A Randomized Trial of Valganciclovir Prophylaxis Versus Preemptive Therapy in Kidney Transplant Recipients

Abstract

Significance statement: Although cytomegalovirus (CMV) infection is an important factor in the pathogenesis of kidney allograft rejection, previous studies have not determined the optimal CMV prevention strategy to avoid indirect effects of the virus. In this randomized trial involving 140 kidney transplant recipients, incidence of acute rejection at 12 months was not lower with valganciclovir prophylaxis (for at least 3 months) compared with preemptive therapy initiated after detection of CMV DNA in whole blood. However, prophylaxis was associated with a lower risk of subclinical rejection at 3 months. Although both regimens were effective in preventing CMV disease, the incidence of CMV DNAemia (including episodes with higher viral loads) was significantly higher with preemptive therapy. Further research with long-term follow-up is warranted to better compare the two approaches.

Background: The optimal regimen for preventing cytomegalovirus (CMV) infection in kidney transplant recipients, primarily in reducing indirect CMV effects, has not been defined.

Methods: This open-label, single-center, randomized clinical trial of valganciclovir prophylaxis versus preemptive therapy included kidney transplant recipients recruited between June 2013 and May 2018. After excluding CMV-seronegative recipients with transplants from seronegative donors, we randomized 140 participants 1:1 to receive valganciclovir prophylaxis (900 mg, daily for 3 or 6 months for CMV-seronegative recipients who received a kidney from a CMV-seropositive donor) or preemptive therapy (valganciclovir, 900 mg, twice daily) that was initiated after detection of CMV DNA in whole blood (≥1000 IU/ml) and stopped after two consecutive negative tests (preemptive therapy patients received weekly CMV PCR tests for 4 months). The primary outcome was the incidence of biopsy-confirmed acute rejection at 12 months. Key secondary outcomes included subclinical rejection, CMV disease and DNAemia, and neutropenia.

Results: The incidence of acute rejection was lower with valganciclovir prophylaxis than with preemptive therapy (13%, 9/70 versus 23%, 16/70), but the difference was not statistically significant. Subclinical rejection at 3 months was lower in the prophylaxis group (13% versus 29%, P = 0.027). Both regimens prevented CMV disease (in 4% of patients in both groups). Compared with prophylaxis, preemptive therapy resulted in significantly higher rates of CMV DNAemia (44% versus 75%, P < 0.001) and a higher proportion of patients experiencing episodes with higher viral load (≥2000 IU/ml), but significantly lower valganciclovir exposure and neutropenia.

Conclusion: Among kidney transplant recipients, the use of valganciclovir prophylaxis did not result in a significantly lower incidence of acute rejection compared with the use of preemptive therapy.

Clinical trial registry name and registration number: Optimizing Valganciclovir Efficacy in Renal Transplantation (OVERT Study), ACTRN12613000554763 .

Graphical abstract

Figure 1

Flow of patients through the study. CMV, cytomegalovirus; D, donor; R, recipient.

Figure 2

Cumulative incidence of acute rejection. Kaplan-Meier curves for rejection-free survival in (A) the entire study population and (B) patients without induction therapy. CI, confidence interval; HR, hazard ratio.

Figure 3

Protocol biopsy findings at 3 months after transplantation. (A) Incidence of subclinical rejection including the Banff borderline category, and (B) Banff interstitial inflammation and tubulitis scores. Data are percentage or mean±SEM.

Figure 4

Cumulative incidence of CMV disease and DNAemia. Kaplan-Meier curves for (A) CMV disease-free survival and CMV DNAemia-free survival in (B) the entire study population, (C) D+R− group, and (D) R+ group. CI, confidence interval; CMV, cytomegalovirus; D, donor; HR, hazard ratio; R, recipient.

Figure 5

Cumulative exposure to valganciclovir for cytomegalovirus prevention in the intention-to-treat population. (A) Duration of therapy, and (B) cumulative valganciclovir dose per patient. Data are mean±SEM. D, donor; R, recipient.

Figure 6

Cytomegalovirus-specific T-cell response by IFN-γ–secreting cells in seropositive recipients. Assessed by the enzyme-linked immunosorbent spot assay after stimulation by (A) pp65 or (B) IE-1 antigen pools and expressed as SFC per 2×10⁵ PBMCs. No significant differences were found in comparisons between prophylaxis and preemptive therapy. In both valganciclovir prophylaxis and preemptive therapy groups, there were significant differences between pre-transplant and post-transplant values in both pp65-specific (P<0.001) and IE-1–specific (P=0.001 and P=0.004) response by Friedman analysis of variance on ranks. Minimum and maximum values excluding outliers are represented by whiskers; median and interquartile range are inside boxes. SFC, spot-forming cell.