Prospective study on CMV-reactivations under preemptive strategy in CMV-seropositive adult liver transplant recipients

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Abstract

Background

Cytomegalovirus (CMV) is a significant infectious agent after liver transplantation. To prevent CMV, most centres use prophylaxis for high-risk CMV-seronegative recipient/seropositive donor and many even for all seropositive recipients. However, pre-emptive therapy is commonly used for seropositive patients.

Objectives

A prospective, long-term follow-up of CMV-seropositive adult liver-transplant patients under pre-emptive strategy was investigated.

Study design

CMV-seropositive liver recipients were monitored for CMV by real-time quantitative plasma polymerase chain reaction (PCR) and received ganciclovir/valganciclovir pre-emptive therapy. The 161 patients with follow-up of >4 years were included in the study.

Results

No CMV was detected in most cases 98/161 (61%), but 63/161 (39%) developed CMV-DNAaemia mean 49 days (7–183 days) after transplantation. Only 25/63 reactivations exceeded 5000 copies/ml, which was considered as cut-off for the pre-emptive treatment by the method used (median 21,500, range 5100–813300 copies/ml) and most were self-limiting, low-level DNAaemias (median 850, range 234–4000 copies/ml). Thus, low-level temporal CMV viraemia occurred in 38/161 patients (23.5%) and only 25/161 (15.5%) demonstrated significant viral loads. Recurrent CMV appeared in one patient with low-level and in 11/25 with high-level DNAaemia, only 5/11 exceeding 5000 copies/ml. CMV infections were successfully treated with ganciclovir/valganciclovir. Four patients with low and three with high DNAaemia have been retransplanted. Five patients with low and two with high DNAaemia have died subsequently. No patient or graft was lost due to CMV.

Conclusions

Most CMV-seropositive liver recipients did not develop CMV reactivation, and if reactivations occurred, most were temporal, low-level DNAaemias. Significant CMV infections were successfully treated and recurrences were rare.

Introduction

Cytomegalovirus (CMV) is a significant infectious agent causing morbidity in transplant patients. CMV infection mostly appears within the first 2–3 months after transplantation. In addition to fever, end-organ disease, such as colitis and hepatitis, are the most common clinical symptoms after liver transplantation.1, 2 To prevent CMV infection, most liver centres use prophylaxis for high-risk CMV-seronegative recipients receiving an organ from a seropositive donor (D+/R−) and additionally many centres even use prophylaxis for all seroposive recipients (R+).1, 3 Pre-emptive treatment is mainly used for those at a moderate or low risk of CMV. Both strategies have decreased the incidence of CMV disease.4 Recent international guidelines summarise the advantages and disadvantages of both strategies in solid-organ transplantation.5 However, in Europe, pre-emptive therapy is commonly used, even for the patients at the risk of primary infection, and especially for (R+) liver-transplant patients.6, 7, 8

A major advantage of pre-emptive therapy is that patients who would not develop CMV disease are not exposed to unnecessary antiviral medication. Other advantages include lower drug costs and lower risk of late-onset CMV disease.4, 5 Pre-emptive therapy is based on screening for early evidence of CMV by frequent monitoring of viral load, usually by quantitative polymerase chain reaction (PCR) methods with specific cut-off levels.4, 5, 9 A disadvantage of pre-emptive therapy is that it might result in the onset of clinical illness prior to laboratory detection of CMV. This is especially the case in patients with primary infections, in which the replication kinetics of the virus can be very rapid.10 In CMV-seropositive recipients, however, pre-emptive strategy may be useful.

As the main interest has been focussed on the high-risk patients D+/R−, very little attention has been paid to the management of CMV in R+ patients. Here we report our experience on the prospective follow-up of CMV replication, demonstrated by quantitative PCR monitoring, in 161 CMV-seropositive (R+) adult liver-transplant patients under pre-emptive strategy.

Section snippets

Objectives

A prospective long-term follow-up of CMV-seropositive adult liver-transplant patients under pre-emptive strategy was investigated.

Study design

CMV-seropositive liver recipients, transplanted during the years 2003–2007, were monitored for CMV by real-time quantitative plasma PCR. The patients received ganciclovir/valganciclovir for pre-emptive CMV therapy. A total of 161 patients with follow-up of >4 years were included in the study.

Patients

Altogether 211 adult patients underwent liver transplantation with grafts from deceased donors at the Helsinki University Hospital during 2003–2007. Sixty-eight percent had end-stage chronic liver disease, 19% had acute liver failure, 9% hepatocellular carcinoma and 4% metabolic disease. The basic immunosuppression consisted of calcineurin inhibitors (cyclosporine or tacrolimus), azathioprine/mycophenole mophetil plus steroids tapered out and discontinued as feasible. Rejections were treated

Monitoring of CMV viral load

The patients were frequently monitored for CMV-DNAaemia from the day of transplantation onwards. Plasma samples were obtained at least weekly during the patients’ hospitalisation and thereafter once in 1–2 weeks for up to 3 months, once in 2–4 weeks for up to 6 months and then in most patients monthly or at least at 9 and 12 months postoperatively and in the case of clinical symptoms. In the case of a positive CMV finding, the patients were monitored until CMV-DNAaemia was no more detected. An

Results

In most cases, 98/161 (61%), no evidence of CMV was seen, and just 63/161 (39%) developed CMV-DNAaemia during the post-transplant year with a mean of 49 days (range 7–183 days) after transplantation. Only 25/63 reactivations exceeded 5000 copies/ml considered as cut-off level for pre-emptive treatment (median 21,500, range 5100–813300 copies/ml), and most had self-limiting, low-level CMV-DNAaemia (median 850, range 234–4000 copies/ml) (Fig. 1). There was a tendency of higher viral loads in the

Clinical outcome of the patients

Acute rejections verified by histology were diagnosed in 10/38 (26%) patients with low DNAaemia, in most (7/10) before CMV activation, only in one case during CMV DNAaemia and two thereafter. The patients with high viral loads had more acute rejections 14/25 (56%) which, however, in most (8/14) preceded CMV activation and only in one case did CMV and acute rejection occur concomitantly. However, there was no significant difference compared to those with no CMV-DNAaemia (42/98, 42%).

Four

Discussion

According to the international consensus guidelines both prophylaxis and a pre-emptive strategy are acceptable in liver transplantation.5 In a survey of CMV prevention strategies of 110 liver transplant centres, prophylaxis was preferred over pre-emptive therapy by the majority of centres in the prevention of CMV infection in the high-risk patients3 However, even 54–60% of the liver centres in Canada and USA have been reported to use prophylaxis also for moderate-risk patients (D−/R+) and

Funding

This work was supported by the grants from Sigrid Juselius Foundation (to KH and IL) and from Helsinki University Hospital Funds (to IL).

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study was approved by the Ethics Committee of Helsinki University Hospital.

Acknowledgement

The authors thank Stephen Venn for correcting the English text.

References (20)

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