Paradoxical Rising Cytomegalovirus Antigenemia during Preemptive Ganciclovir Therapy in Hematopoietic Stem Cell Transplant Recipients: Incidence, Risk Factors, and Clinical Outcomes

Abstract

Preemptive ganciclovir (GCV) therapy is adopted increasingly in hematopoietic stem cell transplant (HCT) recipients, but occasional cases of increasing cytomegalovirus (CMV) antigenemia levels occur during preemptive GCV therapy. This prospective study investigated the incidence, risk factors, and clinical outcomes of paradoxical responses during GCV therapy. Adult patients receiving allogeneic HCTs during a 24-month period were enrolled. Patients were prospectively monitored for CMV antigenemia once a week until 3 months after engraftment. Paradoxical responders were defined as patients exhibiting CMV antigenemia levels elevated from the baseline after the first week of preemptive GCV therapy. Of 252 HCT recipients, 97 (38%) received preemptive GCV therapy due to CMV infection. Of these 97 patients, 23 (24%) were classified as paradoxical responders. Risk factors for paradoxical response were a low white blood cell ( Cytomegalovirus (CMV) diseases, including pneumonitis, gastroenteritis, retinitis, and encephalitis, are among the most important causes of morbidity and mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (HCT) (3,17,18). Recently, the value of noninvasive diagnostic methods such as CMV blood antigenemia assay (1) and CMV DNA assay by PCR (5) in identifying candidates for preemptive therapy after HCT has been demonstrated. While preemptive ganciclovir (GCV) therapy based on the CMV blood antigenemia assay is being adopted increasingly for HCT recipients (2), occasional cases show increasing CMV antigenemia levels during preemptive GCV therapy. However, there are limited data on the clinical characteristics and outcomes of these paradoxical responders to GCV (7-9, 15). We therefore investigated the incidence of and risk factors for paradoxical responses among HCT patients during preemptive GCV therapy and their clinical outcomes.

The impact of drug‐resistant cytomegalovirus in pediatric allogeneic hematopoietic cell transplant recipients: a prospective monitoring of UL97 and UL54 gene mutations

“…A paradoxical rise in viral load after initiation of preemptive therapy was observed in one‐quarter to one‐third of patients in some studies, and is considered to be a result of underlying immunosuppression . In our study, increasing CMV antigenemia at 1 week of antiviral therapy, compared to the beginning of therapy, was also observed in 49% of patients.…”

The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation

“…In the era of World Health Organization (WHO)‐standardized PCR surveillance and preemptive antiviral therapy, our observations add to the current knowledge base regarding the characteristics, complications, and clinical and economic impact of CMV‐I. In this cohort, the incidence of CMV‐I in allogeneic HSCT recipients was lower than in other studies . It is possible that the lower incidence of CMV‐I may be attributable to differences in CMV assays and host characteristics or perhaps to the initial IV dose of acyclovir prophylaxis administered.…”

“…In this cohort, the incidence of CMV-I in allogeneic HSCT recipients was lower than in other studies. 3,6,[17][18][19][20][21][22] It is possible that the lower incidence of CMV-I may be attributable to differences in CMV assays and host characteristics or perhaps to the initial IV dose of acyclovir prophylaxis administered. A protective benefit of highdose acyclovir has been reported in several previous studies, [23][24][25] but with considerable variation in what constitutes a "high" dose and with some question of reproducibility.…”

Viral Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients: Literature Review

“…Risk factors for developing resistance include previous anti-CMV drug exposure for a prolonged duration, inadequate dosing, bioavailability or absorption, profound immunosuppression, and corticosteroids usage. In drug-naïve patients, there might be a modest increase in viral load during the early phase of treatment because of immunosuppression and steroid use, this should not be labelled as clinical resistance and does not necessitate therapy change [71]. The incidence of CMV resistance has been reported to be around 14.5% [72].…”