Managing Post-Transplant Refractory/Resistant CMV Older antivirals for these severely immunocompromised patients are associated with serious toxicities; New agents look like better options. BY CONNI B. KOURY
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ytomegalovirus (CMV) infection is the most common infectious complication in solid organ transplant and hematopoietic stem cell transplant (HSCT) recipients. The incidence varies depending on the type of transplant, CMV serostatus of the donor and recipient, and the level of immunosuppression. Overall, about one-third of transplant patients will have CMV infection, which when left untreated, can progress to clinically severe and sometimes life-threatening disease. CMV infection more than doubles the risk for transplant loss and mortality, according to studies (Virology [Auckl] 2019;10:1178122X19840371. doi: 10.1177/1178122X19840371. eCollection 2019).
Resistant, Refractory Infection Some post-transplant CMV patients will develop infection or disease that is refractory and/or resistant (R/R) to previous anti-CMV treatment. Outside of CMV retinitis, there had been no FDA antiviral drugs approved for post-transplant CMV infection and disease, including R/R CMV. These patients, therefore, have been treated empirically with existing antivirals that include the IV agents ganciclovir, foscarnet and cidofovir, and oral valganciclovir. The older agents have significant challenges to their use, including toxicities, that may lead to premature discontinuation, predisposition to development of resistance, and ultimately failure to control CMV infection. One agent, letermovir (Prevymis, Merck), was approved in
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2017 for CMV prophylaxis. It has a favorable safety profile and is available in IV and oral dosage forms, but is only indicated for adult recipients of an allogeneic HSCT. “Fortunately, with appropriate use of antiviral therapy, both as prophylaxis and as treatment, R/R disease is rare,” said Camille Nelson Kotton, MD, FIDSA, FAST. “But when it does occur, there is significant morbidity and mortality associated with it as these patients are the most vulnerable and immunocompromised and at the highest risk for complications. It is a dreaded and challenging situation,” said Dr. Kotton, who is the clinical director, Transplant & Immunocompromised Host Infectious Disease Group, Infectious Diseases Division at Massachusetts General Hospital, and an associate professor at Harvard Medical School, both in Boston. She presented an overview of posttransplant R/R CMV infection and unmet needs to the FDA’s Antimicrobial Drugs Advisory Committee (ADAC) in October, when they gave the nod to maribavir (Takeda), which is now approved to treat refractory CMV infection and disease. Patients with R/R CMV have increased morbidity and mortality compared with patients who do not have R/R infection (Transplantation 2016;100[10]:e74-80). The treatment options have historically involved switching from oral valganciclovir to ganciclovir, increasing the dose of ganciclovir, or switching to foscarnet or cidofovir. High-dose ganciclovir is poorly tolerated due to neutropenia/cytopenias; forcarnet is associated with a risk for serious renal toxicity and electrolyte abnormalities;
