Cytomegalovirus Resistance Linked to Subtherapeutic Ganciclovir

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The resistance of cytomegalovirus (CMV) to ganciclovir prophylaxis might be related to subtherapeutic levels of the antiviral agent, according to investigators from Loyola University Medical Center in Maywood, Illinois.

Although the study was small, the findings sparked a lively discussion among those attending the session on transplant infections at the International Society for Heart & Lung Transplantation 30th Anniversary Meeting.

CMV results in significant morbidity and mortality after lung transplantation. Prophylaxis with ganciclovir prevents this in the vast majority of cases, but approximately 10% of patients demonstrate resistance to the drug, lead author Jim Gagermeier, MD, told meeting attendees.

He and his colleagues conducted a retrospective review of all patients undergoing lung transplantation between March 2007 and March 2008 to identify ganciclovir resistance in CMV-infected patients. With the exception of patients who were donor-negative/recipient-negative for the virus, all received CMV prophylaxis with intravenous ganciclovir or oral valganciclovir.

Ganciclovir resistance was defined as a 50% inhibitory concentration of more than 1.5 µg/mL, as established by the plaque reduction assay.

The researchers identified 46 patients with CMV infection who were sensitive to ganciclovir and 5 with ganciclovir-resistant infections. Of these 5, all were found to have subtherapeutic ganciclovir trough levels. Four of the 5 had cystic fibrosis (CF), Dr. Gagermeier reported.

Mean trough levels (obtained 60 minutes prior to the next drug dose) were 1.9 µg/mL for the sensitive group, and less than 0.1 µg/mL for the ganciclovir-resistant group. The median time from CMV infection to the development of resistance was 45 days.

"These 5 patients were all on therapy but getting subtherapeutic levels, so they had ample time during which resistance could develop through normal transcription," he said.

"Initially, we only looked at those with ganciclovir resistance documented by CMV DNA sequencing; however, through the course of managing these patients, we became aware of the risk for resistance based on subtherapeutic trough levels. We began obtaining ganciclovir levels proactively in patients with suspected resistance based on a lack of response to treatment," he said.

This group consisted of 10 patients suspected of ganciclovir resistance, 7 of whom proved to be drug sensitive; all 7 had appropriate and therapeutic blood levels.

CMV donor/recipient mismatch was common among the resistant patients (80% vs 35% of the sensitive patients).

"Based on these differences, we can conclude that resistant infection occurs in about 10% of our patients. Admittedly, this is a small population, but all those with resistance had subtherapeutic levels of ganciclovir, and 4 of 5 had CF," he said. "We believe that suboptimal absorption or metabolism may result in subtherapeutic levels of ganciclovir. We therefore feel that patients with CF or known absorption problems may be at risk for drug resistance."

During the discussion, Dr. Gagermeier said that the resistant patients were started on the recommended ganciclovir dose, but the doses were pushed as high as possible when resistance was observed.

"If 5 mg/kg every 12 hours was inadequate, we increased it to 10 mg/kg up to 4 times a day to get to a therapeutic level," he said. "We gave very high doses, even in the face of possible myelosuppression and growth factor support."

The study's findings have led his team to try to identify drug resistance early on, ideally while patients are still hospitalized and receiving intravenous ganciclovir, as opposed to oral valganciclovir later. "Therapeutic levels for outpatients may really drop and allow resistance to develop," he said.

John McDyer, MD, from the Johns Hopkins Comprehensive Transplant Center in Baltimore, Maryland, who participated in the discussion, spoke with Medscape Transplantation. "I understand from our clinical pharmacist that checking ganciclovir levels is not a well-validated approach to monitoring ganciclovir, so I have some concerns about conclusions based on this. Having said that, I thought the data were intriguing, in that the resistance occurred mainly in high-risk patients mismatched for CMV status."

"Based on the timing of resistance (median, 42 days), I wonder if patients are breaking through the prophylaxis, which is a prescription for the development of resistance. At Hopkins, we have seen this phenomenon in patients on oral therapy, and this raises the specter of whether malabsorption is deleterious, especially in the donor-positive/recipient-negative patients who have no immunity to CMV. It may be that intravenous suppression is a safer route. I have not seen breakthroughs with [intravenous] administration."

In addition to the possibility of malabsorption, Vincent Valentine, MD, from the Division of Allergy, Pulmonary, Immunology, Critical Care, and Sleep at the University of Texas Medical Branch in Galveston, said that the resistant patients might simply be noncompliant. "How do you know they were taking the drug," he asked, "especially since they are CF patients and therefore a younger group. I question why we stop prophylaxis at all. When we do, we see problems."

Dr. Gagermeier and Dr. McDyer have disclosed no relevant financial relationships. Dr. Valentine reports being a shareholder of Novartis, Gilead, and Pfizer, and being on the speakers' bureau for Pfizer.

International Society for Heart & Lung Transplantation (ISHLT) 30th Anniversary Meeting: Abstract 189. Presented April 22, 2010.


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