EFFECT OF  MYCOPHENOLATE MOPHETIL ON VIRAL REPLICATION  IN PLASMA AND RESERVOIRS AFTER INTERRUPTION OF HAART IN CHRONIC HIV- INFECTED PATIENTS. A PILOT RANDOMIZED STUDY.

Arnedo M, García F, Plana M, Brunet M, Gil C, Guila T, Castro P, Martorell J, Cruceta A, Miró JM, Mallolas J, Blanco JL, Martínez E, Gallart T, Pumarola T, Gatell JM. Institute of Infectious Diseases and Immunology. IDIBAPS, Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona (Spain)

Background: To study the effect of associating mycophenolate mofetil (MMF) + HAART and holding MMF during the STI cycles and after the definitive interruption of antiretroviral therapy on plasma and tonsillar tissue (TT) viral replication. The  pharmacokinetic profile of MMF and the effect on lymphocyte subsets and proliferative responses (LPR) were also assessed. Material and Methods: 15 CHI patients in very early stage (BVL 200-5,000 c/ml and  CD4+ T cells >500) were treated with abacavir+efavirenz+nelfinavir for 12 months. They were randomized to receive the same HAART plus MMF (0.25 g bid) (MMF group, n=9) vs the same HAART (ART group, n=6) during 4 additional months. Thereafter HAART was discontinued holding MMF in the MMF group. HAART was reintroduced during 4 month if viral load was > 200 c/ml. PVL, tonsillar biopsies (tonsillar tissue viral load (TTVL) and in situ hybridization), lymphocyte subsets and LPR were assessed at baseline, the day of randomization (day0), the day of discontinuation of HAART (day120) and at least 1 months off HAART (day150). Ongoing replication was studied throughout HIV-1 sequence evolution. Clone sequencing of env and pol genes in proviral DNA and RNA at baseline, proviral DNA before interruption and RNA during interruption when VL reach a value above 1000 copies/ml. The pharmacokinetic profile of MPA (AUC_0-12h) was analyzed at 7, 28, 120 and 150 days post MMF treatment. The capacity of the patient sera to inhibit the proliferative response of a T cell line (CEM) was also tested. Results: At day 120 all the patients of the MMF and ART groups had an undetectable level of PVL and TTVL. Five out of 9 patients in MMF group vs 1/6 patients of ART group maintained a VL set-point <200 c/ml (p= 0.28). However, CEM response decreased to <40% in all time-points in only 6 out of 9 patients. We compared viral load rebound in the 6 patients with decreased CEM response (inh-group) vs 3 patients without decreased of CEM response (n= 3) plus control group (n= 6) (no-inh group). Overall, 5 out of 6 patients of inh-group maintained a viral load set-point below 200 copies/ml vs 1/9 patients in the no-inh group (p= 0.005). After first interruption of HAART, doubling time was significantly higher in the inh-group 10.22 +/- 1.3 than in no-inh group 4.6 +/- 1.6 (p= 0.03). At day 120, there was no differences between MMF and ART group or between inh-group and no-inh-group in lymphocyte subset tested, in Ki67+ T cells, anexin V staining levels, or specific HIV-1 lymphoproliferative and CTL responses. After interruption of HAART, there was an increase of Ki67+ cells (p = 0.05) and this increase was significantly lower in inh-group (AUC: 0.98 +/- 0.27) than in no-inh group (AUC 1.94 +/- 0.35)(p = 0.05). Anexin V binding levels did not change over all the time-point tested (p= 0.28). Data on ongoing replication will be shown. Conclusions: Associating MMF + HAART delayed the viral load rebound both in plasma and tonsillar tissue and improve the control of viral replication without HAART only in those patients with a proved inhibition of lymphocyte proliferation (CEM response). This effect seems mediated by a decrease in cell turn-over after interruption of HAART and by inhibiting the initial wave of HIV rebound originating from reservoirs.