Valganciclovir as pre-emptive therapy for cytomegalovirus infection post-allogenic stem cell transplantation: implications for the emergence of drug-resistant cytomegalovirus.
OBJECTIVE
Valganciclovir is a well established drug for the management of cytomegalovirus (CMV) infection in haematopoietic stem cell transplantation (HSCT). Data concerning its safety regarding the development of drug resistance are required. The aim of the present study was to retrospectively investigate CMV drug resistance in a group of HSCT patients experiencing relapses of CMV infection after a first-line pre-emptive antiviral therapy.


METHODS
Thirteen adult HSCT patients out of 26 with asymptomatic CMV infection, experiencing relapsing infections 45-155 days after either intravenous (iv) ganciclovir (2 patients) or valganciclovir (11 patients), were studied. Genotypic assays for mutations in the viral phosphotransferase (UL97) and DNA-polymerase (UL54) genes were directly applied on patient specimens. Baseline CMV sequences were compared with those at the time of relapses to identify drug-resistant strains.


RESULTS
UL97 mutations A594V and M460V known to confer drug resistance developed in one relapsing patient who received iv ganciclovir as first-line therapy, corresponding to a rate of 7.7% of relapses due to drug-resistant strains and an overall 3.8% rate of infections due to CMV drug-resistant strains. UL54 drug resistance mutations were absent. No evidence of drug resistance was found in patients on valganciclovir either as first-line therapy or as treatment for relapses.


CONCLUSIONS
The safety profile of valganciclovir as anti-CMV pre-emptive therapy was confirmed, as well as that monitoring CMV drug resistance with genotypic tests on sequential isolates over the time-course of therapy offers guidance to tailor antiviral treatment in a clinically relevant time frame.
Allice
Tiziano
T
Department of Infectious Disease, Laboratory of Microbiology and Virology, Amedeo di Savoia Hospital, Turin, Italy.
Busca
Alessandro
A
Locatelli
Franco
F
Falda
Michele
M
Pittaluga
Fabrizia
F
Ghisetti
Valeria
V
D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018890:Chemoprevention / Q000379:methods*; D003587:Cytomegalovirus / Q000187:drug effects / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000517:prevention & control*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral; D015774:Ganciclovir / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020125:Mutation, Missense; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D012189:Retrospective Studies; D033581:Stem Cell Transplantation; D000077562:Valganciclovir; D014764:Viral Proteins / Q000235:genetics; D055815:Young Adult
D000998:Antiviral Agents; C109367:UL54 protein, Human herpesvirus 5; D014764:Viral Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D004259:DNA-Directed DNA Polymerase; D000077562:Valganciclovir; D015774:Ganciclovir