Management of refractory and resistant CMV: A step forward but more work needed

Abstract

Dear Editor The past decade has witnessed major advances in the management of CMV infection and disease following transplantation. An improved understanding of viral pathogenesis, advances in rapid molecular diagnostics, and large clinical trials evaluating preemptive and prophylactic strategies have changed the outlook of this previously commonly devastating infection. Ganciclovir and its orally available prodrug, valganciclovir, have traditionally been the backbone of both preventive and therapeutic strategies for CMV. While successful, there are patients with CMV infection who do not respond to ganciclovir (classified as refractory/resistant), or who are intolerant of ganciclovir due to adverse effects. This remains one of the major unmet needs related to CMV, especially since other available alternatives such as foscarnet and cidofovir have significant potential toxicity. The study by Linder et al1 in this issue of the Journal, provides some data around a potential therapeutic alternative for these patients. Indeed, letermovir represents the first new drug approved for CMV in many years. It is a potent inhibitor of viral replication and mediates its effect by binding to the UL56 protein in the viral terminase complex, thereby inhibiting cleavage of concatemeric strands of viral DNA. Based on this unique mechanism of action, letermovir does not exhibit cross-resistance to ganciclovir making it a potentially attractive therapeutic alternative in cases of ganciclovir resistant infection. Currently, letermovir is licensed for use as prophylaxis in hematopoietic stem cell transplant recipients based on a large randomized trial.2 However, data with respect to efficacy outside the prophylaxis setting, and especially for treatment of ganciclovir resistant/refractory disease has been largely limited to case reports and single center series. Linder et al1 report an observational cohort study of letermovir use for this indication across 13 centers in a mixed population of organ and stem cell recipients. They report a total of 47 patients who received letermovir for the treatment of CMV infection, representing the largest reported experience to date. Approximately one-third of these patients were treated with letermovir due to proven antiviral resistance. A mixed set of endpoints was used to define virologic failure. However, in patients who had a baseline CMV viral loads below 1000 IU/ml, response rates werequite favorable. For exampleonly twoof37 (5.4%) patients hadan increase of greater than 1-log10 viral load while on letermovir. However, more mixed response rates were observed in patients whose baseline CMV viral load was above 1000 IU/ml. For example, at the end of treatment or last checked viral load, only six of 10 (60%) had a value< 1000 IU/ml. The study provides valuable additional data to help guide clinicians in the very challenging treatment of these patients. Studies in patients with refractory CMV infection are inherently difficult to conduct, and the authors are to be commended on this. However, the study design does have a number of limitations which leaves significant room for interpretation. The lack of a control group prevents us from determining the exact contribution of letermovir in virologic response. Factors such as reduction in immunosuppression and the development of cellmediated immune responses may lead to spontaneous resolution of viremia and long-term viral control even in the absence of any antiviral therapy. Indeed, it is known that a significant portion of patients with low-level CMV viremia will spontaneously clear detectable viral replication in the absence of any specific intervention.3 This may partially explain the apparent differential effect observed in the current study in high versus low viral load patients. In addition, patients with high burden of replicative virus likely have a lower threshold to resistance emergence. In vitro data suggest that letermovir does indeed have a relatively low barrier to the development of resistance.4 Others limitations include variable doses of letermovir and difficulties in analyzing those that received combination therapy. The latter point was partially assessed by Jorgenson et al also published in this issue of the Journal.5 They evaluated the addition of letermovir to therapeutic dose valganciclovir in eight kidney and kidney-pancreas recipients with refractory viremia in a heavily pre-treated population. All patients had low viral load at the time of letermovir initiation (<1000 IU/ml) but none had complete viral clearance, although significant progression was not observed.One should keep inmind that the uniquemechanism of action of letermovir may mean that some viral genomic DNA is produced in the absence of whole virion production. This could at least theoretically result in ongoing low-level viral load detection by ultrasensitive PCR assays. What does the future state of CMV management look like? We are on the cusp of very significant changes with respect to this. Letermovir is now commonly used for CMV prophylaxis after stem cell transplantation, representing a significant paradigm shift. It is also being evaluated for prophylaxis in kidney transplant recipients in comparison to valganciclovir. On the treatment front, phase 2 studies of maribavir have shown promising results both as firstline preemptive therapy as well as treatment of refractory/resistant disease.6,7 A recent phase three trial ofmaribavir for the later indication has been completed, and full results are pending publication, but will likely lead to significant changes in our approach to this challenging problem. How will letermovir fit into this area of management of CMV infection in patients