Jim Kling

September 20, 2013

DENVER — The new standard of care, valganciclovir, is inferior to established combination therapy in patients undergoing high-risk orthotopic liver transplantation, a new study suggests.

In the pivotal clinical trials on which US Food and Drug Administration approval was based, valganciclovir, a prodrug that is converted to ganciclovir in the liver, appeared to be inferior to ganciclovir in the prevention of cytomegalovirus in liver transplant patients with mismatched donors.

However, the drug has nevertheless become the standard of prophylactic care in these patients, according to Natalie Nierenberg, MD, clinical instructor at Tufts University Medical Center in Boston. "Why is everyone across the country and around the globe still using it as a primary prophylaxis? It has become the standard of care, but we're not sure if what we're doing is best for the patients in this population," she said.

Dr. Nierenberg presented the study results here at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy.

Why is everyone across the country and around the globe still using it as a primary prophylaxis?

The researchers examined outcomes in liver transplant patients. They defined cytomegalovirus disease as organ damage or systemic illness combined with histologic or molecular evidence. The study was limited to high-risk patients (donor-positive and recipient-negative for cytomegalovirus) who underwent primary orthotopic liver transplantation and survived for at least 24 hours.

Of the 68 patients in the final study group, 57% received valganciclovir and 43% received ganciclovir plus cytomegalovirus immune globulin (CMVIg). More patients treated with valganciclovir than with ganciclovir plus CMVIg developed cytomegalovirus (41% vs 7%). In all cases of cytomegalovirus, the condition developed after prophylaxis had been stopped, at a median time of 163 days.

On univariate analysis, significant predictors of cytomegalovirus development were valganciclovir use and severity of liver disease. When severity of liver disease was controlled for in a multivariable model, only the use of valganciclovir, instead of ganciclovir plus CMVIg, was a significant predictor of cytomegalovirus (hazard ratio, 4.87; 95% confidence interval, 1.02 - 23.00; P = .05).

It is not clear whether a difference between the 2 therapies leads to a lower incidence of disease or if valganciclovir is truly inferior. "When I looked at these data, I couldn't help wonder why we are not using CMVIg, and why haven't we tried valganciclovir plus CMVIg. I never got a good answer," said Dr. Nierenberg.

Widely Available, Simple Administration

Pharmacokinetic and pharmacodynamic studies have shown that valganciclovir should be equivalent to ganciclovir. Valganciclovir might have been widely adopted because it is more orally available and administration is simpler, said Michael Green, MD, professor of pediatrics and surgery at Children's Hospital Pittsburgh, who attended the session. "For whatever reason, valganciclovir seems to be potentially inferior in liver patients. However, most people don't believe it and many continue to use it as their prophylaxis," Dr. Green told Medscape Medical News.

This study seems to counter that belief, although only 56 patients were evaluated, Dr. Green cautioned. He noted that one possible explanation is that liver transplant patients might convert valganciclovir to ganciclovir less efficiently. "Or maybe the study is really showing the benefit of CMVIg," he added.

Bias could also be an explanation. Cytomegalovirus has been linked to various complications of liver transplants. As a result, physicians could be looking more intently for infections. "This study was conducted at one of the major centers that pointed out the importance of the indirect effects of cytomegalovirus infection, so they could have a bias toward making the diagnosis in more recent times, and that's when patients got valganciclovir," Dr. Green explained.

Dr. Nierenberg and Dr. Green have disclosed no relevant financial relationships.

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract T-345. Presented September 10, 2013.


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