EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Cytomegalovirus infections cause the most frequent infection after solid-organ transplant. While Cytomegalovirus prophylaxis is established in high-risk patients (donor+/ recipient-), data on Cytomegalovirus prophylaxis in other serostatus constellation are rare. The aim of this study was to evaluate the influence of Cytomegalovirus treatment strategy after a liver transplant (preemptive therapy vs general prophylaxis) in the largest group of patients: Cytomegalovirus seropositive donor and recipient.

Materials and Methods: Forty-seven seropositive recipients of seropositive donor liver transplants (D+/R+, 2005-2012) were included in this retrospective study. Twenty-one patients received oral valganciclovir as Cytomegalovirus prophylaxis 100 days after transplant. Cytomegalovirus infection and Cytomegalovirus disease were monitored during the first 6 months.

Results: A Cytomegalovirus infection could be detected in 4 out of 47 patients (8.5%), including Cytomegalovirus disease in 2 patients (Cytomegalovirus pneumonia and Cytomegalovirus-CNS disease). Three of these patients received no Cytomegalovirus prophylaxis (P = .408). Eight patients developed a graft failure; this occurred more frequently among patients without Cytomegalovirus prophylaxis (P = .044). Patients receiving Cytomegalovirus prophylaxis more often developed leukopenia. No difference was seen regarding the number of platelets, hemoglobin, and creatinine.

Conclusions: Cytomegalovirus prophylaxis can minimize the risk of Cytomegalovirus reactivation and graft failure. However, disadvantages of the prophylaxis as leukopenia should be considered.

Key words : Cytomegalovirus treatment, Preemptive therapy, CMV prophylaxis, Liver transplant

Cytomegalovirus (CMV) is major cause for morbidity in patients receiving a liver transplant, resulting in reduced graft survival, acute or chronic rejection, and reduced overall survival.^1,2 Most CMV infections occur within the first 2 to 3 months after transplant.³ The severity of CMV infection can be differentiated in viral replication without clinical symptoms and symptomatic viremia or tissue-invasive disease (CMV disease).

Generally, the occurrence of CMV infection is significantly lower in CMV seropositive (R+) versus CMV seronegative (R-) patients (19%-33% vs 80%).^4,5 Consequently, risk of CMV infection for an organ recipient can be differentiated according to the CMV serostatus of recipient (R) and donor (D) in high-risk [R CMV-seronegative/D CMV-seropositive (R-/D+)] and intermediate-risk [R CMV-seropositive/ D CMV-seronegative or –positive (R+/D±)] recipients.

There are 2 approaches concerning CMV therapy: universal prophylaxis—daily intake using ganciclovir or valganciclovir for all patients for 100 days adopted to glomerular filtration rate, versus preemptive strategies: administration of an antiviral drug only in patients with viremia to prevent a progression to CMV disease. Most centers use CMV prophylaxis in high-risk seronegative patients who received a seropositive liver (D+/R-), while preemptive therapy is used by many centers for all seropositive recipients.⁶ However, a standardized CMV treatment strategy in the intermediate-risk group is still lacking. Thereby, as CMV is a common virus, a prevailing majority of the transplant recipients are CMV seropositive (R+). Beside the benefits of a treatment strategy therapy, possible adverse effects caused by CMV prophylaxis, including blood count changes, and also economic aspects of treatment costs play a role for decision-making.⁷

Therefore, the aim of the current study was an evaluation of the use of CMV prophylaxis versus preemptive strategy in the largest moderate-risk group: CMV seropositive donors and recipients (D+/R+).

Materials and Methods

Patient recruitment and data collection
Between January 2005 and December 2012, two hundred fifty-seven patients underwent a liver transplant with grafts from deceased donors at the Muenster University Hospital. Included in this study were 47 patients who were CMV serostatus positive (R+) and received a liver from a CMV positive donor (D+). Patient data were entered into a prospective database and analyzed for the purpose of this study retrospectively.

Treatment protocol
After liver transplant, postoperative immunosuppression consisted of tacrolimus, glucocorticosteroids, and mycophenolate mofetil. Patients were separated into 2 groups according to implementation of a CMV prophylaxis (yes [n = 21], no [n = 26]). Patients with CMV prophylaxis received within 10 days posttransplant (as soon as the patient could take oral medication) 450 mg (n = 16) or 900 mg (n = 5) valganciclovir (Valcyte; Hoffmann-La Roche Ltd, Basel, Switzerland) for 100 days posttransplant.

Determination of Cytomegalovirus viremia
In routine control examinations after 3-, 6-, 9-, 12-, 18, and 24-month laboratory tests including CMV virus isolation in blood (by detection of CMV DNA by PCR or CMV antigenemia by detection of pp65), laboratory parameters, and clinical examination, patients were monitored, among other things, for signs and symptoms of CMV disease, treatmentfor CMV disease, opportunistic infections, acute rejection episodes, and graft survival.

Definitions
Cytomegalovirus syndrome was defined as presence of CMV in blood (by detection of DNA by PCR or antigenemia by pp65) plus one or more of the following: fever > 38°C for at least 2 days, malaise, leukopenia, and thrombocytopenia. Cytomegalovirus organ disease was defined as pneumonia, hepatitis, gastrointestinal disease, nephritis, or central nervous system disease as described by Kotton and associates.⁸ Rejection was defined as acute allograft rejection reported up to 6 months after transplant. Leukopenia was defined as less than 2000 cells/µL, thrombocytopenia as less than 50 000/µL, and anemia as hemoglobin less than 10 mg/dL.

Statistical analyses
Data are presented as percentage of the entire patient population including number of patients in the respective group and as mean value ± standard deviation unless otherwise stated. A chi-squared test was used to compare categorical/ordinal variables, and a t test was used to compare categorical/ordinal and continuous variables. A P value ≤ .05 was considered statistically significant. Statistical analyses were performed using SPSS 22.0 for Mac (SPSS, Chicago, IL, USA).

Demographics and clinicopathological characteristics
Two hundred fifty-seven patients underwent a liver transplant from January 2005 through December 2012. A total of 47 patients were CMV serostatus D+/R+ and therefore included in this study: 21 patients received prophylaxis, 26 a preemptive therapy. Table 1 presents the demographic and clinicopathological characteristics of the included patients. The median follow-up was 13 months. Eight out of 47 patients (17%) died during follow-up. No deaths were CMV correlated.

Cytomegalovirus infection and graft rejection
Cytomegalovirus viremia could be detected in 4 out of 47 patients (8.5%); 2 of these patients developed a CMV disease (CMV pneumonia and CNS disease). Three of the patients with a CMV infection received no CMV prophylaxis (P = .408). Table 2 presents an overview of incidence of CMV infection including viremia and graft rejection.

Overall tolerability
Patients receiving CMV prophylaxis more often developed leukopenia (first month after transplant 5.73 cells/μL ± 2.27 vs 6.58 ± 3.39; P = .104; second month 4.26 ± 1.82 vs 5.32 ± 2.48; P = .057; and the third month 3.03 ± 2.08 vs 5.88 ± 2.8; P = .075). Regarding the number of platelets, there was no difference in hemoglobin and blood creatinine levels. Six months after transplant, all laboratory parameters results were comparable (see Table 3).

Cytomegalovirus infections remain the most frequent infection following solid-organ transplant. Incidence and severity of CMV infection depends among others on the CMV serostatus of donor and recipient. Currently, patients most at risk (“mismatch” patients [D+/R-]) receive an established CMV prophylaxis. Thereby, data on CMV prophylaxis in the different serostatus constellation—especially with intermediate risk—are rare, and the effect of treatment strategy on CMV reactivation is not clear.

This clinical study compared the effectiveness of 2 CMV treatment strategies: prophylaxis versus preemptive therapy in CMV seropositive donors and recipients after a liver transplant. This patient collective particularly challenges hospitals, as CMV seropositive patients constitute a significant part of the patient collective.3 In a direct comparison, we could demonstrate that a CMV prophylaxis can reduce the risk of CMV reactivation (1/21 vs 3/26) and graft failure (2/21 vs 2/26).

According to CMV status the incidence of a CMV disease without a CMV prophylaxis was as follows as: D+/R- 44-65%, D-/R+ 18.2%, D+/R+ 7.9%, and D-/R- 1-2%.7 Therefore, most studies divide patient collectively according to the serostatus in high risk recipients (D+/R-) and intermediate risk recipients (D±/R+), but the second group is not divided further. However, in CMV-seropositive liver transplant recipients, donor CMV seropositivity has been shown to be an independent risk factor for CMV reactivation.^4,7 Additionally, Florescu and associates revealed in their study that donor CMV strain more frequently causes CMV infection than the recipient virus.⁹ An earlier study by Gane and associates revealed similar results as our study: D+/R+ patients receiving a CMV prophylaxis with ganciclovir for 3 months developed significantly less CMV disease (2.6% vs 18.2%, P = .002).10 Atabani and associates included patients after liver transplant (n = 374) and kidney transplant (n = 497) who received a preemptive therapy. For the D+/R+ group, 54% of patients developed a viremia. In comparison to all patients after liver transplant, 42% developed a viremia and 5.6% developed a CMV syndrome.¹¹

A recent meta-analysis compared the 2 treatment strategies: CMV prophylaxis versus preemptive therapy in all patients after a liver transplant. In an evaluation of 32 studies, CMV disease rate was comparable in both strategies (10% vs 7%). Unfortunately, a differentiation according to CMV serostatus was impracticable.12 In a prospective study, Lautenschlager and associates evaluated the benefit of preemptive strategy in 161 CMV-seropositive liver transplant recipients with a follow-up of more than 4 years. They demonstrated that most CMV seropositive liver recipients do not develop a CMV disease—and in case of CMV replication (39% of all patients) most of them were temporal, self-limiting, low-level DNAaemias.3 Sun and associates administered 117 patients after liver transplant a preemptive therapy. Cytomegalovirus viremia occurred in 54% of all patients—including 63% of all D+/R+ patients. While patients with CMV viremia treated preemptively did not differ significantly from those who never developed CMV viremia with regard to bacterial (30.7% vs 16.7%) or fungal infections (9.5 vs 5.6%), rejection (30.2 vs 25.9%), and mortality rate (14.3 vs 11.1%), a trend toward an increased risk in case of CMV viremia was offered.¹²

A recent study evaluated the influence of pretransplant CMV antibody titers in CMV-seropositive recipients on the intensity of immunity against CMV reactivation. The included 225 patients did not receive a CMV prophylaxis and underwent close surveillance. Forty-two patients developed a CMV infection. Interestingly, patients who received an allograft from a CMV-seropositive donor (P < .001) had a significantly increased risk of CMV infection, and in a subgroup analysis of these D+/R+ patients the risk of CMV infection was significantly higher among patients with pretransplant CMV IgG titer of < 60 AU/mL (P = .02).13 Moreover, in a recent study, Gao and associates demonstrated in rat liver transplant that CMV infection, achieved by intraperitoneal CMV injection, accelerates the process of chronic liver rejection, detected by liver biopsy and blood sample until day 60 after the operation by aggravating bile duct damage, foam cell obliterative arteriopathy, and liver fibrosis.¹⁴ However, in a current update of the international consensus guidelines concerning management of CMV in solid-organ transplant, both treatment strategies prophylaxis versus preemptive therapy were accepted.8 It is worth mentioning that a preemptive therapy needs optimum patient care with recommended weekly routine checks during the first 12 weeks, which is sometimes difficult to perform.⁷

Possible adverse events of CMV treatment are well-known.⁷ Additionally, patients receiving a CMV prophylaxis in our study more often had leukopenia. Therefore, it should be noted that after transplant, surgical stress, perioperative immunosuppression, and malnourishment influence patients’ immune status including a perioperative leukopenia.¹⁵ Other laboratory parameters were not affected. In this context, it must be noted that we did not use creatinine clearance and neutropenia as possible laboratory parameters, but instead creatinine in serum and leukopenia. This is because of the retrospective design of our study. Finally, resistance to CMV treatment⁸ and late-onset CMV infection^7,8 were increasingly discussed. In our patient collective, no late-onset CMV infection occurred after 6 months (n = 39, 8 patients died during follow-up).

Altogether, a CMV prophylaxis can minimize the risk of CMV viremia, CMV reactivation, and graft failure in D+/R+ patients after liver transplant. However, particularly the potential benefit of reduced incidence of CMV viremia is still under discussion. Preemptive therapy may allow a comparable prevention of CMV disease, but logistics necessary to ensure timely assessment of biomarkers and appropriate and prompt reaction upon receipt of the results must be ensured. Furthermore, disadvantages of the prophylaxis as leukopenia should be respected.

Volume: 14 Issue: 4 August 2016

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