Mycophenalate mofetil in patients with advanced disease and multidrug resistant HIV
Mycophenolic acid reversibly inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH). This enzyme is responsible for the de novo synthesis of guanosine nucleotides.
Limiting the rate of de novo synthesis of cellular guanosine nucleotides should allow more efficient incorporation of guanosine nucleotides provided by guanosine nucleoside analogues such as abacavir. Mycophenalate mofetil (MMF) is the orally bioavailable prodrug of mycophenolic acid and is currently licensed for use in the prevention of allograft rejection (as CellceptTM). MMF is a lymphocyte selective IMPDH inhibitor and is also more active in stimulated than unstimulated lymphocytes. Previously cell culture experiments have demonstrated synergistic inhibition of HIV-1 in PBMC by the combined administration of either abacavir or ddI and mycophenolic acid.
David Margolis of the University of Texas Southwestern Medical Centre, Dallas, presented data at this meeting on 7 patients with multidrug resistant HIV given ‘salvage’ therapy including mycophenalate mofetil (MMF) . This was a 16 week open-label pilot study and all 7 patients had failed 10 or more prior antiretrovirals.
Genotypes prior to enrolment showed means of 3.3 NRTI associated mutations, 4.6 PI and 2.1 NNRTI associated mutations. All subjects received abacavir 300 mg BID, ddI 400 mg QD and MMF 250 mg BID. As there had been no prior use of amprenavir this was also given to all subjects at a dose of 600 mg BID dosed with 200 mg BID of ritonavir. Two subjects also received the NNRTI efavirenz at 600 mg QD. Baseline plasma HIV RNA of the subjects ranged from around 10,000 to 1,000,000 copies/mL and CD4 T-cell counts from almost zero to around 60 cells/mm3.
4/7 patients were classified as responders, showing an initial decline in plasma HIV RNA and rise in CD4 cell count. These initial responses did, however, appear to be returning towards baseline after week 10 in all 4 ‘responders’. Only one subject still had a greater than 1 log decline in HIV RNA at 16 weeks. Of the non-responders, one was non-adherent and viral response was lost at week 2, one was intolerant to the amprenavir/ritonavir and lost their viral response at week 3, the third non-responder had an initial decline in VL of 1.5 logs, but this had returned to baseline by week 16 and new mutations (I84V and L90M) were found in the protease gene.
The mean increase in CD4 T-cell count in the 4 responders was 16 cells/mm3 at week 16 and 37 cells/mm3 at 24 weeks. Interestingly T-cell apoptosis was found to have declined by 25 to 50% in the 4 responders, correlating to CD4 response to therapy. In the non-responders T-cell apoptosis either decreased marginally or actually went up correlating with an overall drop in absolute CD4 cell numbers.
The investigators concluded that the safety profile of MMF in this small cohort with advanced disease and extensive prior antiretroviral treatment was unremarkable for up to 24 weeks and that the use of MMF in HIV therapy deserves further study.
Mycophenolic acid unfortunately looks disappointing in this small study. The in vitro synergy promises enhanced virologic suppression when combined with abacavir and/or ddI, this was not observed in this study.
- Coull JJ, Betts M, Turner D et al. A pilot study of the use of mycophenalate mofetil (MMF) as a component of therapy for multidrug resistant HIV-1. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 11.