EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Cytomegalovirus is the most common viral infection after orthotopic liver transplant. The purpose of the present study was to determine the incidence of cytomegalovirus reactivation in Iranian liver transplant recipients at our center and to evaluate outcomes with preemptive therapy with ganciclovir for pp65 antigenemia.

Materials and Methods: There were 145 patients who had liver transplant and who survived > 2 weeks after transplant. All patients were evaluated for pp65 antigenemia weekly until 90 days after transplant. The diagnosis of cytomegalovirus reactivation was made when a recipient had pp65 antigenemia ≥ 1/50 000 leukocytes. In patients who had cytomegalovirus infection, preemptive therapy with ganciclovir (5 mg/kg, intravenous, twice daily) was started immediately after diagnosis and continued for ≥ 21 days and until cytomegalovirus antigen became undetectable on 2 consecutive tests.

Results: All patients in our study were seropositive for cytomegalovirus before transplant. Follow-up at mean 27 ± 20 months (range, 5.2 to 80.6 mo) after transplant showed that 46 patients (32%) had cytomegalovirus reactivation at mean 56 ± 67 days after transplant (range, 12 to 445 d). There was a higher frequency of female patients in the cytomegalovirus reactivation than non-reactivation group (odds ratio, 2.3; P ≤ .02). The most common causes of liver failure in the cytomegalovirus reactivation group were autoimmune hepatitis, cryptogenic cirrhosis, and hepatitis B virus cirrhosis. There was no significant relation between cause of liver failure, use of steroids before or after transplant, and frequency of acute rejection and cytomegalovirus reactivation. Only 1 patient (2%) developed cytomegalovirus disease at 22 days after transplant, and this patient was treated successfully. There were 6 patients (13%) who developed a second episode of cytomegalovirus reactivation at median 43 days (range, 10 to 176 d) after the first episode; all 6 patients were treated successfully with ganciclovir.

Conclusions: Preemptive treatment with ganciclovir may be an effective approach against cytomegalo-virus in seropositive recipients after liver transplant.

Key words : Ganciclovir, Hepatic failure, Prophylaxis, Treatment

Cytomegalovirus (CMV) is a herpesvirus that infects 60% to 100% humans, especially during the first 2 decades of life.¹ In healthy people, CMV disease may cause mild or no symptoms. However, the infection may remain latent in the host and may be reactivated in immunocompromised patients.

In liver transplant recipients, primary or reactivated CMV infection most commonly occurs within 3 months after transplant and may cause severe CMV disease that reduces graft and patient survival.^2-4 Infection with CMV is the most common viral infection after orthotopic liver transplant, and 8% to 30% liver transplant recipients who do not receive preventive therapy develop CMV disease.⁵ The prevalence of CMV disease is associated with the presence or absence of anti-CMV antibodies in the donor or recipient before transplant. The most commonly affected patients are CMV-seronegative recipients of liver allografts from CMV-seropositive donors (CMV D+/R-), and the next most common patients are recipients who were CMV-seropositive before transplant.⁶

Prophylaxis against CMV is an option because of the high risk of developing CMV disease in liver transplant recipients and the severe complications that may occur. The 2 major methods to prevent CMV include universal prophylaxis and preemptive therapy. In universal prophylaxis, the antiviral drug is given for a defined period to patients who are at risk. In preemptive therapy, patients are monitored closely for CMV infection, and the antiviral drug is given only to patients who are seropositive for CMV as determined from a pp65 antigen test or polymerase chain reaction.⁷

The purpose of the present study was to determine the incidence of CMV reactivation in Iranian liver transplant recipients at our center and to evaluate outcomes with preemptive therapy with ganciclovir for pp65 antigenemia.

Materials and Methods

From 2006 to 2013, there were 155 patients who had primary liver transplant at Imam Khomeini Hospital, Tehran University of Medical Sciences. There were 10 patients who died within 2 weeks after transplant, and the 145 patients (78 male and 67 female) who survived > 2 weeks after transplant were enrolled in the present study (age: mean, 40 ± 12 y; range, 8 to 62 y). Medical records were reviewed retrospectively for clinical data about recipients including demographics, CMV serologic status before transplant, surgical factors, postoperative pp65 antigenemia, CMV infection and disease, and allograft rejection. The study was approved by the Ethical Review Committee of the institute. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration.

Most recipients received immunosuppression with 3 drugs including a steroid, a calcineurin inhibitor, and mycophenolate mofetil. All patients were evaluated for pp65 antigen weekly from 0 to 90 days after liver transplant. The diagnosis of CMV reactivation was defined by pp65 antigenemia ≥ 1/50 000 leukocytes. In patients who had CMV infection, preemptive therapy with ganciclovir (5 mg/kg, intravenous, twice daily) was started immediately after diagnosis and continued for ≥ 21 days and until CMV antigen became undetectable on 2 consecutive tests. The diagnosis of CMV disease was defined by clinical features including fever, bone marrow suppression, and tissue invasive disease.⁶

Statistical analyses
Data analyses were performed with statistical software (IBM SPSS Statistics for Windows, Version 20.0, IBM Corp., Armonk, NY, USA). Patients were grouped as having CMV infection or no CMV infection (control). Within the CMV infection group, patients who had recurrence of CMV infection were compared to patients who had not recurrence of CMV infection. Comparisons were made with 2-tailed t test (quantitative data) and the Fisher exact test (qualitative data). Statistical significance was defined by P ≤ .05.

All patients in our study were seropositive for CMV before transplant. Follow-up at mean 27 ± 20 months (range, 5.2 to 80.6 mo) after transplant showed that 46 patients (32%) had CMV reactivation at mean 56 ± 67 days (range, 12 to 445 d) after transplant. The age of patients who had CMV reactivation (mean, 41 ± 12 y; range, 16 to 61 y) was similar to patients who had no CMV infection (control) (difference not significant). There was a higher frequency of female patients in the CMV reactivation group than control group (odds ratio, 2.3; P ≤ .02). The most common causes of liver failure in the CMV reactivation group were autoimmune hepatitis, cryptogenic cirrhosis, and hepatitis B virus cirrhosis. There was no significant relation between cause of liver failure, use of steroids before or after transplant, and frequency of acute rejection and CMV reactivation (all comparisons, not significant). Only 1 patient (2%) developed CMV disease at 22 days after transplant, and this patient was treated successfully. There were 6 patients (13%) who developed a second episode of CMV reactivation at median 43 days (range, 10 to 176 d) after the first episode; all 6 patients were treated successfully with ganciclovir. There was 1 patient (2%) who died at 7 months after transplant; this patient had CMV reactivation 15 days after transplant that was treated once, and bacterial sepsis was the cause of death.

All liver transplant recipients in the present study were seropositive for CMV before transplant, similar to previous reports that showed a prevalence of CMV antibodies higher in persons who live in Iran than in Western people.^8,9Liver donors were not routinely screened for CMV immunoglobulin G antibodies in the present study. Screening for CMV immuno-globulin G had not been recommended for adult Iranians; almost 100% liver donors are seropositive for CMV because of the socioeconomic status.¹⁰

Patients who are seropositive for CMV have a higher frequency of CMV infection after liver transplant than seronegative recipients of liver allografts from CMV-seronegative donors.¹¹ The CMV infection may be latent in host cells and may be endogenously reactivated in immunocompromised patients after liver transplant.¹² In the present study, the incidence of CMV reactivation was 32%, and previous studies showed that CMV infection may develop in 36% to 100% solid-organ recipients in the absence of prophylactic therapy, mostly within 3 months after transplant.^13,14 Reactivation of CMV may occur in 80% patients within 6 weeks after liver transplant.^13,14 In the present study, CMV was reactivated in 75% patients within 2 months after transplant.

There is controversy about the best approach against CMV infection after liver transplant.¹⁵ In the present patients who had reactivated CMV, only 1 patient (2%) developed CMV disease, consistent with previous findings that preemptive therapy may be effective in preventing CMV disease, especially among seropositive recipients.^16-18

Antiviral prophylaxis commonly is used after transplant in CMV seropositive recipients and may prevent CMV disease early after transplant.¹⁹ However, a major disadvantage of antiviral prophylaxis is the occurrence of late-onset CMV disease.^17,18,20-23 The incidence of late-onset CMV disease after stopping prophylaxis is 2.6% to 7% in patients who receive prophylaxis with ganciclovir.^24,25 Late-onset CMV disease may be caused by antigen presentation to the immune system, and patients may be at risk for developing the disease after the drug is stopped.²⁶ Preemptive therapy may have a beneficial effect on the acquisition of a CMV-specific immune response.²⁷ Therefore, prophylaxis is associated with late-onset disease, and preemptive therapy may be protective against late-onset disease.²⁸ No late-onset CMV disease occurred in the present study.

In summary, preemptive treatment with ganciclovir may be an effective approach against CMV in seropositive recipients after liver transplant and may avoid the risk of late-onset CMV disease.

Volume: 12 Issue: 1 March 2014 - Supplement - 1

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