Valganciclovir for cytomegalovirus prevention in solid organ transplant patients: an evidence-based reassessment of safety and efficacy

Andre C Kalil, Alison G Freifeld, Elizabeth R Lyden, Julie A Stoner, Andre C Kalil, Alison G Freifeld, Elizabeth R Lyden, Julie A Stoner

Abstract

Background: Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention.

Methods: All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence.

Findings: Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I(2) = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm(3)) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I(2) = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I(2) = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I(2) = 10%). For a neutropenia cut-off of <1,000/mm(3), the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I(2) = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I(2) = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus.

Conclusions: Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Quorom Trial Flow.
Figure 1. Quorom Trial Flow.
Figure 2. Efficacy: Reduction in CMV Disease.
Figure 2. Efficacy: Reduction in CMV Disease.
Figure 3
Figure 3
A: Safety: Risk of Absolute Neutropenia. B: Cumulative Safety: Risk of Absolute Neutropenia.
Figure 4. Funnel plot: Evaluation of Publication…
Figure 4. Funnel plot: Evaluation of Publication Bias.

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