Cytomegalovirus (CMV), a ubiquitous herpes virus that infects up to 60% to 100% of humans, is the single most common viral pathogen influencing the outcome of liver transplantation.1 Although a primary CMV infection in immune-competent individuals presents most commonly as an asymptomatic illness or a benign, febrile, infectious mononucleosis-like syndrome, it can lead to a highly morbid and sometimes fatal (if untreated) clinical disease in patients with compromised immune function, such as liver transplant recipients.1
1. Cytomegalovirus (CMV) is a common infection after liver transplantation and manifests as an asymptomatic infection or clinically as CMV syndrome (fever and myelosuppression) or tissue-invasive CMV disease.
2. The most common risk factor for CMV disease is donor positivity and recipient negativity for CMV, and severe impairment in immunity, especially with a pathogen-specific immune response, generally predisposes patients to CMV disease after transplantation.
3. The prevention of CMV disease after liver transplantation consists of preemptive therapy (antiviral therapy is administered only in the presence of a positive CMV polymerase chain reaction or pp65 antigenemia) or antiviral prophylaxis (an antiviral drug is administered to all patients at risk of CMV disease).
4. The treatment of CMV disease consists of intravenous ganciclovir (for severe disease) or oral valganciclovir (for mild to moderate CMV disease). Liver Transpl 16:S45-S53, 2010. © 2010 AASLD.
CLINICAL IMPACT OF CMV
Direct CMV Effects
The classic illness caused by CMV after transplantation manifests as fever, bone marrow suppression, and organ-invasive diseases1; these have been traditionally categorized as CMV syndrome (fever with bone marrow suppression) and tissue-invasive CMV disease (which may involve virtually any organ system).1 The most common organ system involved during CMV disease is the gastrointestinal tract (in the form of CMV gastritis, esophagitis, enteritis, and colitis), which accounts for more than 70% of tissue-invasive CMV disease cases.1-3 The transplanted organ is also predisposed to tissue invasion, so CMV hepatitis occurs more frequently in liver transplant recipients.1-3 Among liver transplant recipients who are not receiving effective antiviral prophylaxis, the direct effects of CMV are observed most commonly during the first 3 months after liver transplantation.2 Overall, it is estimated that 18% to 29% of all liver transplant recipients will develop CMV disease.1-3 However, this incidence varies with the donor and recipient CMV serological status; it may be as high as 44% to 65% in CMV donor-positive/recipient-negative (D+/R−) liver transplant recipients or as low as 8% to 19% in CMV-seropositive [recipient-positive (R+)] liver transplant recipients.1-3 This incidence is markedly reduced in liver recipients who have received 3 months of prophylaxis with valganciclovir or oral ganciclovir (12%-30% of CMV D+/R− liver transplant recipients and <10% of CMV R+ liver transplant recipients).1-3
Indirect CMV Effects
The clinical impact of CMV after liver transplantation extends beyond its direct effects to numerous indirect outcomes that are believed to be mediated by the ability of CMV to modulate the immune system.1 CMV is known to be a potent up-regulator of alloantigens and increases the risk of acute rejection and chronic allograft dysfunction.1 The immunomodulatory effects of CMV have been suggested to account for the higher predisposition to developing infections due to other opportunistic infections, including fungi, other viruses, and bacteria such as Nocardia sp.1 CMV-infected transplant recipients are also more likely to develop Epstein-Barr virus–associated posttransplant lymphoproliferative disorders or coinfections with other viruses such as human herpesvirus 6 and human herpesvirus 7.1 Similarly, a significant association between CMV and hepatitis C virus after liver transplantation has also been described,4 and this clinically manifests as a more accelerated clinical course of hepatitis C virus recurrence among patients who have developed CMV infection and disease.
Impact on Mortality
Through direct, indirect, and possibly immunomodulatory mechanisms, CMV is an important predictor of mortality after transplantation.2, 5, 6 With the use of effective antiviral drugs for prevention and treatment, death due to CMV disease has been remarkably reduced. Several meta-analyses have demonstrated that anti-CMV drugs, through either antiviral prophylaxis or preemptive therapy, are associated with significant reductions in mortality after transplantation.7-12 Despite these improvements in outcome with the widespread use of antiviral drugs, delayed-onset CMV disease after prophylaxis remains significantly associated with an increased risk of mortality after liver transplantation.5, 6
RISK FACTORS FOR CMV DISEASE
Lack or Deficiency of CMV-Specific Immunity
The most important risk factor for the occurrence of CMV disease after liver transplantation is a lack of effective CMV-specific immunity. Specifically, CMV D+/R− patients are at highest risk of CMV disease, whereas CMV R+ patients have a modest risk, and CMV donor-negative/recipient-negative patients have the lowest risk. Defects in innate immunity, such as mutations in innate immunity–associated genes, increase the risk of CMV after liver transplantation. CMV-specific T cells are necessary for adequate control of CMV after liver transplantation, and their deficiency increases the risk.13 Other immune measures, such as programmed death 1 expression, mannose binding lectin levels or gene mutation, and immune evasion genes, have been assessed as prognostic indicators of CMV disease after transplantation.
Severe pharmacological immunosuppression impairs the ability of liver transplant recipients to mount an effective immune response against CMV and thereby predisposes them to a higher risk of CMV disease. The severity of immune dysfunction is particularly intense with the use of lymphocyte-depleting drugs in either induction or rejection therapy, such as muromonab-CD3 (OKT3) and anti-thymocyte globulin. Drugs used for maintenance immunosuppression (particularly high doses of mycophenolate mofetil) have also been associated with CMV disease. More recently, the use of newer maintenance immunosuppressive drugs such as sirolimus and everolimus (mammalian target of rapamycin inhibitors) has been found to be associated with a lower risk of CMV disease.14, 15 However, it is very likely that the specific immunosuppressive drugs predispose patients not only to CMV disease but also to the net state of combined pharmacological immunosuppression that increases the risk of CMV disease after liver transplantation.
Allograft rejection is often associated with CMV reactivation, and thus it is considered a significant risk factor for CMV disease after liver transplantation.16 It has been hypothesized that cytokines released during episodes of acute rejection (particularly tumor necrosis factor α) can transactivate CMV from its state of latency. By enhancing viral replication and impairing the generation of effective CMV-specific cell-mediated immunity, subsequent therapy for allograft rejection with intensified immunosuppression further enhances the risk of CMV disease.
The risk of CMV disease after liver transplantation is associated in direct proportion with the degree of CMV replication, which is partly a function of overimmunosuppression. Other factors associated with CMV disease after liver transplantation include the cold ischemia time, bacterial and fungal infections and sepsis, blood loss, fulminant hepatic failure, age, female gender, and renal insufficiency.
PREVENTION OF CMV DISEASE
There are 2 major strategies for CMV disease prevention after liver transplantation:
- 1Preemptive therapy: Patients are monitored for CMV replication by sensitive assays such as polymerase chain reaction (PCR) and pp65 antigenemia, and upon the detection of asymptomatic CMV replication, antiviral therapy is administered preemptively to prevent progression to symptomatic clinical disease.
- 2Antiviral prophylaxis: Antiviral drugs such as valganciclovir are administered to all patients at risk of CMV disease after liver transplantation (Table 1).
|Modifying Circumstance||Primary (Preferred) Strategy and Agents||Alternative Strategy and Agents||Comments|
|D+/R−||Antiviral prophylaxis preferred: valganciclovir (900 mg po qd for 3 months)||Antiviral prophylaxis: ganciclovir (1 g po tid) Preemptive therapy: valganciclovir (900 mg po bid) or ganciclovir (5 mg/kg IV q12h) for positive CMV PCR or antigenemia test (the duration of treatment is guided by CMV surveillance)||Valganciclovir is not FDA-approved for liver transplant recipients, but it is still the most commonly used drug for prophylaxis. Late-onset CMV disease is the major complication of prophylaxis and occurs in 10% to 30% of D+/R− patients.1 Foscarnet and cidofovir are generally not recommended for primary prophylaxis because of the high risk of toxicity.|
|R+||Antiviral prophylaxis: valganciclovir (900 mg po qd for 3 months)||Ganciclovir (1 g po tid)||There is a low risk of late-onset CMV disease in comparison with D+/R− patients. Foscarnet and cidofovir are not generally recommended for primary prophylaxis because of the high risk of toxicity.|
|Preemptive therapy: valganciclovir (900 mg po bid) for positive CMV PCR or antigenemia (the duration is guided by repeat CMV surveillance)||Ganciclovir (5 mg/kg IV q12h) for positive CMV PCR or antigenemia test (the duration is guided by repeat CMV surveillance)||Oral ganciclovir and valacyclovir should not be used for preemptive therapy. Foscarnet and cidofovir are not generally recommended for preemptive therapy because of the high risk of toxicity.|
|Rejection||Antiviral prophylaxis preferred: valganciclovir s(900 mg qd)||Antiviral prophylaxis: ganciclovir (5 mg/kg IV q12h) Preemptive therapy: valganciclovir (900 mg po bid) or ganciclovir (5 mg/kg IV q12h) for positive CMV PCR or antigenemia test (the duration is guided by repeat CMV surveillance)||There is a high risk of CMV reactivation during the treatment of acute rejection, especially with lymphocyte-depleting agents in D+/R− patients. The duration of antiviral prophylaxis is 2 to 4 weeks. Foscarnet and cidofovir are not generally recommended for primary prophylaxis or preemptive therapy because of associated toxicity.|
The basic principle of preemptive therapy is the detection of CMV replication before the onset of clinical symptoms so that antiviral therapy can be administered early in order to prevent the progression of an asymptomatic infection to full-blown clinical disease.14, 15 Preemptive therapy has the potential advantage of providing therapy to the highest risk patients and thereby decreasing drug costs and toxicity. The success of this approach relies on several factors: (1) optimal laboratory testing and frequency and duration of monitoring, (2) the selection of the appropriate population for preemptive therapy, and (3) the type of antiviral drug and the dose and duration chosen.
Either the CMV pp65 antigenemia assay or quantitative PCR may be used in the preemptive approach. The optimal interval and duration of monitoring are unknown, but approximately once weekly testing for 12 weeks after transplantation is suggested. Several studies have reported the success of intravenous (IV) or oral ganciclovir or valganciclovir in the preemptive treatment of CMV reactivation in liver transplant recipients, including high-risk CMV D+/R− patients. Recent meta-analyses that have collectively analyzed data from prospective clinical trials have demonstrated the benefits of preemptive therapy in preventing CMV disease.8 When it was conducted properly, preemptive therapy using oral ganciclovir, IV ganciclovir, or valganciclovir resulted in a reduction of CMV disease of approximately 70%.8 Moreover, preemptive therapy is much less likely to be associated with late-onset CMV disease (unlike antiviral prophylaxis, as discussed next). Currently, valganciclovir is the drug most commonly used for preemptive therapy, and in one uncontrolled study, it was as effective as IV ganciclovir in terms of clinical and virological response.
Antiviral prophylaxis is highly effective in preventing the direct and indirect effects of CMV after liver transplantation.1, 8, 14, 15, 17 In comparison with patients who received a placebo or no treatment, patients who received antiviral prophylaxis had a lower incidence of CMV disease (58%-80% reduction) and CMV infection (an approximately 40% reduction).8 In one meta-analysis, a 25% reduction in the incidence of acute allograft rejection was observed. In 2 studies, a reduction in all-cause mortality was observed,8 and this was mainly due to a decline in CMV-related death. A reduction in the incidence of other herpes viruses, bacterial infections, and protozoan infections were also observed.8 Because of these additional benefits, liver transplant centers prefer antiviral prophylaxis over preemptive therapy in the prevention of CMV disease, particularly in CMV D+/R− liver transplant recipients.18
A ganciclovir-based regimen is more effective than acyclovir or immunoglobulins in reducing the incidence of CMV after liver transplantation. Valganciclovir, a valine ester of ganciclovir, provides systemic ganciclovir levels that are comparable to those provided by IV ganciclovir. Pharmacokinetic studies have indicated that a 900-mg dose of valganciclovir achieves a daily area under the concentration-time curve similar to that achieved by a 5 mg/kg dose of IV ganciclovir. Hence, valganciclovir [900 mg once a day (qd)] has the advantage of avoiding the costs and risks of IV ganciclovir and the pill burden and poor absorption of oral ganciclovir. The role of valganciclovir in the prevention of CMV disease after liver transplantation was evaluated in a multicenter, randomized, noninferiority clinical trial that compared it to oral ganciclovir in a cohort of 364 CMV D+/R− solid organ transplant (including liver transplant) recipients.19 The 6-month incidence of CMV disease was 12% and 15% in the valganciclovir and oral ganciclovir groups, respectively.19 Follow-up at 1 year demonstrated that the incidence of protocol-defined CMV disease in all patients was 17% and 18% with valganciclovir and oral ganciclovir, respectively.19 Overall, valganciclovir was as clinically effective and well tolerated [except for a higher incidence of neutropenia (8% and 3%, respectively)] as oral ganciclovir for CMV prevention in high-risk solid organ transplant recipients. However, in a subgroup analysis of the 177 liver transplant recipients who participated in the clinical trial, the incidence of CMV disease was 19% in the valganciclovir group versus only 12% in the ganciclovir group.19 There was also a higher incidence of tissue-invasive CMV disease in the valganciclovir group.19 As a result of these findings, valganciclovir prophylaxis has not gained approval from the US Food and Drug Administration (FDA) for prophylaxis against CMV disease after liver transplantation. Although valganciclovir is not FDA-approved for prophylaxis in liver transplant recipients, it is the most widely used drug for the prevention of CMV disease after liver transplantation.18
Delayed-Onset and Late-Onset CMV Disease
With the success of a 3-month anti-CMV prophylaxis program (in terms of the almost complete elimination of CMV disease among individuals actively taking the antiviral drugs), the challenge of delayed-onset and late-onset CMV disease has emerged. Indeed, in many high-risk CMV D+/R− individuals, the use of antiviral prophylaxis has only delayed the onset of CMV disease to 3 to 6 months after liver transplantation.2, 14, 15, 17, 19, 20 In a retrospective study, CMV disease occurred in 14 of 54 CMV D+/R− liver transplant recipients (26%) who completed at least 3 months of valganciclovir prophylaxis. In our analysis of 67 CMV D+/R− LT recipients who received 3 months of oral ganciclovir and valganciclovir prophylaxis, the 2-year incidence of CMV disease was 29%.2 Thus, 1 of every 4 CMV D+/R− liver transplant recipients will develop late-onset CMV disease after cessation of antiviral prophylaxis. Delayed-onset CMV disease appears to be clinically less severe, although it is associated with significant mortality after liver transplantation.6
Because of the negative effect of late-onset CMV disease on outcomes, a better method of CMV prevention is needed for CMV D+/R− liver transplant recipients. The current guidelines from the American Society of Transplantation and the Transplantation Society suggest that the duration of antiviral prophylaxis may be prolonged up to 6 months (versus the standard duration of 3 months) in CMV D+/R− liver recipients.14, 15 This recommendation is based on a trial that investigated the approach in CMV D+/R− kidney recipients.20 It should be emphasized that this has not yet been studied in liver transplant recipients. In this study of kidney recipients, the incidence of CMV disease was reduced from 36.8% in patients who received valganciclovir prophylaxis for 3 months to 16.1% in those who received valganciclovir prophylaxis for 6 months.20
TREATMENT OF CMV DISEASE
The first-line treatment of CMV disease after transplantation is IV ganciclovir or valganciclovir (Table 2).21, 22 In contrast, oral ganciclovir should not be used for the treatment of active CMV disease because of its poor bioavailability. In addition, the degree of drug immunosuppression should be reduced.14, 15 In a multicenter, noninferiority trial that enrolled 321 transplant recipients (including liver transplant recipients) with nonsevere CMV disease, there were similar clinical and virological responses between the groups of patients randomized to valganciclovir [900 mg 2 times a day (bid)] or IV ganciclovir (5 mg/kg bid) for a fixed 21-day course followed by valganciclovir (900 mg qd) maintenance treatment for 4 weeks.21, 22 The overall time to viral eradication was 21 days with valganciclovir and 19 days with IV ganciclovir. The calculated viral decay was 11.5 days with valganciclovir and 10.4 days with IV ganciclovir. However, in real-life clinical practice, the duration of treatment of CMV disease should be individualized.14, 15 The persistence of the virus at the end of therapy is associated with a higher risk of clinical relapse.23 It is now generally accepted that multiple (at least 2) weekly negative CMV PCR results should be obtained before antiviral therapy is discontinued. However, the utility of such an approach may not necessarily apply to some tissue-invasive disease, which may manifest as compartmentalized disease.23
|Type of CMV Disease||Preferred/First-Line Agent||Alternative Drugs||Comments|
|Asymptomatic CMV infection*||Valganciclovir (900 mg po bid)||Ganciclovir (5 mg/kg IV q12h)||Consider reducing immunosuppression. The duration of treatment is individualized and preferably lasts until 2 weeks after the clearance of viremia.|
|CMV syndrome†||Valganciclovir (900 mg po bid) Ganciclovir (5 mg/kg IV q12h) If the patient is starting with IV ganciclovir, switch to valganciclovir when clinically and virologically improving.||Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Consider reducing immunosuppression. The duration of treatment is individualized and preferably lasts until 2 weeks after the clearance of viremia and clinical resolution.|
|Tissue-invasive CMV disease||Ganciclovir (5 mg/kg IV q12h) Valganciclovir (900 mg po bid) The patient may start with IV ganciclovir and switch to valganciclovir when clinically and virologically improving.||Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Reduce immunosuppression. The duration of treatment is individualized and usually prolonged. Treat until 2 weeks after the clinical and virological clearance of infection. Some cases of tissue-invasive CMV disease are compartmentalized, and CMV testing in the blood may not reflect the extent of disease.|
|CMV pneumonia||Ganciclovir (5 mg/kg IV q12h)||Foscarnet (60 mg/kg q8h or 90 mg/kg q12h)Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Reduce immunosuppression. Valganciclovir is not preferred as a first-line agent because of the potentially severe and fatal outcome of CMV pneumonia. The patient may transition from IV ganciclovir to valganciclovir (900 mg po bid) when he is clinically stable. Some add CMV hyperimmune globulin, especially if the patient's condition is clinically severe.|
|Gastrointestinal CMV disease||Ganciclovir (5 mg/kg IV q12h)||Valganciclovir (900 mg po bid) Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Reduce immunosuppression. Valganciclovir is not preferred as a first-line agent in severe cases of gastrointestinal disease because of concerns about absorption. The patient may transition from IV ganciclovir to valganciclovir (900 mg po bid) when he is clinically stable. Some cases of gastrointestinal CMV disease are compartmentalized, and CMV testing in the blood may not reflect the extent of disease.|
|CMV retinitis||Ganciclovir (5 mg/kg IV q12h) Valganciclovir (900 mg po bid)||Intravitreal ganciclovir (consult an ophthalmologist) Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Reduce immunosuppression. Intravitreal fomivirsen has been used (consult with an ophthalmologist). The duration of treatment is guided by repeat fundoscopic examination by an ophthalmologist.|
|CMV CNS disease||Ganciclovir (5 mg/kg IV q12h)||Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Reduce immunosuppression. IV ganciclovir is recommended over valganciclovir as the first-line agent so that high systemic levels can be immediately achieved.|
|Severe CMV disease‡||Ganciclovir (5 mg/kg IV q12h)||Reduce immunosuppression. Some add CMV hyperimmune globulin. Valganciclovir has not been studied for the treatment of severe CMV disease. The patient may transition from IV ganciclovir to valganciclovir (900 mg po bid) when he is clinically stable.|
|Ganciclovir-resistant CMV disease (see Fig. 1)||Reduce immunosuppression. Ganciclovir (7.5-10 mg/kg IV q12h) for low-level UL97 resistance4 Foscarnet (60 mg/kg q8h or 90 mg/kg q12h) Ganciclovir and foscarnet in combination||Cidofovir (5 mg/kg weekly for 2 weeks and every 2 weeks thereafter)||Test for UL97 and UL54 gene mutations to guide the treatment choice. Leflunomide and artesunate have been used (see Fig. 1). Some add CMV hyperimmune globulin. Adoptive immunotherapy (an infusion of CMV-specific CD8+ T cells) remains experimental.|
Treatment of Ganciclovir-Resistant CMV Disease
Ganciclovir-resistant CMV is now emerging as an important complication of antiviral drug use after transplantation.24 Currently, ganciclovir-resistant CMV is rarely seen in liver transplant recipients. The estimated incidence of ganciclovir-resistant CMV after liver transplantation is less than 0.5%. Risk factors include CMV D+/R− status, high levels of viral replication, potent immunosuppressive therapy, and suboptimal ganciclovir levels. The vast majority of drug-resistant cases involve the selection of viral strains with the UL97 (kinase) mutation,24 which confers resistance to ganciclovir, although in some cases, a concomitant UL54 mutation (polymerase) is also observed; in this case, cross-resistance with cidofovir and/or foscarnet is likely.24 Treatment of ganciclovir-resistant CMV should therefore be guided by genotypic analysis (Fig. 1). In patients in whom foscarnet or cidofovir was used for therapy, nephrotoxicity was a major and common adverse effect.24 Other potential treatments of multidrug-resistant CMV include the off-label use of immunoglobulins, leflunomide, and artesunate, although data supporting their use are only anecdotal.15, 25 The potential clinical utility of maribavir in the treatment of resistant CMV has also been suggested; however, the clinical development of this drug has been halted because of disappointing results from a phase 3 clinical trial.
CMV is one of the most important opportunistic pathogens causing clinical disease after liver transplantation. It not only causes febrile illness associated with bone marrow suppression and tissue invasion but also indirectly increases the risk of other clinically relevant outcomes (eg, it increases the risk of other opportunistic infections and lowers overall rates of allograft and patient survival). There are many risk factors for CMV disease, but the most commonly recognized is CMV D+/R− mismatch status. A deficiency of pathogen-specific immunity generally characterizes the occurrence of CMV disease in liver transplant recipients. Antiviral prophylaxis or preemptive therapy is highly effective in reducing the incidence of CMV disease, but late-onset CMV disease has emerged as a significant problem with the use of antiviral prophylaxis. The treatment of CMV disease consists of IV ganciclovir (for severe disease) or oral valganciclovir (for mild to moderate disease). CMV resistant to ganciclovir is emerging as a complication of prolonged antiviral drug use and is currently difficult to treat with very limited and potentially toxic therapeutic options.