs in subjects with CD4 < 350 cells/mm³ at BL may help explain their sustained CD4 rise and provides the potential for using serum markers to predict immunologic outcomes.