Drug Resistant CMV in Pediatric Hematopoietic Stem Cell Transplant Recipients

Background

            Drug resistant cytomegalovirus (CMV) has been described in pediatric hematopoietic stem cell (HSCT) patients; however, clinical significance is poorly described. 

Methods  

            With IRB approval we performed a retrospective analysis of HSCT recipients with CMV reactivation between January 2009 and February 2014.  Per institution guidelines, peripheral blood was screened twice weekly after transplant via CMV polymerase chain reaction (PCR).  Patients with reactivation (>200 copies/ml) received pre-emptive therapy with ganciclovir.  Patients with neutropenia (ANC< 500/mcl) received foscarnet.  Indications for CMV drug resistance gene testing included reactivation lasting beyond 2 weeks of therapy, 10-fold rise in PCR or development of CMV disease.  Viracor IBT Laboratories performed PCR gene-sequencing analysis for mutations of the UL97 phototransferase and UL54 DNA polymerase genes. 

Results

            Of 34 patients with CMV reactivation, 5.8% (n=2) had drug resistant virus.  One patient received only foscarnet and had ganciclovir resistant virus. This patient had both significantly elevated and prolonged positive viral load.  The second patient was exposed to foscarnet, ganciclovir and cidofovir prior to resistance testing and had virus resistant to ganciclovir and cidofovir.  

            We hypothesize patients with CMV disease are at risk of having drug resistant virus if they also have >20-fold rise in viral copies and/or prolonged viremia.  Five patients had >20 fold increase in viral copies after starting anti-viral therapy, one of which had ganciclovir resistant virus.  The second patient with drug resistant virus had only a 5-fold rise in viral copies but failed to respond to anti-viral therapy with persistent viremia 30 weeks from the start of anti-viral therapy.  Both patients with drug resistant virus developed CMV disease.  In contrast, 3 patients (8.8%) were not screened or negative for resistant virus and had CMV disease. 

Discussion

            Drug resistant CMV in pediatric HSCT recipients is rare and associated morbidity is poorly characterized.  Anti-viral exposure may not be associated with drug resistant virus in this population.  Our data implies a potential risk for community acquired ganciclovir resistant virus.  Both patients with drug resistant virus had clinical disease suggesting patients with drug resistant virus are at greater risk of developing CMV disease.  A prospective evaluation of gene mutation status at reactivation, after anti-viral therapy, with elevated viral load and with prolonged viremia is needed to better characterize drug resistant CMV. 

Primary Disease	Transplant	Resistance	Weeks of elevated PCR	Fold PCR increase	Anti-Viral Therapies	Disease
ALL	Allo UPSCT	N	9	54	Fos/Gan/Val	N
CML	Allo UBMT	N	4, 20	19, 64	Gan	N
AML	Allo UBMT	UL54 site T5031	20	69	Fos/Gan/Cid	Colitis
AML	Allo UPSCT	N	3	23	Fos	N
ALL	Allo UPSCT	UL97 site A594V	30	5	Fos/Val	Pneumonitis
HLH	Allo RBMT	NA	7	295	Fos	N