Management of cytomegalovirus infection after liver transplantation

Abstract

Cytomegalovirus (CMV) infection is one of the primary causes of morbidity and mortality following liver transplantation (LT). Based on current worldwide guidelines, the most effective strategies for avoiding post-transplant CMV infection are antiviral prophylaxis and pre-emptive treatment. CMV- IgG serology is the established technique for pretransplant screening of both donors and recipients. The clinical presentation of CMV infection and disease exhibits variability, prompting clinicians to consistently consider this possibility, particularly within the first year post-transplantation or subsequent to heightened immunosuppression. At annual symposia to discuss CMV prevention and how treatment outcomes can be improved, evidence on the incorporation of immune functional tests into clinical practice is presented, and the results of studies with new antiviral treatments are evaluated. Although there are ongoing studies on the use of letermovir and maribavir in solid organ transplantation, a consensus reflected in the guidelines has not been formed. Determining the most appropriate strategy at the individual level appears to be the key to enhancing outcomes. Although prevention strategies reduce the risk of CMV disease, the disease can still occur in up to 50% of high-risk patients. A balance between the risk of infection and disease development and the use of immunosuppressants must be considered when talking about the proper management of CMV in solid organ transplant recipients. The objective of this study was to establish a comprehensive framework for the management of CMV in patients who have had LT.

Key Words: Liver transplantation; Cytomegalovirus; Antiviral prophylaxis; Preemptive treatment; Valganciclovir; Ganciclovir

Core tip: Cytomegalovirus (CMV) is a significant factor in the development of opportunistic infection complications following liver transplantation. Antiviral prophylaxis and pre-emptive treatment are the most effective approaches for preventing post-transplant CMV infection, as stated by current worldwide standards. CMV-IgG serology is still the standard method for screening both donors and recipients prior to transplantation. When discussing the appropriate management of CMV in solid organ transplant recipients, it is important to examine the balance between the use of immunosuppressants and the risk of infection and disease progression.

INTRODUCTION

The management of infections in liver transplantation (LT) recipients begins by identifying pretransplant risk factors for potential opportunistic infections. This includes the identification of latent infections, evaluation of immune response status, provision of vaccinations, and management of pre-existing chronic diseases prior to transplantation[1]. Cytomegalovirus (CMV) infection is prevalent in patients receiving multiple immunosuppressive medications, such as LT recipients, and causes significant morbidity and mortality, impacting post-transplant outcomes directly[2]. Over the past two decades, the spectrum of CMV-related disease in transplant recipients has expanded significantly, particularly in terms of its role in chronic rejection and transplanted graft loss. High-level CMV viremia has been linked to tissue-invasive disease and adverse outcomes after solid organ transplantation[3]. CMV infections can affect various organs, including the colon, esophagus, lungs and brain[4]. CMV syndrome has also been linked to tissue-invasive disease, increased predisposition to graft rejection and death, rapid hepatitis C relapse, and heightened vulnerability to other opportunistic infections[5].

The risk category of post-transplant CMV disease is determined by analyzing the results of CMV serology in both LT recipients and possible donors. In particular, CMV-related complications are a significant concern for CMV-seronegative recipients who receive organs from CMV-seropositive donors[6]. Valganciclovir, used for antiviral prophylaxis, is the most frequently used method of preventing viral infections in transplant recipients, particularly those who have undergone LT[6]. Nevertheless, CMV infection continues to be a prevalent opportunistic infection in LT, even with the implementation of preventive measures[7]. Despite prevention strategies used after LT that reduce the risk of CMV disease[8], CMV disease occurs in ~50% of high-risk solid organ transplantation recipients (CMV-seropositive donor/CMV-seronegative recipients, D+/R) and can still occur in 17% of CMV-seropositive recipients (R+)[9]. The comprehensive management of CMV infection spans prevention, treatment, diagnosis, immunology, drug resistance, and pediatric issues[10]. Pediatric LT recipients exhibit a higher incidence of CMV infection than adults[11]. Prevention and management of CMV infection after LT are crucial to improve outcomes. One-year survival after LT currently reaches 80%–90%[12]. The dynamics of the plasma virome, including CMV, in LT recipients can be clinically significant and influence patient outcomes[13]. Studies have not yet shown that prevention of CMV always reduces mortality rates[14]. All patients should be routinely monitored for long-term complications after LT. The objective of this research is to evaluate the diagnosis, prevention, and treatment of CMV infection in the LT population.

MANAGEMENT OF CMV INFECTION IN LT RECIPENTS

CMV infection and disease are preventable and treatable infectious complications following LT[15,16]. According to all published guidelines, the donor’s and recipient’s CMV status prior to transplantation determines the risk of developing CMV infection or disease after solid organ transplantation[10,17,18]. Prior to or during transplantation, all organ donors and recipients should undergo testing for CMV (IgG antibody) serostatus. If the donor’s CMV serostatus is unknown and the recipient is either seronegative or the CMV status is undetermined, the donor is categorized as seropositive, and the recipient as CMV seronegative (D+/R)[17,18]. The donor should be classified as positive if their CMV-IgG serology is borderline or uncertain (strong, low). If the recipient’s CMV-IgG is borderline or uncertain, it should be evaluated based on donor serology. If donor CMV serology is positive, the recipient will be considered CMV-seronegative (i.e., CMV D+/R) (strong, low). If donor CMV serology is negative, it will be considered CMV-seropositive (i.e., CMV D/R+) (strong, low)[17]. Since CMV-seronegative recipients (R) who obtain organs from CMV-seropositive donors (D+) are most at risk for CMV infection and disease, it is crucial to consider both donor and recipient’s CMV serostatus when discussing CMV infection[19]. LT from a CMV-seropositive donor (D+) to a CMV-seropositive recipient (R+) or organ transplantation from a CMV-seronegative donor (D) to a CMV-seropositive recipient (R+) represents an intermediate risk, whereas organ transplantation from a seronegative donor (D) into a seronegative recipient (R) is classified as low risk[20,21]. Another critical risk factor for CMV infection is a low lymphocyte count[22]. Immunosuppressive agents, including corticosteroids, are frequently used in the treatment of LT recipients, further increasing their susceptibility to CMV infection[2]. Most centers use two or three immunosuppressive agents to prevent allograft rejection after LT. Generally, this combination consists of prednisone, calcineurin inhibitors (cyclosporine or tacrolimus), plus one of mycophenolate mofetil, azathioprine, sirolimus. Certain underlying liver diseases have been associated with the risk of CMV infection in LT candidates[23]. Advanced liver disease, or cirrhosis is linked to an increased susceptibility to infections, including CMV viremia, after LT[24]. A multivariate analysis also showed that pre-LT CMV donor–recipient risk cluster and primary sclerosing cholangitis were independent risk factors for post-transplant CMV infection[25]. Universal prophylaxis and pre-emptive treatment are the main approaches to prevent CMV after solid organ transplantation. Another option that includes both of these procedures is called post-prophylaxis surveillance. Based on experience with pre-emptive treatment, it is administered weekly for 8–12 wk after prophylaxis has ended (weak, low)[10]. A hybrid surveillance strategy after prophylaxis using weekly CMV may be particularly important and useful in high-risk solid organ transplant recipients with viral load monitoring to detect infection following initial prophylaxis. Despite the fact that experts have adopted this method, the guidelines’ low recommendation and evidence level ratings indicate that it is not well supported by the evidence[10]. For universal prophylaxis, 3–6 mo of prophylaxis is recommended for all at-risk LT recipients (except D/R). Prophylaxis begins within 10 d after LT, and valganciclovir is generally used in this setting[10]. For patients with normal renal function, a daily dose of 900 mg is advised for valganciclovir prophylaxis. Regular monitoring of the complete blood count, at least every 2 wk during valganciclovir treatment, is advised. CMV monitoring and the initiation of preventive therapy are recommended in cases of valganciclovir-induced neutropenia. Foscarnet, valacyclovir and cidofovir are not recommended for prophylaxis in LT recipients[17]. Before switching to oral valganciclovir in the early post-transplant phase, intravenous ganciclovir might be administered for a few days. While early CMV replication or infection is exceptionally rare, late CMV infection or disease is common within 3–6 mo after prophylaxis ends[10]. Weekly CMV DNAemia monitoring and the initiating of antiviral therapy when the viral load exceeds a predetermined threshold constitute a pre-emptive strategy. Pre-emptive therapy has the advantages of decreasing drug toxicity and the incidence of late CMV. However, coordinating pre-emptive treatment can be challenging due to the logistics of weekly testing, result review, prompt initiation of treatment after positive tests, and subsequent monitoring and management. It is challenging to apply this technique at transplant centers with large numbers of transplants since it calls for more complex logistics. Early CMV replication/infection is prevalent. Valganciclovir is the most common antiviral used for pre-emptive therapy. It is not advised to use cidofovir, valacyclovir, oral ganciclovir, or foscarnet as preventive therapy. Oral ganciclovir is no longer commercially available[17]. Both prophylactic and pre-emptive strategy aim to prevent CMV disease, but the impact of pre-emptive therapy on the indirect effects of CMV, including the prevention of opportunistic infections, remains unclear[10]. Details are given in Table 1.

Table 1 Recommended approaches for cytomegalovirus prevention in liver transplantation[17].

CMV serostatus	Comments
D/R; low risk	Antiviral prophylaxis: CMV D-/R- LT recipients do not require anti-CMV prophylaxis; but if they are HSV1-or HSV2-seropositive, they should receive anti-HSV prophylaxis during the early period after LT (strong, high)
	Alternative: (1) Pre-emptive therapy (if higher risk, i.e., significant transfusions): If blood transfusion is required, CMV D/R patients should receive; and (2) CMV-seronegative or leuko-reduced blood products (strong, high)
D+/R+; D/R+; intermediate risk	Antiviral prophylaxis: (1) Drugs: valganciclovir1 900 mg po every 24 h; (2) ganciclovir 5 mg / kg (iv) 1×/d; and (3) duration: 3 months (strong, high)
	Alternative: (1) Pre-emptive therapy (if logistic support is available) (strong, high); (2) weekly CMV QNAT (or pp65 antigenemia) for 12 wk after LT; and (3) if a positive CMV threshold is reached, treat with valganciclovir 900 mg (po) BID (preferred), or ganciclovir 5 mg/kg (iv) every 12 h until negative test
D+/R; high risk	Antiviral prophylaxis: (1) Drugs: valganciclovir 900 mg (po) every 24 h; (2) ganciclovir 5 mg/kg (iv) 1×/d; and (3) duration: 3 mo (strong, high), 6 mo (strong, moderate)
	Alternative: (1) Pre-emptive therapy (if logistic support is available) (strong, high); (2) weekly CMV QNAT (or pp65 antigenemia) for 12 wk after LT; and (3) if a positive CMV threshold is reached, treat with valganciclovir 900 mg (po) BID (preferred), or ganciclovir 5 mg/kg (iv) every 12 h until negative test

¹Valgansiklovir use in LT recipients is not US FDA approved because of high rate of tissue-invasive disease, however experts still recommend its use for CMV prophylaxis in liver recipients (strong, moderate). Ease of administration. Leukopenia is major toxicity.

CMV: Cytomegalovirus; HSV: Herpes simplex virus; QNAT: Quantitative nucleic acid amplification test.

DIAGNOSIS AND CLOSE FOLLOW-UP OF CMV INFECTION IN LT PATIENTS

CMV infection occurs primarily in the first year after LT or during the period of intense immunosuppression. It typically happens within the first 3–4 mo following transplantation (in the setting of preemptive therapy) or after prophylaxis has ended[26]. The definition of CMV infection is when the virus or the viral proteins (antigens) or nucleic acid are found in any sample of any body fluid or tissue sample, indicating evidence of CMV replication, regardless of symptoms. The definition of CMV disease involves attributable symptoms accompanied by evidence of CMV infection.

CMV disease can also be classified as a viral syndrome (i.e., fever, malaise, fatigue, leukopenia and/or thrombocytopenia) or a tissue-invasive (end-organ) disease[15]. Diagnostics primarily rely on serology, viral load testing, CMV-specific cellular immunoassays, viral culture, pathology and immunohistochemistry. The identification of CMV in the tissue sample provides the basis for the definitive diagnosis of tissue-invasive disease. The gold standard for the diagnosis of tissue-invasive disease is the detection of CMV antigens or cytopathic alterations via immunohistochemistry[15]. Diagnosis and follow-up of CMV infection in LT recipients can be done by various methods. The use of CMV DNA tests, such as quantitative polymerase chain reaction (PCR), is a widely used laboratory parameter to diagnose and monitor CMV infection[27]. CMV DNAemia is usually detected within the first few weeks after transplantation[28]. Regular monitoring of CMV viral load will help predict the development of CMV disease[29]. The term DNAemia is chosen over viremia in CMV guidelines because it describes the detection of CMV DNA in blood or plasma, whether the virus is reproducing or not[10].

For increased accuracy, terms such as viral load, nucleic acid test, or quantitative nucleic acid amplification test (QNAT) are utilized instead of PCR. Viral culture, antigen testing, and nucleic acid testing (CMV DNAemia or RNAemia) can all be used to identify CMV replication. Latent virus (low-level CMV DNAemia) can be distinguished from CMV replication (linked to a high viral load) using CMV QNAT. The precision of QNAT results requires at least a threefold change to signify biologically significant alterations in viral replication. QNAT variability is largest for viral loads of 1000 IU/mL and lower, hence, for a change to be considered significant, it must be greater than fivefold[30,31].

CLINICAL EVALUATION AND TREATMENT IN LT PATIENTS WITH CMV INFECTION

The clinical spectrum of CMV infection identified in solid organ transplant recipients includes pneumonia, gastrointestinal disease, hepatitis, retinitis, nephritis/cystitis, pancreatitis, myocarditis and cranial nervous system disease. Gastrointestinal tract infection and disease are the most common clinical manifestations of CMV infection[32]. From asymptomatic clinic to viral syndrome and end-organ disease (colitis, pneumonitis, hepatitis and retinitis), CMV can have a wide variety of direct effects. indirect effects of CMV infection can have a major influence on the results of transplants. High infection rates (bacterial, viral and fungal), Epstein–Barr virus (EBV)-associated post-transplant lymphoproliferative disease, arteriosclerosis, cardiovascular events, new-onset diabetes mellitus after LT, immune senescence, acute rejection, mortality, and hepatic artery thrombosis specifically after LT can all be associated with CMV infection[33,34]. CMV infection can cause significant clinical consequences in LT recipients. CMV infection can cause a mononucleosis-like syndrome (fever, myalgia, arthralgia and malaise), bone marrow suppression (hematological abnormalities), and tissue invasion, including the transplanted liver allograft (hepatitis). CMV infection has also been associated with accelerated reactivation and replication of hepatitis C virus and decreased overall patient survival and allograft survival[35]. CMV infection increases the possibility of acute and chronic allograft rejection fourfold by potentiating alloantigens[36]. Thrombosis of the graft due to the proinflammatory state caused by CMV infection has also been described[37]. CMV infection can directly affect the allograft through CMV hepatitis and indirectly affect transplant outcome by increasing the risk of allograft rejection, other infections, graft loss and mortality[24]. CMV has immunosuppressive effects through the disruption of CD4 T cells and macrophages, reducing interleukin 1 and 2 levels and increasing interferon levels. The risk of invasive fungal infections, bacteremia, EBV-associated post-transplant lymphoproliferative illness, and cardiovascular disease is increased by all of these indirect effects[36,38]. It is crucial to note that CMV infection can significantly affect transplant results and can have both direct and indirect consequences following LT[39].

Physical examination may reveal oral lesions, visual changes, pneumonitis, abdominal tenderness, and rarely, neurological alterations. Computed tomography of the abdomen and/or chest can help to identify organ involvement. It is important for clinicians to be aware that, in cases of gastrointestinal and pulmonary disease, CMV viral load testing may come back negative. Diagnosing CMV infection can be challenging, particularly in cases of CMV colitis. Immunohistochemistry staining of endoscopic biopsies can confirm the diagnosis of CMV colitis in LT recipients[7]. Furthermore, it has been demonstrated that an intestinal biopsy for CMV culture improves endoscopy’s diagnostic sensitivity[40]. CMV infection may be obscured after organ transplantation, and its clinical presentation can vary. Clinicians should frequently consider the possibility of CMV infection, especially within the first year post-transplantation or after increased immunosuppression. Management of CMV in LT recipients also includes treatment of CMV disease. The primary antiviral drugs used in the treatment of CMV disease are intravenous ganciclovir and oral valganciclovir[39]. The choice of antiviral therapy depends on factors such as the patient’s renal function, drug interactions, and the presence of drug resistance[39]. Currently, the first-line treatment of CMV infection starts with intravenous ganciclovir at a dose of 5 mg/kg twice daily, continued for at least 2 wk. Maintenance treatment can then be administered at 5 mg/kg/d. Valganciclovir treatment dose is 900 mg twice daily. When compared to intravenous ganciclovir, the VICTOR study showed that oral valganciclovir treatment was not inferior[41]. When a patient has a disease that could threaten their life or vision, an extremely high viral load, or uncertain gastrointestinal absorption, intravenous ganciclovir is recommended. The CMV viral load should be monitored at least weekly to determine the duration of treatment. Evaluation of the virological response to treatment should be done once a week using CMV QNAT (or pp65 antigenemia) (strong, high). Treatment is usually continued until all clinical signs of CMV disease have disappeared and CMV DNAemia has been eradicated. It is defined in the guidelines as negativity in a high-sensitivity test (lower limit < 200 IU/mL) or two consecutive less sensitive assays[10]. The failure to eradicate plasma DNAemia at the end of treatment is the main determiner of virological relapse. Weekly monitoring of CMV DNAemia is advised to detect refractory/resistant CMV[10].

DEVELOPMENT OF RESISTANT/REFRACTORY (R/R) CMV INFECTION

Patient and graft survival may be negatively impacted by the emergence of CMV resistance. It has been documented to happen in 5%–12% of solid organ transplant recipients following ganciclovir therapy[10]. Resistant CMV infection is defined as the detection of a viral genetic mutation(s) known to reduce sensitivity to one or more anti-CMV drugs.

Refractory CMV infection is characterized by ongoing CMV disease signs and symptoms and/or persistent CMV DNAemia that does not resolve. It is defined as a < 1 log¹⁰ (< 10×) reduction in CMV viral load or increases after at least 2 wk of appropriate antiviral therapy[42]. When persistent or recurrent CMV DNAemia or disease occurs during long-term antiviral therapy, antiviral drug resistance should be suspected. Long-term treatment for ganciclovir is generally ≥ 6 wk of cumulative drug exposure, including full-dose therapy continued for ≥ 2 wk[43]. Guidelines recommend high doses of ganciclovir (7.5–10.0 mg/kg every 12 h in appropriate renal function) for low-level DNAemia or patients with few or no symptoms[10]. This dose is double that of the usual; therefore, monitoring for bone marrow suppression and dose adjustment for renal function are necessary. International guidelines recommend the use of foscarnet in cases of serious, life-threatening or sight-threatening diseases[10]. Some UL97 mutations, associated with lower levels of ganciclovir resistance, may allow increasing ganciclovir dosage with optimization of host factors if severe disease is absent[44]. One of the patients included in the study of Gracia-Ahufinger et al[44], in which the results of six patients were shared, was a D+/R LT patient who developed asymptomatic viremia on day 200 after receiving steroid boluses for acute rejection after 3 mo of valganciclovir prophylaxis. Mutation in the UL97 gene was detected after an increase in viral load was noted following 2 wk of treatment with standard dose valganciclovir. All patients were reported to respond to treatment, including those with mutations associated with high-level ganciclovir resistance[44]. It was concluded that if a mutation gives rise to higher levels of ganciclovir resistance or if UL97 and UL54 mutations combine to give rise to higher levels of ganciclovir resistance and often cidofovir cross-resistance, switching to Foscarnet is recommended. Because of their significant risk of nephrotoxicity, cidofovir and foscarnet are regarded as second-line agents. Foscarnet rescue therapy is usually empirically successful, but there is not enough information about the effectiveness of cidofovir as rescue therapy in solid organ transplantation[10]. Details are given in Table 2. Maribavir has recently been approved in the USA and Europe for the treatment of R/R CMV. According to a recent Phase 3 trial, this oral drug is a safe and effective therapeutic agent[45]. In the SOLSTICE study, maribavir resulted in higher CMV clearance rates compared to treatment with polymerase inhibitors in hematopoietic stem cell transplants and solid organ transplant recipients with R/R CMV[45,46].

Table 2 Treatment of cytomegalovirus disease and algorithm for evaluation and management of refractory and resistant cytomegalovirus infection and disease[19].

CMV treatment
Valganciclovir 900 mg (po) BID (preferred), or ganciclovir 5 mg/kg (iv) every 12 h until negative test; antiviral treatment of CMV disease should be continued until the following criteria are met (strong, high): resolution of clinical symptoms, virological clearance below a threshold negative value based on laboratory monitoring with CMV QNAT or pp65 antigenemia once weekly, and minimum 2 wk of antiviral treatment
Suspect drug resistance1: (1) If cumulative ganciclovir exposure > 6 wk; and (2) if treatment failure after 2 wk of ongoing full dose ganciclovir or valganciclovir. Tests should be performed to detect specific mutations in the UL97 and UL54 genes. Decrease immunosuppressive therapy if possible. Assess severity of CMV infection. Definitive antiviral treatment should be guided by results of genotypic testing (strong, moderate to high)	Severe CMV disease present; foscarnet2 (add or switch); foscarnet 60 mg/kg IV every 8 h (or 90 mg/kg every 12 h)
	No severe CMV disease present; high (up to 10 mg/kg q 12 h, renally adjusted) or full dose (5 mg/kg bid iv) ganciclovir

¹Options for empiric treatment of suspected resistant cytomegalovirus (CMV) disease include high-dose intravenous ganciclovir (up to 10 mg/kg q 12 h, renally adjusted) or foscarnet (weak, low to moderate). Definitive antiviral treatment should be guided by results of genotypic testing (strong, moderate to high). Other therapeutic options are cidofovir (weak, low), participation clinical trials (e.g., maribavir treatment of refractory and resistant CMV) (strong, low), and off-label letermovir (weak, very low).

²Foscarnet, second-line alternative agent for treatment. Highly nephrotoxic. Used for UL97-mutant ganciclovir-resistant CMV infection or disease.

CMV: Cytomegalovirus; HSV: Herpes simplex virus; QNAT: Quantitative nucleic acid amplification test.

DISCUSSION

CMV infection is a significant cause of morbidity and mortality after LT[47]. The incidence of CMV infection and disease exhibits variability among LT recipients, with some studies reporting a 55.7% incidence for CMV infection and 5.5% for CMV disease[48]. The degree of immunosuppression, the donor’s and recipient’s serostatus, and the prophylactic approach all affect the incidence of CMV disease following LT[49]. Some studies have reported that 31.3% of LT recipients developed CMV disease despite prophylaxis[50]. After LT, all patients are started on immunosuppressive treatment as standard. Immunosuppressive drugs facilitate the reactivation of latent CMV infections in LT recipients. The first 3 mo after LT are the period in which immunosuppressive treatment is most intensively applied, and CMV infections generally occur during this period[51]. The intensity of the immunosuppressive regimen administered during the post-transplant phase is a significant factor in assessing the patient’s overall immunological status[52,53]. Many post-transplant complications mimic infectious processes, and more than one infection can occur simultaneously in the same patient.

Therefore, the patient should be evaluated in the context of pretransplant infections, serological profiles to demonstrate infection latency, available culture data from mucosal surfaces, concomitant LT complications at the patient’s institution, and available antimicrobial prophylaxis. The management of CMV in LT recipients has evolved over time, guided by the development of consensus guidelines that aim to standardize approaches to prevention, treatment and diagnosis[10,33]. The prevention of CMV infection in LT recipients is typically achieved through antiviral prophylaxis or pre-emptive therapy. Antiviral prophylaxis involves using valganciclovir for a period of time after LT to prevent CMV infection[1,6]. Pre-emptive treatment includes regular monitoring of CMV DNAemia and initiation of antiviral treatment of viral replication is detected above predetermined threshold values[54]. This approach allows individualized treatment based on the patient’s viral load and immune status. However, there is no widely applicable viral load threshold to guide preemptive treatment, and thresholds may be risk group specific[1]. Both strategies, antiviral prophylaxis and pre-emptive therapy, have demonstrated effectiveness in controlling CMV and preventing CMV disease after LT[26]. Similar effectiveness in preventing CMV disease was validated by a meta-analysis with a sizable number of LT recipients, and there were no differences in mortality, graft loss or acute rejection[10]. A recent study evaluating the prevention strategies of 224 transplant centers showed that universal prophylaxis was used in 90% of centers for D+/R solid organ transplantation recipients[55]. Prophylaxis was administered to 50% of LT patients during the first 3 mo and 50% for the first 6 mo. Fifty percent of hospitals use a prophylactic approach for CMV seropositive patients, while other centers prefer a pre-emptive strategy[55]. The most common side effect noted by several centers is myelotoxicity caused by valganciclovir, which can lead at least 10% of patients to stop their treatment[55]. In a randomized trial, the relative costs of prophylactic or pre-emptive therapy for the prevention of CMV disease were assessed in the high-risk recipient CMV-seronegative/donor CMV-seropositive group. Pre-emptive therapy has been determined to be the most effective CMV prevention strategy due to its association with reduced incidences of CMV illness and lower overall costs when compared to prophylaxis in recipients who are D+/R[56]. Using pre-emptive therapy instead of antiviral prophylaxis reduced the incidence of CMV disease throughout a 12-mo period in another randomized clinical trial among CMV-seronegative LT recipients with seropositive donors, run by the same research team. The rates of allograft rejection, opportunistic infections, graft loss and neutropenia did not show significant differences between the pre-emptive therapy and antiviral prophylaxis groups[6]. Despite the superiority of pre-emptive therapy over universal prophylaxis in preventing CMV disease in the CAPSIL randomized trial among CMV D+R LT recipients, its real-world effectiveness may be lower due to logistic concerns regarding pre-emptive therapy. Among 12-mo survivors in the CAPSIL study, pre-emptive treatment was associated with less mortality and CMV DNAemia compared to universal prophylaxis[19]. Again, in a meta-analysis published in our country, it was concluded that pre-emptive treatment is an alternative to prophylaxis. Unfortunately, the studies used in this meta-analysis did not include data from our country, and only studies on kidney transplant patients were included[57]. The study supports the use of the pre-emptive strategy as an alternative to universal prophylaxis, even though universal prophylaxis performed better than the pre-emptive strategy in preventing CMV disease. This is because there were no differences observed between the two preventive strategies to prevent acute rejection and graft loss. Studies on recipients of kidney, liver and heart allografts claim that universal prophylaxis leads to better results, but other research indicates that individuals treated with a pre-emptive strategy have similar outcomes to those who receive prophylaxis[58,59]. Another study indicated that pre-emptive treatment might be more effective in reducing the incidence of CMV disease compared to prophylaxis[21]. Additionally, some research even suggests that after LT, CMV infection may increase allograft acceptance. The causative mechanisms require further investigation but the underlying mechanisms are probably connected to the profound and sustained impact of CMV infection on the immune system[60]. To summarize, for D+/R and/or R+ kidney transplant and LT recipients, universal prophylaxis and a pre-emptive strategy involving once-weekly CMV surveillance for 3–4 mo are comparable ways to prevent CMV disease[10]. The choice between pre-emptive therapy and antiviral prophylaxis is a crucial consideration in CMV management, and the decision varies among organ transplant centers based on their individual profit and loss analysis. The main challenges when using prophylaxis are the management of resistance caused by the choice or dose of prophylaxis and treatment-emergent adverse events[43]. Late-onset disease may develop due to the suppression of antigen stimulation during the re-establishment of T-lymphocyte responses. Several risk factors for the development of ganciclovir resistance have been identified, including high viral load and high-risk (D+/R) solid organ transplant recipients, especially those receiving multivisceral allografts, as well as suboptimal dosing of ganciclovir prophylaxis[61,62]. In a study of 304 LT recipients, 40% of patients receiving valganciclovir prophylaxis and 16% of those not receiving prophylaxis developed neutropenia. It was identified as an independent predictor of overall mortality[63]. Many centers use low-dose valganciclovir (450 mg daily) prophylaxis to lower the risk of neutropenia; nevertheless, this unfortunately leads to breakthrough viremia, particularly because of ganciclovir-resistant CMV[64]. Therefore, there is a necessity for an antiviral drug that is as effective as valganciclovir in preventing CMV and does not have the risk of myelotoxicity. A recent clinical study in adult high-risk D+/R kidney transplant recipients demonstrated that letermovir prophylaxis was not inferior to valganciclovir in preventing CMV disease during the first year after transplantation. It has been approved for such use in some regions due to its lower myelotoxicity rate[65]. Letermovir has been previously approved for prophylaxis in patients undergoing hematopoietic stem cell transplantation[66],but it is not approved for the treatment or prevention of CMV in recipients of solid organ transplants[66,67].

A study involving adult patients undergoing abdominal solid organ transplantation supported the possibility of switching from valganciclovir to letermovir in the setting of leukopenia[68]. Presently, antiviral prophylaxis with valganciclovir remains the most commonly used prevention strategy in LT recipients, typically administered for 3–6 mo[6]. The optimal duration of CMV prophylaxis in LT recipients is still a matter of debate as no randomized clinical trials have evaluated the optimal duration. However, the general consensus suggests that prophylaxis duration should be individualized based on the patient’s risk factors and clinical course[1]. In conclusion, letermovir may be just as effective as valganciclovir in preventing CMV disease with fewer hematological adverse effects, despite the fact that valganciclovir has been highly effective for > 20 years. The treatment of R/R CMV infection with maribavir is now approved. Further studies are still needed to improve the sustained virological clearance rate and outcomes in this setting[39]. Close monitoring and early detection of CMV infection are important for timely intervention and management. Setting a low threshold for considering a diagnosis of CMV infection within the first year after solid organ transplantation will ensure staying in the safe zone. Although guidelines suggest that monitoring for an infection is not necessary during prophylaxis[10], it is necessary to check for CMV if there are clinical signs or symptoms of infection. It should be noted that CMV infection may occur despite prophylaxis due to an inappropriately low prophylaxis dose, the development of antiviral resistance, excessive immunosuppression, or drug incompatibility. Additionally, monitoring CMV-specific cell-mediated immunity before and after transplantation may be useful in predicting the occurrence of post-transplant CMV infection[69]. Kumar et al[70] used Quantiferon-CMV testing to guide subsequent management at the end of treatment of CMV viremia and demonstrated the effectiveness of CMV-specific cell-mediated immunity testing to guide changes in the management of CMV infection. In those who were Quantiferon-CMV positive and discontinued antivirals early, only a single patient experienced a low-level asymptomatic relapse, whereas 69.2% of Quantiferon-CMV negative patients experienced a recurrence of infection despite longer courses of antivirals. It would be helpful to know which population clinicians should concentrate their attention on, even though it is still unclear what to do with Quantiferon-CMV-negative patients. After the third international consensus guideline on CMV management in solid organ transplantation was published[10], the first international CMV symposium held during the COVID-19 pandemic in 2021 focused on the concept of monitoring cell-mediated immunity to guide the management of CMV disease[71]. It is thought that once an ideal cell-mediated immunity test is determined, the risk of CMV will be better understood in both solid organ transplantation and hematopoietic cell transplantation. Feasible alternatives to antiviral therapy, such as cellular or immune therapies, have been proposed to evolve to make management protocols more individualized based on the patient’s immune footprint. It has been emphasized that prophylaxis should be reserved for use in high-risk donor (D)+/recipient (R) patients[71]. Most recently, at the International CMV Symposium held in Barcelona in May 2023, the issues of adapting advances in immunotherapy and cell-mediated immunity monitoring into routine clinical practice, antiviral prophylaxis, or pre-emptive therapy in managing the risk of CMV infection after transplantation were discussed. Since few randomized controlled trials have compared the two strategies, the choice between universal prophylaxis and pre-emptive therapy (initiating antiviral therapy at the earliest signs of viral replication) remains unclear. Both have pros and cons, but guidelines currently cannot personalize the best course of prophylaxis and treatment for individual patients[72]. In addition to antiviral prophylaxis and pre-emptive therapy, other preventive measures may be taken to reduce the risk of CMV infection in LT recipients. These include infection control practices such as hand hygiene, isolation precautions, and minimizing exposure to CMV-positive individuals[1]. Vaccination against CMV is not currently available for routine use in transplant recipients[10]. Through methods like immunization or pathogen inactivation, the risk of CMV infection after solid organ transplantation can be eliminated. This will revolutionize the field of solid organ transplantation and likely result in less complicated clinical care, fewer diagnoses, fewer hospitalizations, and better overall outcome.

CONCLUSION

Prevention and management of CMV infection in LT recipients involves a combination of strategies, including antiviral prophylaxis, pre-emptive therapy and infection control measures. The choice of strategy depends on factors such as patient risk factors, donor–recipient serostatus, and clinical course. The duration of prophylaxis and the optimal management approach may vary between transplant centers, and individualized patient care is essential. A multidisciplinary approach involving infectious disease specialists, transplant surgeons, and immunologists is crucial for the optimal management of CMV infection in LT recipients. As the immune system is more effectively suppressed, resulting in lower rates of organ rejection with better long-term outcomes, a situation that frequently results in higher rates of opportunistic infections, including CMV, requires greater recognition of risk and better optimization of prevention methods. Further research is essential to refine and optimize prevention and treatment strategies for CMV in LT recipients.