Valganciclovir usage in adult SOT patients has been shown to be safe and efficacious in some studies and controversial in others (18
). It is widely utilized in pediatric SOT although evidence in pediatric liver transplant recipients specifically is limited. Few trials are available that include pediatric patients, and fewer still that only include liver transplants. This current study included patient’s ≤ 21 years of age who received a liver transplant at CCHMC. There was not a trend in primary liver disease and incidence of CMV infection or disease, or with any other demographic variable. There was a higher percentage of patients in the ganciclovir group in the 0–2 years age range as compared to the valganciclovir group. Due to the increased risk of acquisition of CMV in younger patients this difference could skew the results in the ganciclovir group, and could be a source of bias. No statistically significant difference was found between the numbers of patients in each age range. Of the total 56 patients evaluated 0/19 valganciclovir patients and 2/37 ganciclovir patients had documented early onset CMV disease. Late onset incidence of infection and disease was also evaluated due to information alluding to the idea that antiviral prophylaxis may only delay the onset of CMV (20
). Four of 18 valganciclovir and 3/37 ganciclovir patients had documented late onset CMV disease. This difference was not statistically significant. Due to the small sample size and discrepancy between the numbers of patients in each group it is difficult to discern clinical significance from this result. Six of the seven cases of late onset disease occurred within 60 days of discontinuation of antiviral therapy. Of the nine cases of CMV disease, three were considered to be tissue invasive and six were defined as CMV syndrome. Overall the incidence of CMV disease in the studied population was 16%, which is similar to that reported in previous studies (1
). There were no documented recurrences of CMV infection or disease in any patient within 200 days of transplant.
This study found no statistically significant difference when comparing the incidence of early and late onset CMV infection and disease between patients treated with oral ganciclovir or valganciclovir, although it was not adequately powered to do so. The original hypothesis that the incidence of early onset CMV infection was less in the valganciclovir group as compared to the ganciclovir group could not be accepted or rejected due to the small population size; no difference was found between the groups. The rates of discontinuation of antiviral therapy as well as the incidence of bone marrow toxicity, defined as anemia, thrombocytopenia, neutropenia and leukopenia, were similar between the two groups.
This study’s limitations include its design being one of a retrospective chart review wherein rare instances the definitions dictated by the CCHMC evidence based care guidelines were not followed in chart documentation and diagnosis codes by physicians. Further some patients were on sulfamethoxazole/trimethoprim therapy which can also cause bone marrow suppression. A limitation of this study method was the interpretation of chart documentation to determine the true cause of bone marrow suppression. Many more patients exhibited signs of anemia, thrombocytopenia, leukopenia and/or neutropenia, however only the sulfamethoxazole/trimethoprim was discontinued as the probable offending agent. The practice of discontinuing sulfamethoxazole/trimethoprim alone versus sulfamethoxazole/trimethoprim and the antiviral agent appeared physician specific. Some patients (n=valganciclovir, ganciclovir) also received other immune suppressing agents including azathioprine (n=1,0), mycophenolate mofeteil (n=7,7), sirolimus (n=2,2), pentamidine (n=7,11), and mercaptopurine (n=1,0). All patients in both treatment groups were receiving tacrolimus during all or part of the study period. Differences in cytopenia outcomes when taking into account these medications were not compared due to the small sample size. The true rate of adverse effects from valganciclovir and ganciclovir may therefore be higher than reported. The indication of the antiviral agent as the primary cause of the abnormal lab value of anemia, thrombocytopenia, leukopenia or neutropenia was dependent on documentation by the physician. Another limitation was the ability to determine reasoning for early discontinuation of therapy. Besides documentation of adverse drug events the reason for early discontinuation is unknown. Two patients were difficult to classify because they were treated as high risk patients despite the fact that their CMV serology status was unknown at the time of transplant.
There were only 56 patients that were able to be included in this study, thus with the small number that met inclusion criteria, this study was not powered to find a difference between the treatment groups. Therefore we are unable to make any concluding statements that one antiviral agent is superior or inferior to the other based on this study’s results. Although the total patient population included is small, when considering the fact that this is a pediatric study evaluating a very specific population, the (n) is actually relatively large for a single center pediatric liver transplant cohort.
Our study raises the need for future research to investigate the true incidence of late onset disease and whether there is an association between valganciclovir and an increased risk of late onset disease. This current study found an increased percentage of CMV disease in the valganciclovir group of 22.2% compared to 8.1% in the ganciclovir group. Although this difference was not statistically significant and the low number of occurrences limits the ability to determine a true clinical significance, this finding is concerning and does warrant future research. This result is particularly alarming considering the results of the Valganciclovir SOT Study Group led by Paya and colleagues (1
). The Valganciclovir SOT Study Group published an article which compared the Efficacy and Safety of Valganciclovir versus Oral Ganciclovir for Prevention of CMV Disease in Solid Organ Transplantation. It included patients greater than the age of thirteen who received their first heart, liver, kidney, kidney-pancreas, kidney-heart, or kidney-liver transplant with a CMV serology status of (D+)/ (R−). A population of 185 out of 372 total patients was liver transplant recipients. Incidence of CMV disease in the liver subgroup was 19% with valganciclovir and 12% with ganciclovir. Significant tissue invasive CMV disease was also found to be 4.5 times higher in the valganciclovir group (14% vs. 3%) at the time point of 6 months post-transplant. Due to the outcome of increased CMV disease in the valganciclovir arm compared to oral ganciclovir in liver transplant patients, valganciclovir did not receive FDA approval for CMV prophylaxis. Subsequent studies have shown no difference in the incidence of late onset CMV disease (4
); however this current study’s results do mimic those reported by Paya et al. Reasons for this reported difference in the liver transplant population are not known.
Thus to conclude, our results are inconclusive as to whether a difference exists in the safety and efficacy outcomes between ganciclovir and valganciclovir for prophylaxis of both early and late onset CMV infection and disease in pediatric liver transplant patients. Valganciclovir’s association with late onset CMV disease warrants further investigation. A larger multi-center prospective clinical trial in the pediatric liver transplant population may be warranted to address the important concerns raised by our single center retrospective review.