Variable viral clearance despite adequate ganciclovir plasma levels during valganciclovir treatment for cytomegalovirus disease in D+/R- transplant recipients

Abstract

Background: Valganciclovir, the oral prodrug of ganciclovir, has been demonstrated equivalent to iv ganciclovir for CMV disease treatment in solid organ transplant recipients. Variability in ganciclovir exposure achieved with valganciclovir could be implicated as a contributing factor for explaining variations in the therapeutic response. This prospective observational study aimed to correlate clinical and cytomegalovirus (CMV) viral load response (DNAemia) with ganciclovir plasma concentrations in patients treated with valganciclovir for CMV infection/disease.

Methods: Seven CMV D+/R- transplant recipients (4 kidney, 2 liver and 1 heart) were treated with valganciclovir (initial dose was 900-1800 mg/day for 3-6.5 weeks, followed by 450-900 mg/day for 2-9 weeks). DNAemia was monitored by real time quantitative PCR and ganciclovir plasma concentration was measured at trough (Ctrough) and 3 h after drug administration (C3h) by HPLC.

Results: Four patients presented with CMV syndrome, two had CMV tissue-invasive disease after prophylaxis discontinuation, and one liver recipient was treated pre-emptively for asymptomatic rising CMV viral load 5 weeks post-transplantation in the absence of prophylaxis. CMV DNAemia decreased during the first week of treatment in all recipients except in one patient (median decrease: -1.2 log copies/mL, range: -1.8 to 0) despite satisfactory ganciclovir exposure (AUC0-12 = 48 mgxh/L, range for the 7 patients: 40-118 mgxh/L). Viral clearance was obtained in five patients after a median of time of 34 days (range: 28-82 days). Two patients had recurrent CMV disease despite adequate ganciclovir exposure (65 mgxh/L, range: 44-118 mgxh/L).

Conclusions: Valganciclovir treatment for CMV infection/disease in D+/R- transplant recipients can thus result in variable viral clearance despite adequate ganciclovir plasma concentrations, probably correlating inversely with anti-CMV immune responses after primary infection.

Figure 1

CMV treatment with valganciclovir in patients 1-6. valganciclovir dosage (red rectangle), ganciclovir plasma concentration (closed white circle: concentration measured at trough, closed white triangle: concentration measured 3 h after last dose, red line: concentration predicted by population pharmacokinetic model), CMV viremia (blue square and solid blue line) and symptoms period (blue diamond)

Figure 2

CMV prophylaxis and treatment with valganciclovir in patient 7. valganciclovir dosage (red rectangle), ganciclovir plasma concentration (closed white circle: concentration measured at trough, closed white triangle: concentration measured 3 h after last dose, red line: concentration predicted by population pharmacokinetic model), CMV viremia (blue square and solid blue line), symptoms period (blue diamond), EBV viremia (green triangle and dotted green line), anti-CMV IgM and IgG (IgM: closed white square and dotted blue line, IgG: blue circle and solid blue line), anti-EBV IgM and IgG (IgM: closed white square and dotted green line, IgG: closed green circle and solid green line), CMV specific T-cell response and EBV specific T-cell response (Interferon-γ, IF-γ -: negative; IF-γ +: positive)