The effect of mycophenolate mofetil on hepatitis B viral load in stable renal transplant recipients with chronic hepatitis B.

Abstract

Mycophenolate mofetil (MMF) (CellCept; Hoffmann-LaRoche, Basel, Switzerland) acts as a potent inhibitor of inosine 5′-monophosphate dehydrogenase (1). This enzyme is not only a key enzyme in lymphocytes for de novo purine synthesis and for glycosylation of adhesion molecules, it also causes depletion of the intracellular (deoxy)guanosine triphosphate pool, with resultant antimicrobial effects (2-3). Recently, mycophenolic acid was shown to inhibit hepatitis B virus (HBV) replication in cultures of human hepatocytes (4). Since HBV infection is still a major problem in renal transplant patients, we prospectively evaluated the effect of MMF on HBV replication in 12 stable renal transplant recipients (age 49±8 years; weight 66±10 kg) with chronic active HBV infection (positive for hepatitis B surface antigen and HBV-DNA), acquired while on hemodialysis therapy. After three baseline levels of HBV replication with a 1-month interval, treatment with MMF at a mean dose of 2 g/day for 1 year was started, followed by determination of three levels of HBV-DNA with a 1-month interval. HBV replication was assessed by the polymerase chain reaction-based Amplicor HBV-Monitor test (Roche Diagnostic Systems, Hoffmann-LaRoche, Basel, Switzerland). As shown in Figure 1, the mean of three baseline HBV-DNA levels compared with the mean of three levels after 1 year of treatment with MMF was not significantly different (2.8×109 versus 2.5±3.3×109 copies/ml; Mann-Whitney U test). HBV viremia decreased slightly in nine patients, whereas it increased in four patients; however, HBV-DNA viremia changed >1 log copies/ml in only three patients, with a decrease in two and an increase in one. No significant correlation was found between the HBV viremia and the trough level of cyclosporine or the administered dose of cyclosporine, corticosteroids, azathioprine, or MMF. There was no significant change in liver tests or hematological cell counts. Figure 1: Mean of three HBV-DNA concentrations (×106 copies/ml plasma) before and 1 year after introduction of MMF in each patient.Several factors have to be taken into account when interpreting these results. First, the in vitro results obtained with MMF in cell cultures of HBV-infected hepatocytes need further expansion. Perhaps MMF, by depleting the intracellular (deoxy)guanosine triphosphate pools, may not inhibit HBV replication in a sufficient way in monotherapy, but only potentiates drugs with activity against HBV, like nucleoside analogs (5). Second, the levels of HBV viremia in our patients are approximately 1 log higher than usually seen in non-transplant recipients. In this study, MMF was introduced in patients with a longstanding immunocompromised state, because all patients were infected during hemodialysis before transplantation. Elimination of HBV was therefore not only impaired by the “uremic immune defect” but also by the intake for an average period of 10 years of drugs (corticosteroids and cyclosporine) stimulating HBV replication. Whether MMF is able to suppress HBV replication in humans with a recent HBV infection after transplantation and/or without concomitant intake of immunosuppressive drugs remains unanswered. In conclusion, this pilot study suggests that introduction of MMF does not affect HBV replication in stable HBV(+) renal transplant recipients with high viremia on maintenance therapy containing corticosteroids and/or cyclosporine. Whether MMF is able to suppress HBV replication in association with other antiviral agents in renal transplant patients needs further investigation. Acknowledgments. Y. Vanrenterghem is the holder of the Baxter Chair for Renal Transplantation at the Catholic University of Leuven. B. Maes is the holder of the Janssens-Cilag Chair for Nephrology at the Catholic University of Leuven. The authors thank the Leuven Collaborative Group for Transplantation for their enthusiastic collaboration. Bart D. Maes1,2 Jos F. van Pelt3 Jacques C. Peeters1 Frederik Nevens3 Pieter Evenepoel1 Dirk Kuypers1 Thierry Messiaen1 Johan Fevery3 Yves F. Ch. Vanrenterghem1