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The incidence and impact of cytomegalovirus (CMV) disease that occurs despite CMV prophylaxis among liver transplant recipients have been incompletely defined.The incidence and risk factors for CMV disease during the first posttransplant year in a cohort of liver transplant recipients who received antiviral prophylaxis with oral ganciclovir were retrospectively analyzed using Cox proportional-hazard regression models.CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04–0.11]) at a median of 4.5 months posttransplant, included syndrome (63%) or tissue-invasive disease (37%), and was independently associated with an increased risk of mortality during the first posttransplant year (hazard ratio 14 [95% confidence interval 3.8–54], P=0.0007). The incidence was higher (10/38 [26%] vs. 8/180 [4.5%], P<0.0001) in seronegative recipients (R−) of an organ from a seropositive donor (D+) compared with seropositive (R+) patients, respectively. D+R− status was the only variable significantly associated with CMV disease in multivariate analysis.Late CMV disease develops in a substantial proportion of D+R− recipients after prophylaxis is discontinued, is not accurately predicted by patient factors, and is associated with increased mortality. New strategies to identify D+R− patients at risk and to reduce the incidence and impact of late CMV disease in this group are warranted.