Randomized Controlled Trials to Define Viral Load Thresholds for Cytomegalovirus Pre-Emptive Therapy.
Griffiths PD, Rothwell E, et al.PLoS One 2016; 11(9): e0163722.
Aims
This study aimed to identify when to start and when to stop pre-emptive therapy for cytomegalovirus infection in renal, liver and bone marrow transplant recipients.
Interventions
Patients with two consecutive viraemia episodes each below 3000 genomes/ml were randomized to continue monitoring or to immediate treatment (Part A). A separate group of patients with viral load greater than 3000 genomes/ml were randomized to stop pre-emptive therapy when two consecutive levels less than 200 genomes/ml (168 IU/ml) or less than 3000 genomes/ml were obtained (Part B).
Participants
Adult kidney, liver or haematopoietic stem cells patients undergoing CMV surveillance in a single institution because of allogeneic transplantation were included.
Outcomes
The primary outcome was to define the number of patients with CMV viraemia who subsequently develop a viral load greater than 3000 genomes/ml in both parts of the study.
Follow-up
For part A of the study follow up was 57.5 days in the monitor arm, and 49 in the immediate treatme
CET Conclusions
This complex study investigated the triggers for starting and stopping pre-emptive therapy for CMV infection following transplantation. In the first part of the study, patients with low-level viraemia were randomised to continue monitoring or start immediate treatment. It demonstrated no difference in the proportion of patients going on to develop high level viraemia or tissue-invasive disease. The second part of the study randomised patients to stop therapy at different viral loads (200 copies/ml vs. 3000 copies/ml). Again, there was no difference in the proportion of patients developing a rebound high-level CMV PCR, and no difference in the rate of tissue invasive disease. Whilst the duration of antiviral treatment was shorter in those patients stopping treatment at a higher viral load, the requirement for subsequent treatment for high loads meant that the overall duration of therapy was not significantly different between groups. This is an interesting study that attempts to answer a very relevant question. There are some caveats. Inclusion of a heterogeneous group of liver, kidney and bone-marrow transplant recipients potentially limits generalisability (although randomisation was stratified to ensure balance between the groups). Whether the sample size is adequate is also questionable, as the first part of the study did not meet the recruitment target (only 59 of the required 72 patients were recruited) and many of the assumptions made in the sample size calculations did not turn out to be true.
Data analysis
Modified intention-to-treat analysis
Trial registration
ClinicalTrials.gov - NCT00947141