Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants

Lancet. 2000 Aug 19;356(9230):645-9. doi: 10.1016/S0140-6736(00)02607-6.

Abstract

Background: Concerns have been raised about emergence of ganciclovir resistance as a result of the advent of both routine oral ganciclovir prophylaxis and highly potent immunosuppression. We retrospectively assessed the occurrence of ganciclovir-resistant cytomegalovirus disease among transplant recipients who had received oral ganciclovir prophylaxis and highly potent immunosuppression.

Methods: We studied 240 recipients of liver, kidney, or pancreas transplants. Antiviral susceptibility testing of blood cytomegaloviral isolates was done when patients failed to respond to intravenous ganciclovir treatment for symptomatic cytomegalovirus infection. Portions of the UL97 gene associated with ganciclovir resistance were sequenced in cytomegalovirus isolates with phenotypic resistance to ganciclovir.

Findings: Ganciclovir-resistant cytomegalovirus disease developed in five (7%) of 67 seronegative recipients of cytomegalovirus-seropositive organs (D+/R-) compared with none of 173 seropositive recipients (p=0.002). Among the 25 (10.4%) patients who developed cytomegalovirus disease within 1 year after transplantation, five had ganciclovir-resistant cytomegalovirus disease. Among D+/R-transplant recipients, ganciclovir-resistant cytomegalovirus disease was more common among the group receiving the most potent immunosuppression--ie, recipients of kidney and pancreas or pancreas alone (four of 19) compared with all other transplant recipients (one of 48, p=0.02). Ganciclovir-resistant cytomegalovirus disease was diagnosed at a median of 10 months after transplantation (range 7-12) after lengthened exposure to ganciclovir, was associated with previously described mutations of the UL97 gene, and led to serious clinical complications.

Interpretation: Ganciclovir-resistant cytomegalovirus is an important cause of late morbidity among D+/R- transplant recipients who have had lengthened exposure to ganciclovir and have received highly potent immunosuppression. Strategies to reduce this complication, especially among D+/R- patients, are warranted.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / therapeutic use*
  • Cytomegalovirus / drug effects
  • Cytomegalovirus / genetics
  • Cytomegalovirus / isolation & purification
  • Cytomegalovirus Infections / drug therapy*
  • Cytomegalovirus Infections / epidemiology
  • Drug Resistance, Microbial / genetics
  • Female
  • Foscarnet / therapeutic use
  • Ganciclovir / therapeutic use*
  • Humans
  • Immunosuppression Therapy / adverse effects*
  • Inhibitory Concentration 50
  • Kidney Transplantation / adverse effects
  • Liver Transplantation / adverse effects
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • Odds Ratio
  • Opportunistic Infections / epidemiology
  • Opportunistic Infections / virology
  • Organ Transplantation / adverse effects*
  • Pancreas Transplantation / adverse effects
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Retrospective Studies

Substances

  • Antiviral Agents
  • Foscarnet
  • Phosphotransferases (Alcohol Group Acceptor)
  • ganciclovir kinase
  • Ganciclovir