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Division of Infectious Diseases and Multi-Organ Transplant Program, University of Toronto, Toronto, Canada
We assessed valganciclovir for the treatment of cytomegalovirus (CMV) in organ-transplant recipients. Virologic and clinical outcomes were compared with those in matched historical control individuals. Thirty-two patients (23 with symptomatic disease) received valganciclovir, and 32 patients received intravenous (iv) ganciclovir. The rate of virologic clearance by day 21 of therapy was similar in the valganciclovir arm (50.0%) and the ganciclovir arm (46.9%) (P value not significant). The change from baseline viral load by day 7 and day 14 of therapy was similar in both arms. Two patients treated with valganciclovir required a switch to iv ganciclovir, because of a lack of response. Valganciclovir is useful for the treatment of CMV infection and disease in selected organ-transplant recipients.
Cytomegalovirus (CMV) infection remains a relatively common problem in organ-transplant recipients, despite the widespread use of prophylaxis [1]. Treatment of CMV infection and disease has traditionally been with intravenous (iv) ganciclovir [2]. Although iv therapy is effective, oral therapy would be preferable for many patients.
Oral ganciclovir is not recommended for treatment of CMV disease, because of poor bioavailability and concerns about efficacy [2]. Oral valganciclovir is an oral prodrug of ganciclovir that is rapidly hydrolyzed to ganciclovir after ingestion. It has an improved bioavailability of 60%, compared with 6%9% for standard oral ganciclovir [3, 4]. Although valganciclovir has been well studied as prophylaxis in organ-transplant recipients and as treatment of CMV retinitis in patients with AIDS, fewer data are available on treatment of CMV infection in solid-organtransplant recipients. In the present study, we prospectively assessed clinical and virologic outcomes in patients treated with valganciclovir for CMV infection and CMV disease and compared these outcomes with those in patients who received iv ganciclovir.
Patients and methods.
Informed consent was obtained from all patients for participation in the study. Human-experimentation guidelines of the authors' institution were followed in the conduct of this clinical research.
Patients with CMV infection and symptomatic disease were given therapeutic doses of oral valganciclovir. Guidelines regarding treatment with valganciclovir were provided, but the ultimate decision as to whether a patient was eligible for oral treatment was based on the judgment of the treating physician. Guidelines for oral treatment included evidence of CMV infection or disease, white blood cell count >1.0 billion cells/L, the ability to absorb oral medication (no severe diarrhea or mucositis), and no apparent immediately life-threatening CMV disease. Patients did not receive any immunoglobulin for concurrent treatment. Valganciclovir was given at standard treatment doses (900 mg twice daily, adjusted for renal function). The suggested minimum duration of treatment (unless therapy failed) was 2 weeks, although the treating physician determined the final duration.
Patients treated with valganciclovir were compared with a historical control group of consecutive matched patients treated with iv ganciclovir. Ganciclovir was given at doses of 5 mg/kg iv twice daily, adjusted for renal function. To allow for an accurate comparison of valganciclovir- and ganciclovir-treated patients, patients were matched according to type of transplant and viral load at the start of therapy (viral load within 0.5 log10 copies/mL at day 0, in a comparison between valganciclovir-treated patients and ganciclovir-treated patients).
All patients had to have a positive day-0 (start of therapy) antigenemia assay and viral load as assessed by polymerase chain reaction (PCR). After that, antigenemia and viral loads were assessed at regular intervals (a minimum of once per week) for a minimum of 4 weeks from the start of therapy. Antigenemia assay results were used to judge clinical response. Viral load data were not available to treating physicians.
Viral load testing (quantitative PCR) was performed using a commercially available LightCycler-based real-time PCR assay (Artus Biotech), in accordance with the manufacturer's instructions. The lower limit of detection for this assay is 10100 copies/mL. Any copy number <100 copies/mL was classified as "undetectable."
The primary outcome was the clearance of viremia (as determined by quantitative PCR) by day 21 of therapy (±48 h if no day-21 viral load data were available). Secondary outcomes included change in viral load by day 7 and day 14 of therapy (compared with day 0) and clearance of CMV antigenemia. Clinical response was assessed on the basis of a resolution of symptoms (if present) or ultimate clearance of viremia without the need for a change in therapy.
CMV infection was defined as any detectable virus, as assessed by antigenemia assay and quantitative PCR, and could be present in patients with or without symptoms. Symptomatic CMV disease was defined in accordance with criteria from a recently published Canadian consensus conference on CMV [5] and included viral syndrome and tissue-invasive disease.
Categorical variables were compared using 2 or Fisher's exact test. Continuous variables were compared using the Mann-Whitney U test. All statistical analysis was performed with SPSS (version 13.0).
Results.
Baseline characteristics, transplant types, and immunosuppression are shown in table 1 and were comparable between arms. A total of 64 patients were analyzed (32 patients treated with iv ganciclovir and 32 patients treated with valganciclovir). Two patients in the valganciclovir arm initially received iv ganciclovir but had their treatment changed to valganciclovir in 48 h and, therefore, were analyzed in the valganciclovir arm. The duration of induction therapy was 20.2 ± 12.7 days in the ganciclovir arm and was 20.5 ± 10.2 days in the valganciclovir arm (P = .5).
In the ganciclovir arm, 21 (65.6%) of 32 patients had symptomatic CMV disease, versus 23 (71.9%) of 32 patients in the valganciclovir arm (P = .8). The remainder of the patients had asymptomatic viremia or had nonspecific symptoms. Tissue-invasive disease was diagnosed in only 2 patients in the ganciclovir arm (1 with colitis and 1 with hepatitis) and 3 patients in the valganciclovir arm (2 with colitis and 1 with hepatitis). Pretransplant donor/recipient (D/R) serostatus was similar between arms (table 1). Prior CMV prophylaxis was very common in both arms, with 62.5% and 78.1% of patients having received prophylaxis in the ganciclovir and valganciclovir arms, respectively (P = .3). Prophylactic regimens included oral ganciclovir (n = 28), iv ganciclovir (n = 8), and valganciclovir (n = 9) for 3 months after transplant, at standard doses.
Virologic and clinical outcomes were compared in the 2 arms, and data are shown in table 2. The median viral load at the start of therapy (day 0) was 3.9 log10 copies/mL (range, 2.76.0 log10 copies/mL) in the ganciclovir arm and 3.8 log10 copies/mL (range, 2.26.0 log10 copies/mL) in the valganciclovir arm (P = .2). The median viral load in patients with CMV disease was 3.96 log10 copies/mL (range, 2.205.33 log10 copies/mL), versus 3.70 log10 copies/mL (range, 2.216.04 log10 copies/mL) in asymptomatic patients (P = .047). Clearance of viremia by day 21 of therapy was observed in 46.9% of ganciclovir-treated patients and in 50.0% of valganciclovir-treated patients (P = 1.0). In contrast, when the antigenemia assay was used to calculate clearance rates, a negative antigenemia by day 21 of therapy was observed in 29 (90.6%) of 32 and 26 (81.3%) of 32 patients, respectively (P = .5). The decrease in viral load by day 7 of therapy was similar between arms (0.64 log10 copies/mL decrease for ganciclovir vs. 0.73 log10 copies/mL decrease for valganciclovir) (P = .8). The decrease in viral load by day 14 of therapy was 1.30 log10 copies/mL for ganciclovir, versus 1.20 log10 copies/mL for valganciclovir (P = .3).
All patients in the ganciclovir arm were assessed as having had a clinical response to therapy. In the valganciclovir arm, 2 patients were switched to iv ganciclovir because of a lack of response, as determined by the treating physician. One patient (heart transplant; CMV viral syndrome; CMV D+/R+) was switched to iv ganciclovir after 5 days of oral therapy. His viral load at day 0 was 6.02 log10 copies/mL; at day 7, his viral load remained high, at 5.97 log10 copies/mL. He ultimately did not respond to iv ganciclovir and was successfully treated with foscarnet. Sequencing of the UL97 gene [6] from the day-0 sample demonstrated a mutation conferring ganciclovir resistance (Leu595Ser). The patient had previously received 3 months of oral ganciclovir treatment (1 g 3 times daily, adjusted for renal function) for CMV prophylaxis. The second patient (kidney transplant; CMV viral syndrome) was switched to iv ganciclovir after 1 week of oral therapy. Her day-0 viral load was 4.44 log10 copies/mL, and her day-7 viral load had increased to 5.85 log10 copies/mL. She did have a clinical and virologic response to iv ganciclovir, and no resistance mutations (in UL97 or UL54) could be demonstrated by sequencing. A virologic relapse (i.e., a positive viral load or antigenemia) occurred in 11 (34.4%) of 32 patients in both arms. Symptomatic relapse occurred in 8 (25%) of 32 patients in the ganciclovir arm and in 4 (12.5%) of 32 patients in the valganciclovir arm (P = .3).
The most significant adverse reactions were related to neutropenia. In both arms, 2 patients (6.25%) developed significant neutropenia (<1.0 billion cells/L). All of these patients were treated with granulocyte colony-stimulating factor. Three additional patients in the valganciclovir arm and 1 patient in the ganciclovir arm developed milder neutropenia, resulting in dose reduction or temporary discontinuation of therapy.
Discussion.
We have shown that oral valganciclovir is a useful option for therapy in asymptomatic CMV viremia and symptomatic CMV disease in solid-organtransplant recipients. Compared with those in historical control subjects matched for viral load at onset and for transplant type, CMV viral load kinetics in response to therapy in subjects in the present study were similar. Specifically, the rate of viral clearance (quantitative PCR or antigenemia assay) by day 21 and the log10 change in viral load by day 7 and day 14 were very similar in both arms of the study. However, patients being considered for oral therapy should be selected carefully. Patients with evidence of malabsorption or patients with life-threatening CMV disease are likely better suited for iv treatment. Also, although viral kinetics were similar in both arms, 2 (6.25%) of 32 patients treated with valganciclovir required a switch to iv ganciclovir therapy. We would recommend careful virologic and clinical monitoring of patients treated with oral therapy, to determine response and allow for prompt changes to alternative therapy if no response is evident. Our practice is to switch to iv ganciclovir in patients with increasing viral loads or lack of clinical response by day 7.
Valganciclovir has been well studied as prophylaxis in organ-transplant recipients. In a randomized trial comparing 3 months of prophylaxis with valganciclovir versus oral ganciclovir in 364 D+/R- transplant recipients, the incidence of CMV disease and viremia was comparable in both arms [1]. Fewer data are available on the use of valganciclovir for treatment of established symptomatic disease in this patient population. A randomized study in patients with AIDS who had CMV retinitis demonstrated equal rates of photoprogression in patients treated with iv ganciclovir and valganciclovir [7]. Mattes et al. [8] preemptively treated 22 patients (15 liver transplant recipients and 7 kidney transplant recipients) with CMV viremia (all asymptomatic) with oral valganciclovir and compared viral kinetics with those of 23 patients who received iv ganciclovir [8]. Viral kineticsincluding half-life, time to resolution of viremia, and change in viral load at day 7 and day 14were similar in both arms [8]. Kalpoe et al. [9] evaluated 15 kidney and kidney-pancreas transplant recipients treated preemptively for CMV viremia a total of 27 times. In a comparison of 18 treatment episodes with valganciclovir and 9 treatment episodes with iv ganciclovir, the median CMV DNA log10 reduction per day was similar with either treatment. Singh et al. [10] evaluated preemptive valganciclovir treatment in 17 liver transplant recipients. Successful clearance of antigenemia was documented in all patients, and no patient developed subsequent CMV disease. Our data support the findings of these previous studies but also extend them to the treatment of symptomatic CMV disease in addition to asymptomatic viremia.
The primary limitation of our study is that it was not a randomized controlled trial but, rather, compared outcomes with those of historical control subjects. This may result in certain biases. To try to prevent this, we used a virologic outcome as an objective primary end point. We also tried to carefully balance the 2 groups by using historical control subjects who were matched for type of transplant and viral load at onset of therapy. We believe that this resulted in 2 treatment arms that were very similar in terms of immunosuppression, D/R CMV serostatus, and symptom status. Another limitation was that patients treated with valganciclovir were carefully selected, and the number of patients with tissue-invasive disease was small. Therefore, the data are insufficient to recommend oral valganciclovir for therapy of tissue-invasive disease at this time. We did not assess long-term data on the treatment of recurrences. Use of multiple courses of valganciclovir in the setting of recurrent CMV infection may impact on ganciclovir resistance. Also, the use of lengthy courses of valganciclovir for suppression of viremia in patients with previous episodes of CMV infection was not assessed in the present study. Both these areas warrant further study.
In summary, valganciclovir is a reasonable option for the treatment of CMV infection and symptomatic CMV disease in solid-organtransplant recipients. Virologic and clinical outcomes are similar to those achieved with iv ganciclovir. However, careful clinical and virologic follow-up is required to detect early treatment failure and allow for a switch to alternative therapy, if necessary.
Acknowledgments
We are grateful to Tony Mazzulli for providing laboratory support and to Guy Boivin for performing ganciclovir resistance testing for 2 of the patients.
References
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