Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation

Abstract

Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

Figure 1.

Flow of patients through the study.

Figure 2.

Kaplan-Meier curves for the cumulative probability of freedom from cytomegalovirus (CMV) disease, CMV viremia, late-onset CMV viremia, and biopsy-proven acute rejection. (A) The incidence of CMV disease was similar in both groups. Significantly increased incidence of (B) CMV viremia and (D) acute rejection was observed in the pre-emptive group, whereas (C) late-onset CMV viremia was more common with valacyclovir prophylaxis. Late-onset CMV viremia was defined as the first episode of CMV viremia ≥3 months after transplant and/or recurrent episode of CMV viremia ≥3 months after transplant at least 1 month after clearance of an early CMV viremia episode. Arrow denotes 12 months after transplantation; from this point, CMV disease or viremia were assessed only if clinically indicated.

Figure 3.

Quantitative intrarenal mRNA gene expression on protocol biopsy at 36 months after transplant. Results are expressed as the ratio of the gene of interest to the housekeeping glyceraldehyde-3-phosphate dehydrogenase gene. The box plots show 25th and 75th (boundaries of boxes), 50th (median), and 10th and 90th (error bars) percentile values. Mann-Whitney U test was used for comparison between pre-emptive therapy and valacyclovir prophylaxis groups.

Figure 4.

Kaplan-Meier curves for the cumulative probability of graft loss uncensored for death. Significantly better graft survival was observed in patients managed by pre-emptive therapy compared with valacyclovir prophylaxis (A) and in patients without late-onset CMV viremia (B). Late-onset CMV viremia was defined as the first episode of CMV viremia ≥3 months after transplant or recurrent episode of CMV viremia ≥3 months after transplant at least 1 month after clearance of an early CMV viremia episode. Effect of late-onset CMV viremia was analyzed only in patients with functioning graft at 3 months after transplantation. *Adjusted for expanded-criteria donor, delayed graft function, and biopsy-proven acute rejection. Reasons for graft loss in the pre-emptive therapy group: two cases of antibody-mediated rejection, one case of IF/TA; reasons in the valacyclovir prophylaxis group: three cases of antibody-mediated rejection (in combination with T cell–mediated rejection in one case), three cases of interstitial fibrosis and tubular atrophy, one case of primary nonfunction, one case of recurrence of IgA nephropathy, and one death with function.