EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Cytomegalovirus infection is a major cause of morbidity and mortality in solid-organ transplant. Low doses of valacyclovir have been administered as cytomegalovirus prophylaxis in our institution for years. To the best of our knowledge, there is no published study of a low-dose regimen for cytomegalovirus prophylaxis in heart transplant patients. Therefore, our aim was to determine the results of low doses of valacyclovir in heart transplant.

Materials and Methods: Between September 2006 and December 2014, sixty-eight patients underwent orthotopic heart transplants. All of the patients received triple immunosuppressive therapy after surgery. During the next 6 months, sulfamethoxazole/trimethoprim was administered for Pneumocystis jiroveci pneumonia, and toxoplasmosis. Additionally all patients received valacyclovir hydrochloride (1000 mg/d, oral) for cytomegalovirus prophylaxis and nystatin oral rinse for prophylaxis of fungal infections.

Results: There was only 1 cytomegalovirus infection at follow-up. The patient had cytomegalovirus pneumonia at 17-month follow-up. In response to treatment with 1-week intravenous ganciclovir, the patient was discharged with a further 6-month oral valacyclovir therapy (1000 mg/d).

Conclusions: In this study, we hypothesized that daily use of low-dose valacyclovir (1000 mg/d) is not only sufficient for cytomegalovirus prophylaxis but also beneficial in terms of cost.

Key words : Treatment outcome, Valganciclovir, Solid-organ transplant

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in solid-organ transplant patients.¹ Many varieties of antiviral agents, with administration at different doses, have been used so far in the treatment of transplant patients with CMV infection and disease. Recently, some guidelines and reviews have recommended valganciclovir as the prophylactic agent of choice,² although prophylactic antiviral therapy (agent, dose, and duration) varies between centers, especially because of adverse effects and increased costs of the agents. In recent years, many studies have reported that valacyclovir, which is a prodrug converted in vivo to acyclovir, is effective both for CMV prophylaxis and for reducing transplant rejection.^3-5 However, the standard dosage protocol of 2000 mg valacyclovir every 6 hours may be responsible for neuropsychiatric symptoms in patients.⁶ A low dosage of valacyclovir has been used for CMV prophylaxis in our institution for years. To the best of our knowledge, there is no published study of a low-dose prophylactic regimen for CMV in heart transplant patients. Therefore, our aim in this study was to determine the results of low-dose valacyclovir in these patients.

Materials and Methods

Patient population
Between September 2006 and December 2014, sixty-eight patients underwent orthotopic heart transplant. Of these, 48 were male (70.5%). Patients ranged in age from 13 to 61 years old (mean age, 37 ± 13.6 y). The major indication for heart transplant was dilated cardiomyopathy (72.1%). Of 68 patients, 24 (35.2%) had undergone a previous cardiac surgery. All of the transplant procedures had been performed with bicaval surgical technique.

Postoperative treatment
Triple immunosuppressive therapy (5-10 mg/kg/d cyclosporine, 1 mg kg/d corticosteroid, and mycophenolate mofetil) was administered to all of our patients after surgery. Basiliximab induction therapy was administered on the day of surgery and at postoperative day 4. Antibiotic prophylaxis with cefazolin (1 g every 6 h intravenously) was continued until the chest tube was removed. For the next 6 months, sulfamethoxazole/trimethoprim (960 mg/d orally) was administered for Pneumocystis jiroveci pneumonia, and toxoplasmosis. Additionally all patients received valacyclovir hydrochloride (1000 mg/d orally) for CMV prophylaxis and nystatin oral rinse (5 mL/d) for prophylaxis of fungal infections. Antibiotic prophylaxis (sulfamethoxazole/trimethoprim, nystatin, and valacyclovir hydrochloride) was terminated 6 months after transplant.

Postoperative follow-up
At our institution, follow-up is monthly for the first 6 months and then every 3 months. All patients received detailed physical examinations, laboratory tests (biochemistry, total blood count, urine analysis, nasal, throat, and urine culture analyses), chest radiograph, and echocardiography examination during each office visit. Endomyocardial biopsy was performed at week 1 and week 2 after transplant and then at the first, third, sixth, and 12th months. Pulse methylprednisolone therapy (1 g/d for 3 d) was initiated for episodes of acute rejection. At 1 year after transplant, patients without major complications were followed every 3 months and examined by noninvasive procedures.

We administered a prophylactic regimen of oral valacyclovir in all of our transplant patients. Unless there are symptoms of CMV infection or disease, we do not screen CMV routinely with antigen titers or polymerase chain reaction analyses. If a recipient is suspected of having CMV, then these measures are requested.

Statistical analyses
Continuous variables are shown as means ± standard deviation or shown as median values with range if not normally distributed. Categoric variables are expressed as numbers and percentages. All statistical analyses were performed using SPSS statistical software (SPSS for Windows 15.0; SPSS Inc., Chicago, IL, USA).

The mean follow-up was 33.7 ± 31.4 months. Findings for the patient who had the longest follow-up were shown to be uneventful at 8.3 years. In 10 patients, there was a need for conversion of cyclosporine to other agents as a result of cyclosporine toxicity (5 to tacrolimus, 4 to everolimus, and 1 to sirolimus). There was only one CMV infection at follow-up (positive pp65 antigenemia), in which a patient had CMV pneumonia at month 17. After treatment with 1-week intravenous ganciclovir, the patient was discharged with a further 6-month oral valacyclovir therapy (1000 mg every 6 h). Four patients showed agitation postoperatively in the intensive care unit. However, administration of the drug (valacyclovir) was never interrupted. These agitations disappeared, with patients responding normally within 2 days. This situation was considered to be related to cardiopulmonary bypass; therefore, valacyclovir dosage reduction or discontinuation was not performed. Endomyocardial biopsy was performed as described above in the “Postoperative follow-up” section. In 231 biopsies, no chronic rejection was noticed. Three patients had angina and segmental wall contraction deterioration, as shown by echocardiography. These patients were diagnosed as allograft coronary vasculopathy after coronary angiography. Complications during follow-up are listed in Table 1.

Cytomegalovirus infection is defined as the isolation of Cytomegalovirus DNA or antigen from samples. On the other hand, CMV disease is defined as clinical findings and/or organ dysfunction along with evidence of cytomegalovirus infection.⁷ Although CMV infection after transplant is usually caused by donor origin, it may be caused by reactivation of the latent virus in the recipient. Manifestations of CMV disease in solid-organ transplant patients have a wide spectrum of clinical presentation (from a mild febrile illness to potentially fatal multiple organ failure), which is markedly more prevalent in the first 6 months after transplant.⁸

Cytomegalovirus infection is a major cause of morbidity and mortality in solid-organ transplant recipients. In addition, it has been shown that CMV infection is an independent risk factor for indirect acute or chronic allograft rejection.⁹ Prophylactic therapy or preemptive treatment is used to reduce the episodes of CMV infection in solid-organ transplant patients.¹⁰The certain consensus is that the prophylactic therapy is effective in reducing CMV infection rates and organ failure, even if there are controversies about which prophylactic strategy is better.¹¹ Common prophylactic antiviral agents include high-dose acyclovir, immunoglobulins, ganciclovir, and recently valganciclovir and valacyclovir. However, the main problem of the prophylactic strategy is the cost and adverse effects because of dosage levels.^12,13Therefore, there is still no optimal prophylactic strategy (agent, dose, and duration) for CMV infection. Intravenous immunoglobulin therapy brings increased costs, and it also has been documented that the effectiveness of this treatment is no better than ganciclovir.¹³ The effectiveness of oral acyclovir has been studied in many trials; however, it has been shown that the effectiveness is not adequate for donor seropositive/recipient seronegative patients.^14,15

Valacyclovir is a newly introduced agent to reduce CMV infections and rejections. Valacyclovir prophylaxis has been shown to reduce the incidence of CMV disease from 22% to 2%.¹⁶ Lowance and associates reported that high-dosage valacyclovir prophylaxis (8 g/d) was an effective modality.¹⁷ However, they indicated that the prophylactic therapy had to be discontinued for 38% of the patients because of neurologic adverse effects. Low-dose valacyclovir prophylaxis (3 g/d) has to be shown to be effective as a high-dose regimen. Despite low-dose levels, there are still occurrences of adverse effects.^18,19 Reddy and associates stated that the rate of drug discontinuation due to adverse effects was 6%.¹⁸ On the other hand, Sund and associates reported no neurologic adverse effects with low-dose valacyclovir prophylaxis (3 g/d).¹⁹ Toussaint and associates studied the efficacy of low-dose valacyclovir (3 g/day for 3 mo) and intravenous CMV immunoglobulin (1.8 g/wk) in donor seropositive/recipient seronegative patients. The incidence of CMV disease in their study was 5% at 6 months and 10% at 4 years.²⁰

The well-accepted opinion for the minimum dosage of valacyclovir in patients with glomerular filtration rate below 10 mL/min or in dialysis patients is 1500 mg.^19,20

The only patient group that does not require CMV antiviral prophylaxis is donor seronegative/recipient seronegative patients.²¹However, these patients are rarely encountered, and all recipients require antiviral prophylaxis against herpes simplex virus and varicella-zoster virus.²² For this reason, we do not test donors or recipients for CMV immunoglobulins M or G. We administer a lower dosage regimen for heart transplant patients (1 g/d) beginning at postoperative day 1, which is continued for 6 months. In our study, the incidence of CMV disease in the 8-year period was 1.4%, with 1 patient having CMV pneumonia.

A lower dosage regimen yields an additional benefit regarding cost of treatment. Legendre and associates reported valacyclovir as the most cost-effective prophylactic regimen in a study that compared the efficacy and costs of 8 g/day of valacyclovir versus oral ganciclovir.²³

In our study, we tried to show that use of low-dose valacyclovir 1000 mg/d is sufficient for prophylaxis of CMV and is beneficial in terms of cost.

The small number of patients, the fact that CMV immunoglobulins were not monitored in both donor and transplant patients, and the fact that comparisons of different doses were not made were the limitations of our study. However, we consider that this study, which consists of a small group of patients, showed the effective treatment with such low doses and will prompt the formation of larger studies in the future.

Volume: 14 Issue: 5 October 2016

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