Valganciclovir Treatment of Cytomegalovirus Disease: A Promising But Not Yet Fully Validated Therapeutic Approach

To the Editor: The data presented by Fellay et al. (1) represent important information that supports the possible use of valganciclovir as an alternative to the ‘gold standard’ of intravenous (i.v.) ganciclovir therapy for cytomegalovirus (CMV) disease treatment in solid organ transplant (SOT) recipients, a substitution that is theoretically possible based on pharmacokinetic data (2). However, despite these promising results, high-quality evidence that valganciclovir is equivalent to i.v. ganciclovir with respect to efficacy and safety in this setting is lacking. Hopefully, this issue will be resolved when the results of an international multi-center randomized controlled trial, currently in progress, comparing valganciclovir to i.v. ganciclovir for CMV disease treatment are available. In the interim, it is premature to recommend valganciclovir as first-line therapy for CMV disease treatment. The data presented (1) support the need to implement several recommendations regarding CMV disease treatment outlined in the Canadian (3) and American (4) guidelines and reinforce the research priorities identified. Fellay et al. (1) identify treatment as having a high-dose ‘induction/treatment’ phase and a low-dose ‘maintenance’ phase. It is very important to differentiate true ‘treatment’—the use of drugs at full therapeutic doses—from ‘maintenance’ that is really secondary prophylaxis. In the setting of CMV disease, full-dose therapy (i.v. ganciclovir 5 m/kg q12h, adjusted for renal function) is recommended until at least 1 week after CMV viral load in peripheral blood, which if initially present, is undetectable in order to reduce the risk of relapse (1, 3). Whether Fellay et al. (1) may have been able to reduce rates of virologic and clinical relapse by using equivalent doses of valganciclovir and following the approach outlined above with respect to duration of therapy is unknown. ‘Undetectable viral load’ is difficult to define precisely as assays vary significantly; international standardization of quantitative viral load assessments and determination of clinically meaningful therapy endpoints that predict protection against relapse are clearly needed. Is there really any need for universal secondary prophylaxis or can clinical or laboratory parameters be used to identify the subset of patients who might benefit from secondary prophylaxis after receiving a full therapeutic course? Secondary prophylaxis, as described by Fellay et al. (1), is not without risks. Virologic relapse with high levels of virus replication in the presence of sub-therapeutic levels of ‘maintenance therapy’ are ideal conditions for the development of ganciclovir resistance. This is of particular concern when low doses of valganciclovir, below the 900 mg/day demonstrated to be of benefit as CMV prophylaxis (5), are being used, not as dose adjustments for renal impairment but in an attempt to reduce costs. That is why the guidelines recommend viral load monitoring during secondary prophylaxis and the use of granulocyte colony stimulating factor (G-CSF) rather than dose adjustment for managing ganciclovir-induced neutropenia (3, 4). It is critically important that we do not become complacent, believing that valganciclovir is ‘taking care of the CMV risk’ and, in the face of CMV disease, avoid lowering immunosuppression to the lowest levels possible. It is the restoration of CMV-specific immune responses and not valganciclovir that will ensure long-term freedom from CMV reactivation and disease. We hope that future data will allow us to recommend the use of valganciclovir as a first-line option for CMV disease treatment in SOT, as described by Fellay et al. (1), with its logistic simplicity, lower costs and avoidance of parenteral therapy risks.

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