Letermovir-inclusive combination therapy for a refractory and resistant infection by cytomegalovirus with UL54 mutation following a hematopoietic stem cell transplant for MHC class II deficiency.

Cytomegalovirus (CMV) infection remains one of the most common and challenging post-transplant infections. Children with inborn errors of immunity (IEI) and T-cell dysfunction are at high risk for CMV infection, which can be complicated by refractory and/or resistant cases. This case describes a Nepalese girl with MHC class II deficiency, who presented at 3 months of age with CMV and Pneumocystis jirovecii pneumonia. Hematopoietic stem cell transplantation (HSCT) was planned as a curative treatment for IEI. Initial antiviral therapy with ganciclovir, followed by foscarnet, achieved undetectable CMV viral loads. However, the viral load rebounded during foscarnet therapy. HSCT was performed at 7 months of age using peripheral blood stem cells from her CMV-seropositive father, despite the recipient's high CMV viral load. Empiric combination therapy with cidofovir (an unapproved drug in Japan), foscarnet, leflunomide, and artesunate was initiated. CMV genetic testing revealed UL54 mutations conferring high-level resistance to foscarnet and moderate-level resistance to ganciclovir. The regimen was adjusted to letermovir, ganciclovir, leflunomide, and artesunate, which successfully suppressed the viral load following engraftment. At three months post-HSCT, combination therapy was discontinued after sustained undetectable CMV viral loads. Although CMV infection was controlled, the patient died from idiopathic pulmonary hemorrhage at five months post-HSCT. This case highlights the potential efficacy of a letermovir-inclusive therapy regimen in managing drug-resistant CMV with UL54 mutations in a pediatric HSCT recipient.