Background:  While the determinants of immune deficiency and immune restoration in chronic HIV-1 infection are not well understood, immune activation has been proposed as central to HIV pathogenesis. An earlier uncontrolled study indicated that co-administration of cyclosporine A (CsA) with initial ART to persons with recent HIV infection increased CD4 T-cell recovery dramatically.

Methods:  We performed a randomized controlled trial of 2 weeks of CsA vs no CsA during the first 2 weeks of standardized ART vs standardized ART among 42 persons with chronic HIV-1 infection, CD4 T cells  >100/µL, and plasma HIV-1 RNA ≥5000 copies/mL. Enrollees were mostly males (93%) and white (57%). Median age was 37, baseline CD4 cell count was 269/µL and HIV RNA 5.0 log₁₀. For the first 2 weeks patients recieved zidovudine, lamivudine, and abacavir. At 2 weeks, efavirenz was added. CsA levels were monitored and dosage was adjusted to maintain  levels between 250 and 450 ng/mL. The study had an 80% power to detect a 75-cell greater CD4⁺ T-cell change from baseline to week 8 in the CsA plus ART group.

Results:  Coadministration of CsA provided a significant  increase in CD4 T-cell restoration at days 3 and 7 (median +140 and +128 cells/µL vs +17 and +31 cells/µL in the no-CsA group, p <0.002), but by day 14 and through week 48, these significant differences were no longer observed. The early enhancement in circulating T-cell restoration was largely restricted to T cells expressing the CCR7 chemokine receptor.  CsA did not affect plasma HIV RNA decay or the sustained suppression of HIV replication. At 48 weeks 76 and 79% of persons had plasma HIV RNA <50 copies/mL in the CsA and no-CsA groups, respectively. Assays of T-cell expansion and antibody responses to hepatitis A vaccine in vitro were unaffected by CsA administration, but antibody responses to rabies vaccine were attenuated. There were 3 HIV-related diagnoses in the CsA arm vs 1 in the no-CsA arm.

Conclusions:  CsA coadministered for the first 2 weeks of ART did not provide sustained immunologic benefit to persons with chronic HIV-1 infection. The modest accelerated increase in circulating CCR7⁺ T cells likely reflects early release from sequestration in lymphoid tissues. If immune activation drives progressive immune deficiency in chronic HIV-1 infection, these activation pathways may not be cyclosporine-sensitive; other pathways of immune activation should be pursued.