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 .

• MeSH
• Antiviral Agents adverse effects   MeSH
• Cytomegalovirus Infections * epidemiology   MeSH
• Cytomegalovirus genetics   MeSH
• Humans MeSH
• Neutropenia * chemically induced   complications   MeSH
• Transplant Recipients MeSH
• Kidney Transplantation * adverse effects   MeSH
• Valganciclovir adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Antiviral Agents MeSH
• Valganciclovir MeSH

BACKGROUND: Cytomegalovirus (CMV) prophylaxis may prevent CMV indirect effects in renal transplant recipients. This study aimed to compare the efficacy of valganciclovir and valacyclovir prophylaxis for CMV after renal transplantation with the focus on chronic histologic damage within the graft. METHODS: From November 2007 through April 2012, adult renal transplant recipients were randomized, in an open-label, single-center study, at a 1:1 ratio to 3-month prophylaxis with valganciclovir (n = 60) or valacyclovir (n = 59). The primary endpoint was moderate-to-severe interstitial fibrosis and tubular atrophy assessed by protocol biopsy at 3 years evaluated by a single pathologist blinded to the study group. The analysis was conducted in an intention-to-treat population. RESULTS: Among the 101 patients who had a protocol biopsy specimen available, the risk of moderate-to-severe interstitial fibrosis and tubular atrophy was significantly lower in those treated with valganciclovir (22% versus 34%; adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.90; P = 0.032 by multivariate logistic regression). The incidence of CMV disease (9% versus 2%; P = 0.115) and CMV DNAemia (36% versus 42%; P = 0.361) were not different at 3 years. CONCLUSIONS: Valganciclovir prophylaxis, as compared with valacyclovir, was associated with a reduced risk of moderate-to-severe interstitial fibrosis and tubular atrophy in patients after renal transplantation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12610000016033 ). Registered on September 26, 2007.

• Keywords
• Cytomegalovirus, Fibrosis, Prophylaxis, Renal transplantation, Valganciclovir,
• MeSH
• Intention to Treat Analysis MeSH
• Antibiotic Prophylaxis methods   MeSH
• Antiviral Agents therapeutic use   MeSH
• Cytomegalovirus Infections epidemiology   prevention & control   MeSH
• Cytomegalovirus drug effects   MeSH
• Adult MeSH
• Fibrosis epidemiology   prevention & control   MeSH
• Transplantation, Homologous adverse effects   MeSH
• Incidence MeSH
• Kidney drug effects   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Kidney Diseases epidemiology   prevention & control   MeSH
• Graft Survival drug effects   MeSH
• Kidney Transplantation * adverse effects   statistics & numerical data   MeSH
• Valacyclovir therapeutic use   MeSH
• Valganciclovir therapeutic use   MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH
• Geographicals
• Australia epidemiology   MeSH
• Names of Substances
• Antiviral Agents MeSH
• Valacyclovir MeSH
• Valganciclovir MeSH

BACKGROUND AND OBJECTIVES: Both valganciclovir and high-dose valacyclovir are recommended for cytomegalovirus prophylaxis after renal transplantation. A head-to-head comparison of both regimens is lacking. The objective of the study was to compare valacyclovir prophylaxis with valganciclovir, which constituted the control group. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: In a randomized, open-label, single-center trial, recipients of renal transplants (recipient or donor cytomegalovirus-seropositive) were randomly allocated (1:1) to 3-month prophylaxis with valacyclovir (2 g four times daily) or valganciclovir (900 mg daily). Enrollment occurred from November of 2007 to April of 2012. The primary end points were cytomegalovirus DNAemia and biopsy-proven acute rejection at 12 months. Analysis was by intention to treat. RESULTS: In total, 119 patients were assigned to valacyclovir (n=59) or valganciclovir prophylaxis (n=60). Cytomegalovirus DNAemia developed in 24 (43%) of 59 patients in the valacyclovir group and 18 (31%) of 60 patients in the valganciclovir group (adjusted hazard ratio, 1.35; 95% confidence interval, 0.71 to 2.54; P=0.36). The incidence of cytomegalovirus disease was 2% with valacyclovir and 5% with valganciclovir prophylaxis (adjusted hazard ratio, 0.21; 95% confidence interval, 0.01 to 5.90; P=0.36). Significantly more patients with valacyclovir prophylaxis developed biopsy-proven acute rejection (18 of 59 [31%] versus 10 of 60 [17%]; adjusted hazard ratio, 2.49; 95% confidence interval, 1.09 to 5.65; P=0.03). The incidence of polyomavirus viremia was higher in the valganciclovir group (18% versus 36%; adjusted hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.96; P=0.04). CONCLUSIONS: Valganciclovir shows no superior efficacy in cytomegalovirus DNAemia prevention compared with valacyclovir prophylaxis. However, the risk of biopsy-proven acute rejection is higher with valacyclovir.

• Keywords
• cytomegalovirus, prevention, renal transplantation, valacyclovir, valganciclovir,
• MeSH
• Acyclovir administration & dosage   adverse effects   analogs & derivatives   MeSH
• Acute Disease MeSH
• Intention to Treat Analysis MeSH
• Antiviral Agents administration & dosage   adverse effects   MeSH
• Biomarkers blood   MeSH
• Biopsy MeSH
• Time Factors MeSH
• Cytomegalovirus Infections diagnosis   immunology   prevention & control   virology   MeSH
• Cytomegalovirus drug effects   genetics   MeSH
• DNA, Viral blood   MeSH
• Adult MeSH
• Ganciclovir administration & dosage   adverse effects   analogs & derivatives   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Graft Survival drug effects   MeSH
• Graft Rejection diagnosis   immunology   prevention & control   MeSH
• Drug Administration Schedule MeSH
• Kidney Transplantation adverse effects   MeSH
• Valacyclovir MeSH
• Valganciclovir MeSH
• Valine administration & dosage   adverse effects   analogs & derivatives   MeSH
• Viral Load MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Comparative Study MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Acyclovir MeSH
• Antiviral Agents MeSH
• Biomarkers MeSH
• DNA, Viral MeSH
• Ganciclovir MeSH
• Immunosuppressive Agents MeSH
• Valacyclovir MeSH
• Valganciclovir MeSH
• Valine MeSH