[16] THE ADDITION OF MYCOPHENOLATE MOFETIL CAN INDUCE DECREASES IN HIV-1 RNA AND INTRACELLULAR DEOXYGUANOSINE TRIPHOSPHATE

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] THE ADDITION OF MYCOPHENOLATE MOFETIL CAN INDUCE DECREASES IN HIV-1 RNA AND INTRACELLULAR DEOXYGUANOSINE TRIPHOSPHATE

[AUTHOR(S):] D Margolis¹, M Hossain¹, L Shaw² and D Back³
¹ Dallas VA and University of Texas Southwestern Medical Center, Dallas, Tex., USA; ² University of Pennsylvania, Philadelphia, Pa., USA; and ³ University of Liverpool, Liverpool, UK
Antivir Ther. 2001;6 Suppl 1:11

BACKGROUND: Mycophenolic acid (MPA) enhances the activity of abacavir against wild-type and nucleoside analogue resistant HIV-1 in vitro. This may occur via depletion of intracellular deoxyguanosine triphosphate (dGTP) and/or a relative increase in the intracellular concentration of the active antiviral metabolite of abacavir, carbovir triphosphate (CBVTP). Mycophenolate mofetil (MMF) 500 mg twice daily was added to the therapy of five patients receiving maximal available antiretroviral therapy, including abacavir. We measured viral load, plasma MPA and intracellular CBV-TP/dGTP.

METHODS: In a pilot study of MMF as a component of therapy for multi-drug-resistant HIV, two HIV-positive subjects (A and B) receiving antiretrovirals added MMF 500 mg twice daily. Three subjects (C, D and E) receiving MMF 250 mg twice daily for more than 6 months dose-escalated to 500 mg twice daily. Plasma total and free MPA levels were determined by high Scottsdale, Arizona, 4–8 June 2001 Antiviral 12 al Therapy 6, Supplement 1 performance liquid chromatography (HPLC). Area under the curve (AUC) was calculated from levels drawn at trough, 40 and 120 min after dosing. Peripheral blood mononuclear cell (PBMC) extracts were made and intracellular CBV-TP and dGTP measured by a competitive enzymatic assay.

RESULTS: HIV RNA (VL) in subject A (CB), 4.71 log₁₀ copies/ml at entry, were stable for the prior 8 weeks. VL declined 1.2 log₁₀ copies/ml at week 3. Following a period of non-adherence, VL returned to baseline by week 12. CBV-TP/dGTP at week 8 was not increased. Subject B (JDH) reinitiated MMF 500 mg twice daily after 9 weeks off 250 mg twice daily. VL was 5.63 log₁₀ copies/ml, increasing more than 1 log₁₀ in the prior 4 weeks. VL declined 0.73 log₁₀ copies/ml at week 6, and was 0.46 log₁₀ copies/ml below baseline at week 12. CBV-TP/dGTP was increased at weeks 2 and 8. In subject C (PAG), VL was 4.73 log₁₀ copies/ml at entry, increasing more than 2 log₁₀ copies/ml in the prior 8 weeks. VL declined 1.23 log₁₀ copies/ml at week 4, and 0.67 log₁₀ copies/ml at week 8. CBVTP/ 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 0.51–0.94 μg/ml, peak 2.44–7.77 μg/ml.

CONCLUSION: HIV-1 RNA declined a mean of 1.05 log₁₀ copies/ml 3–6 weeks following only the addition or dose escalation of MMF. Plasma MPA levels appear linearly correlated with dose. Measurable changes in the CBV-TP/dGTP ratio appear to be achievable with doses of MMF 50% lower than those used in organ transplantation.

PRESENTING AUTHOR: D Margolis

Download Presentation

010604
16

Copyright © 2001, 2011 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.