Viral factors influencing the outcome of human cytomegalovirus infection in liver transplant recipients

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Abstract

Background

Cytomegalovirus (CMV) remains the leading viral cause of disease following orthotopic liver transplantation (OLT) despite the availability of antiviral agents for prophylaxis and therapy.

Objective

Examine the viral factors that influence the outcome of CMV infection following valganciclovir prophylaxis or laboratory-guided preemptive therapy in OLT recipients.

Study design

The value of valganciclovir prophylaxis and laboratory-guided preemptive therapy for the prevention of CMV infection and disease was observed in 64 OLT recipients. Prophylaxis was given to all CMV seronegative recipients receiving a liver from a seropositive donor (D+R−; n = 15), and all other recipients were randomised to receive either prophylaxis (n = 24) or laboratory-guided preemptive therapy (n = 25). Recipients were monitored for CMV DNAemia, viral load, emergence of antiviral resistant strains and co-infections.

Results

CMV end-organ disease and antiviral resistant strains only occurred in D+R− recipients despite the use of prophylaxis in these patients. The D+R− recipients commencing prophylaxis immediately following transplantation had better outcomes compared to those for whom prophylaxis was delayed due to renal impairment. Prophylaxis reduced the incidence of CMV DNAemia, persistent infection, and high viral loads for CMV seropositive (D−R+and D+R+) recipients, but laboratory-guided preemptive therapy effectively controlled CMV infection and prevented disease in these OLT recipients.

Conclusion

Delaying the commencement of valganciclovir prophylaxis may be associated with worse outcomes for high-risk OLT recipients. Laboratory-guided pre-emptive therapy remains an alternative approach for seropositive recipients at lower risk of CMV disease.

Section snippets

Background

Human cytomegalovirus (CMV) is one of the most common opportunistic viral infections following orthotopic liver transplantation (OLT), causing life-threatening illness in 5–10% of recipients.1, 2, 3, 4 The viral factors associated with clinical outcome of CMV infection post-OLT include initial viral load, replication kinetics and emergence of antiviral resistant strains.5, 6, 7, 8, 9 Other viral characteristics postulated to influence the course of post-OLT infection include CMV genotype,10

Objectives

Examine viral factors that influence CMV infection outcomes following valganciclovir prophylaxis or laboratory-guided preemptive therapy in OLT recipients.

Recruitment and randomisation

Adults undergoing OLT at the Liver Transplant Unit, Austin Health were recruited to a randomised study comparing valGCV prophylaxis with laboratory-guided preemptive therapy. The study was approved by the relevant ethics committees (Austin Health 01943, SESIAHS 06/029 and UNSW 06145) and patient consent obtained from all participants. Donor (D) and recipient (R) serostatus were determined pre-transplant. It is well established that prophylaxis is important in reducing the incidence of CMV

CMV infection and disease in D+R− OLT recipients receiving antiviral prophylaxis

Despite receiving prophylaxis, most (80%) D+R− recipients were infected with CMV post-transplant, and over half developed a persistent CMV infection with high viral load (Table 1). DNAemia usually developed following cessation of prophylaxis, but persistent infection was detected during prophylaxis for 5/15 recipients. CMV infection progressed to clinical disease for 3/15 D+R− recipients. One patient given valGCV prophylaxis immediately following transplantation, developed CMV hepatitis

Discussion

Transplantation from seropositive donors to seronegative recipients (D+R−) continues to be the major risk factor for development of CMV disease post-OLT, despite valGCV prophylaxis. Although insignificant due to low numbers, our results show delayed initiation of prophylaxis potentially contributes to worse outcomes for these recipients, and early, reduced dosage of valGCV may be a better strategy for prevention of CMV in recipients with renal impairment. The shortage of CMV seronegative donors

Conflict of interest

No conflict of interest.

Ethical approval

This study was approved by the ethics committees of Austin Health (01943), SESIAHS (06/029) and UNSW (06145).

Acknowledgements

The technical assistance of Zubair Waliuzzaman, Nikolas Rismanto and Catherine Smith and financial support of Roche Products, Australia is acknowledged with appreciation. This study is registered by ANZCTR (http://www.ANZCTR.org.au/ACTRN12610000787088.aspx) ACTRN: ACTRN12610000787088.

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