14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 28)

E Connick¹, Derek Shenefelt^1,2, J Folkvord¹, M Thrun³, S MaWhinney¹, J Gathe⁴, S Lundy⁵, and S Becker^6
1Univ of Colorado Hlth Sci Ctr, Denver, US; ²Weber State Univ, Ogden, UT, US; ³Denver Dept of Publ Hlth, CO, US; ⁴Therapeutic Concepts, Houston, TX, US; ⁵Pharma Product Devt, Inc, Menlo Park, CA, US; and ⁶AnorMED Inc, Langley, Canada

BACKGROUND: Gut-associated lymphoid tissue (GALT) harbors the majority of CD4+ T cells and is rapidly depleted in early HIV infection. Previous studies suggest that reconstitution of CD4+ T cells in HAART-treated individuals is less complete in GALT than in peripheral blood. Most studies have evaluated GALT by flow cytometry, which provides relative estimates of CD4+ T cells. We hypothesized that reconstitution of CD4+ T cells in GALT may have been underestimated by this method and that absolute numbers of CD4+ T cells reconstituted in GALT exceed those in peripheral blood.

METHODS: We enrolled 8 untreated AIDS patients in a clinical trial who underwent colonic biopsies and provided peripheral blood samples at baseline, 24 and 48 weeks after starting nevirapine (NVP)/trizivir (TZV); 4-µm sections of GALT biopsies were stained with CD3 and CD4 antibodies, and analyzed by immunofluorescent microscopy. Numbers of lamina propria CD4+ T cells/mm³ were calculated and tissue histology observed. A mixed model was used to account for within subject correlations.

RESULTS: All but 1 subject achieved a viral load <400 copies/mL by week 48. Mean peripheral blood CD4+ T cells/mm³ increased from 65 at baseline to 192 at week 24 (p <0.15) and 216 at week 48 (p = 0.08 vs baseline). Mean GALT CD4+ T cells/mm³ were 279 at baseline, which was higher than that in peripheral blood (p = 0.08). Mean GALT CD4+ T cells increased through week 24 to 890 cells/mm³ (p <0.0001), a larger increase than was observed in peripheral blood (p = 0.0006). Mean GALT CD4+ T cells decreased to 759 cells/mm³ at week 48, but remained significantly different than baseline (p <0.0001) and still reflected a larger increase than in peripheral blood (p = 0.0096). Peripheral blood and GALT reconstitution were calculated as a percentage of normal values assuming a norm of 1000 cells/mm³ in peripheral blood and using values for GALT CD4+ T cells obtained in 2 control colonic biopsies. At baseline, mean CD4+ T cells were 7% in peripheral blood and 16% in GALT of normal values (p = 0.21). At week 24, peripheral blood and GALT values were 19% and 52% (p = 0.011 GALT vs peripheral blood increase), and at week 48, 22% and 44% (p = 0.12 GALT vs peripheral blood increase over baseline) of normal values. Lymphoid aggregates were observed in colonic tissue of 1 subject at baseline, 6 subjects at week 24 (p = 0.04), and 5 subjects at week 48 (p = 0.12 vs baseline).

CONCLUSIONS: NVP/TZV in advanced HIV-1 infection results in substantial recovery of CD4+ T cells and reconstitution of tissue architecture in GALT. Increases in CD4+ T cells are significantly larger in GALT than peripheral blood, particularly during the first 24 weeks of therapy.

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2007-02-25
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