A Randomized Trial of Valganciclovir Prophylaxis Versus Preemptive Therapy in Kidney Transplant Recipients
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 .
CET Conclusion
| Reviewer: | Mr Keno Mentor, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford |
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| Conclusion: | The relative benefits of CMV prophylaxis versus pre-emptive therapy (i.e. treatment only when early viral replication is demonstrated) is currently controversial. This RCT investigated one clinical aspect in which these two approaches are compared – the impact on acute rejection. 140 kidney transplant recipients were randomised to either strategy, and the rate of biopsy-proven rejected at 12 months was compared between groups. There was a numerically decreased rate of rejection in the prophylaxis group, but this did not reach statistical significance. Predictably, the prophylactic arm had lower positive rates of markers of CMV replication, but at the cost of higher rates of neutropaenia. The authors conclude that studies with longer follow up periods are required to address this question. However, with multiple other clinical considerations (e.g. practicality of CMV surveillance, resistance, late-onset disease), larger trials will be required to determine the specific patient sub-groups who would benefit from each approach. |
Methodological quality
| Jadad score | 3 |
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| Allocation concealment | YES |
| Data analysis | INTENTION TO TREAT |
Study Details
| Aims: | The aim of this study was to evaluate the effect of valganciclovir prophylaxis treatment in comparison to preemptive therapy in kidney transplant patients. |
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| Interventions: | Participants were randomly assigned to either valganciclovir prophylaxis or preemptive therapy. |
| Participants: | 146 adult kidney transplant recipients |
| Outcomes: | The primary endpoint was the incidence of acute rejection. The secondary endpoints were subclinical rejection, neutropenia, and cytomegalovirus (CMV) disease and DNAemia. |
| Follow Up: | 12 months |
Metadata
| Funding: | Non-industry funding |
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| Publication type: | Randomized Controlled Trial, Randomised Controlled Trial |
| Trial registration: | ACTRN12613000554763 |
| Organ: | Kidney |
| Language: | English |
| Author email: | reischig@fnplzen.cz |
| MeSH terms: | Humans; Valganciclovir; Antiviral Agents; Kidney Transplantation; Cytomegalovirus Infections; Cytomegalovirus; Neutropenia; Transplant Recipients; GCU97FKN3R (Valganciclovir); 0 (Antiviral Agents) |