351   Mycophenolate Mofetil (MMF) Induces a Decrease in HIV-1 RNA Associated with Guanosine Depletion.

D. Margolis*¹, M. Hossain¹, L. Shaw², and D. Back³.
¹Dallas VA and Univ. of Texas Southwestern Med. Ctr.;²Univ. of Pennsylvania, Philadelphia; and³Univ. of Liverpool, UK.

Background:Mycophenolic acid (MPA) enhances the activity of abacavir (ABC) against wild-type and nucleoside analogue-resistant HIV-1 in vitro. This may be due in part to depletion of cellular deoxyguanosine triphosphate (dGTP), increasing the intracellular ratio of the active antiviral metabolite of ABC, carbovir triphosphate (CBV-TP), to dGTP. Following the administration of MMF we measured viral load and plasma MPA and determined intracellular CBV-TP/dGTP.

Methods:In a pilot study of MMF as a component of therapy with ABC and other antivirals for multidrug- resistant HIV, two HIV⁺subjects (A and B) added MMF 500 mg bid. A third (C), receiving MMF 250 mg bid for more than 6 months, dose escalated to 500 mg bid. Plasma MPA levels were determined at week 2 by HPLC. PBMC extracts were prepared at weeks 2 and 8; intracellular CBV-TP and dGTP was measured by a competitive enzymatic assay.

Results:HIV RNA (VL) in subject A, 4.71 log₁₀copies/mL at entry, was stable for the prior 8 weeks. VL declined 1.2 log₁₀copies/mL at week 3. Following a period of nonadherence, VL returned to baseline by week 12. CBV-TP/dGTP at week 8 was not increased. Subject B reinitiated MMF 500 mg bid after 9 weeks off 250 mg bid. VL was 5.63 log₁₀copies/mL, with an increase of more than 1 log₁₀in the prior 4 weeks. VL declined 0.73 log₁₀copies/mL at week 6 and was 0.46 log₁₀copies/mL below baseline at week 12. CBV-TP/dGTP was increased at weeks 2 and 8. In subject C, VL was 4.73 log₁₀copies/mL at entry, increasing more than 2 log₁₀copies/mL in the prior 8 weeks. VL declined 1.23 log₁₀copies/mL at week 4 and 0.67 log₁0 copies/mL at week 8. CBV-TP/dGTP was increased at weeks 2 and 8. Therapy is well tolerated thus far; no toxicities have been observed. CD4⁺cell counts are increased or stable. Trough plasma MPA levels ranged from 0.51—0.94mg/ml, peak 2.44—7.77mg/ml.

Conclusions:HIV-1 RNA declined a mean of 1.05 log₁₀copies/mL 3 to 6 weeks following only the addition or dose escalation of MMF. Plasma MPA levels appear linearly correlated with dose. Modulation of the CBV-TP/ dGTP ratio may be achievable with doses of MMF 50% lower than those used in organ transplantation.