Evolution of mutations conferring multidrug resistance during prophylaxis and therapy for cytomegalovirus disease.
In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.
Chou
S
S
Medical and Research Services, VA Medical Center, Oregon Health Sciences University, Portland 97201, USA.
Marousek
G
G
Guentzel
S
S
Follansbee
S E
SE
Poscher
M E
ME
Lalezari
J P
JP
Miner
R C
RC
Drew
W L
WL
D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000517:prevention & control / Q000821:virology*; D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D003586:Cytomegalovirus Infections / Q000150:complications / Q000188:drug therapy* / Q000517:prevention & control / Q000821:virology; D003596:Cytosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D017245:Foscarnet / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D006801:Humans; D008297:Male; D009154:Mutation; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D017245:Foscarnet; D003596:Cytosine; D017853:Phosphotransferases (Alcohol Group Acceptor); C075365:ganciclovir kinase; D012194:RNA-Directed DNA Polymerase; D000077404:Cidofovir; D015774:Ganciclovir