Management of cytomegalovirus infection and disease in liver transplant recipients

Table 1 Direct and indirect clinical effects of cytomegalovirus after liver transplantation

Direct effects	Indirect effects
CMV syndrome	Acute allograft rejection
Fever	Chronic allograft rejection
Myelosuppression	Vanishing bile duct syndrome
Malaise	Chronic ductopenic rejection
Tissue-invasive CMV disease1	Hepatitis C virus recurrence
Gastrointestinal disease	Allograft hepatitis, fibrosis
(colitis, esophagitis, gastritis,	Allograft failure
enteritis)	Opportunistic and other infections
Hepatitis	Fungal superinfection
Pneumonitis	Nocardiosis
CNS disease	Bacterial superinfection
Retinitis	Epstein-Barr virus and PTLD
Mortality	HHV-6 and HHV-7 infections
	Vascular thrombosis
	New onset diabetes mellitus
	Mortality

¹Any organ system may be affected by cytomegalovirus (CMV). Data adapted from Ref. [104]. PTLD: Post-transplant lymphoproliferative disease; HHV: Human herpes virus.

Table 2 Estimated incidence of cytomegalovirus disease during the first 12 mo after liver transplantation

	Use of anti-CMV prophylaxis for 3-6 mo
	Yes1	No
CMV D+/R-	12%-30%	44%-65%
CMV D+/R+	2.70%	18.20%
CMV D-/R+	3.90%	7.90%
CMV D-/R-	0%	1%-2%
All patients	4.80%	18%-29%

¹Most cases occur as delayed-onset cytomegalovirus (CMV) disease. CMV disease occurs rarely during prophylaxis with oral valganciclovir. Data adapted from Ref. [4,5,92,104]. D: Donor; R: Recipient.

Table 3 Actors associated with increased risk of cytomegalovirus disease after liver transplantation

CMV D+/R- > CMV R+

Allograft rejection

High viral replication

Mycophenolate mofetil

Anti-thymocyte globulin

Alemtuzumab

Human herpesvirus-6

Human herpesvirus-7

Renal insufficiency

Deficiency in CMV-specific CD4+ T cells

Deficiency in CMV-specific CD8+ T cells

Toll-like receptor gene polymorphism

Mannose binding lectin deficiency

Chemokine and cytokine defects (IL-10, MCP-1, CCR5)

Expression of immune evasion genes

Programmed cell death 1 expression

Others1

¹Others include re-transplantation, volume of blood transfusion, sepsis and other factors associated with high tumor necrosis factor-α secretion. D: Donor; R: Recipient; IL-10: Interleukin-10; MCP-1: Monocyte chemotactic protein-1; CCR5: Chemokine (C-C motif) receptor 5; CMV: Cytomegalovirus.

Table 4 Currently available antiviral drugs for cytomegalovirus prophylaxis and treatment in liver transplant recipients

Drug	Route	Usual adult prophylaxis dose	Usual adult treatment dose	Comments on use and major toxicity
Ganciclovir	Intravenous	5 mg/kg once daily	5 mg/kg twice daily	Intravenous access; leukopenia
Ganciclovir	Oral	1 g three times daily	Not applicable	Low oral bioavailability; high pill burden
Valganciclovir	Oral	900 mg once daily	900 mg twice daily	Ease of administration; leukopenia
Foscarnet	Intravenous	Not recommended	60 mg/kg every 8 h (or 90 mg/kg every 12 h)	Second-line drug Intravenous access; nephrotoxicity
Cidofovir	Intravenous	Not recommended	5 mg/kg once weekly × 2 then every 2 wk thereafter	Third-line drug Intravenous access; nephrotoxicity