How I treat resistant cytomegalovirus infection in hematopoietic cell transplantation recipients

Abstract

Cytomegalovirus (CMV) infection is a significant complication in hematopoietic cell transplantation (HCT) recipients. Four antiviral drugs are used for preventing or treating CMV: ganciclovir, valganciclovir, foscarnet, and cidofovir. With prolonged and repeated use of these drugs, CMV can become resistant to standard therapy, resulting in increased morbidity and mortality, especially in HCT recipients. Antiviral drug resistance should be suspected when CMV viremia (DNAemia or antigenemia) fails to improve or continue to increase after 2 weeks of appropriately dosed and delivered antiviral therapy. CMV resistance is diagnosed by detecting specific genetic mutations. UL97 mutations confer resistance to ganciclovir and valganciclovir, and a UL54 mutation confers multidrug resistance. Risk factors for resistance include prolonged or previous anti-CMV drug exposure or inadequate dosing, absorption, or bioavailability. Host risk factors include type of HCT and degree of immunosuppression. Depending on the genotyping results, multiple strategies can be adopted to treat resistant CMV infections, albeit no randomized clinical trials exist so far, after reducing immunosuppression (if possible): ganciclovir dose escalation, ganciclovir and foscarnet combination, and adjunct therapy such as CMV-specific cytotoxic T-lymphocyte infusions. Novel therapies such as maribavir, brincidofovir, and letermovir should be further studied for treatment of resistant CMV.

Donor mucosal immunocytes perpetuate refractory GVHD after intestinal transplantation without engrafting in recipient bone marrow: Case report and review of the literature

“…Consistent with the impression that GVHD and CMV viremia may be surrogates for over‐immunosuppression in our patient, the peak in serum CMV viral load temporally corresponded with the occurrence of GVHD and a decline in recipient immune cells in the allograft mucosa. Treatment is particularly difficult in patients like ours with UL97 mutations which confer medication resistance . This may account for her second episode of CMV viremia which was again associated with a GVHD flare.…”

“…Chimerism studies revealed 19.14% donor cells in the peripheral blood. Discovery of UL97 mutation confirmed resistance to ganciclovir . As a result, foscarnet was started and tacrolimus dose was decreased further to achieve target levels of 3‐5 ng/mL.…”

Specific Adoptive Cellular Immunotherapy in Allogeneic Stem Cell Transplantation

“…Especially during that critical time of depressed immunity, infections can cause severe medical conditions [44]. Therapy-related complications after allo-HSCT can especially arise from opportunistic and drug-refractory viral infections mediated by Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human adenovirus (HAdV) [45][46][47]. There is clear evidence that infections can be treated by the adoptive transfer of T cells specifically targeting viral antigens, and a number of technologies have been developed [48].…”

Treatment and Prevention of CMV Disease in Transplant Recipients: Current Knowledge and Future Perspectives

“…This is likely because these patients are experiencing primary CMV infection in the setting of intense exogenous immunosuppression and are therefore predisposed to prolonged high‐level viral replication, which in the setting of drug exposure may lead to the development of resistance . Although resistant CMV infections in HSCT or solid‐organ transplant recipients may not be common or well defined, they are associated with high morbidity and mortality . Resistance should be suspected in patients who fail to achieve a significant reduction in CMV DNAemia following at least 2 weeks of full‐dose CMV antiviral therapy, particularly in those who have previously received a CMV antiviral agent for at least 6 weeks .…”

“…Subtherapeutic dosing has been associated with the development of ganciclovir resistance . In addition to the administration of antiviral therapy, a reduction in the degree of immunosuppression should be considered, particularly among patients with severe and/or persistent CMV infection …”