Long-Term Valcyte Therapy in Transplant Patients and the Development of Ganciclovir Resistant CMV

CMV infection occurs most frequently in the first three months following transplantation and following treatment for acute rejection; both instances can be related to relatively high levels of immunosuppression relative to stable long-term allograft recipients. Disease then can occur and is manifest as fever, low white blood cell count, pneumonitis, gastroenteritis, hepatitis, retinitis, and a multitude of other symptoms.

Ganciclovir, a potent inhibitor of the herpesviridae DNA polymerase encoded for on the unique long (UL54) region of the CMV genome, has had a significant impact on both the prophylaxis and treatment of CMV infection in transplant patients. CMV-infected cells produce a phosphotransferase, or kinase (UL97 region) that phosphorylates ganciclovir to ganciclovir-triphosphate. The triphosphate product inhibits CMV replication by competitively inhibiting the incorporation of deoxyguanine triphosphate (dGTP) into the DNA region encoding the polymerase (UL54 region), thus resulting in the premature termination of viral DNA synthesis. Resistance to ganciclovir is conferred when mutations occur on the UL97 region of the CMV genome.

Ganciclovir is available in either an oral or an intravenous formulation. The obvious advantages of the oral formulation are somewhat offset by the fact that its bioavailability is only 8 to 10%. The product has been reformulated with the addition of an L-valyl ester; the resulting compound, valganciclovir (Valcyte™) is metabolized to ganciclovir and has a 3 to 7 fold increase in bioavailability and is able to maintain serum concentrations equivalent to the intravenous formulation. This provides a convenient method for obtaining therapeutic concentrations of ganciclovir for extended periods of time without the need for in-dwelling intravenous lines.

The optimal length of treatment has not been established and relapse rates as high as 25% are common upon cessation of the antiviral agent.6 Patients with CMV disease are initially treated with intravenous ganciclovir for two or more weeks, and then with an oral agent for many weeks thereafter. Current laboratory technology allows detection of active viral replication, either through the detection of the pp65 antigen on the surface of infected leukocytes or through the use PCR amplification for the detection of viral DNA. It is however, still unclear whether the best therapeutic option is to treat until symptoms disappear or to treat until evidence of active viral replication ceases.

The question of whether or not prolonged exposure to ganciclovir will result in an increase in the incidence of resistant CMV strains has not been answered. There is also a theoretical increase in the risk of selection pressure for resistant CMV when the lower dose of valganciclovir (450 mg) is used. This proposal will document the emergence of ganciclovir-resistant strains of CMV in high-risk kidney, pancreas, or combined kidney/pancreas transplant patients receiving long-term suppressive therapy with Valcyte™ and will also address the issue of selection pressure by randomizing for low and high dose valganciclovir prophylaxis. Emergence of resistance will be defined as detection of a resistance-conferring mutation in the UL97 (phosphotransferase) or UL54 (DNA polymerase) open reading frame of detectable CMV.