Cytomegalovirus: Updated Approach to Management for Kidney Transplant Recipients

Abstract

Cytomegalovirus (CMV) is the most common opportunistic infection after kidney transplantation. A cause of symptomatic infection, it has also been associated with an increased risk of other infections, rejection, allograft loss, and mortality. Recent advances in diagnosis, prevention, and treatment have improved the management of this infection. This article reviews updated therapeutic and diagnostic approaches, highlighting the recommendations of the International CMV Consensus Conference and noting those areas in which further research is needed.

CMV is a human herpes virus that has profound effects on solid organ transplant recipients and is a major cause of morbidity and mortality. After kidney transplantation, CMV infection has been associated with an increased risk of allograft failure and death.¹ After primary infection, CMV establishes lifelong latency via several immune-evasion strategies. Reactivation of infection occurs most commonly at times of increased immunosuppression. CMV reactivation is controlled by cytotoxic CD8 and CD4 T-cells, and infection typically occurs when T-lymphocyte function is severely impaired. The primary source of CMV infection in organ transplant recipients is transmission to transplant recipients via infected donor organs. The highest rates of CMV infection and disease are observed among seronegative transplant recipients (R-) with a seropositive organ donor (D+).

Who is at the Risk of CMV Infection or Disease After Transplant

Identifying key risk factors placing kidney transplant recipients (KTRs) at higher risk of CMV infection and disease is imperative, because these factors are important in informing preventative strategies. Various factors have been found to be associated with an increased risk of CMV after kidney transplantation, including D+/R- serostatus, low absolute lymphocyte count, certain immunosuppressive agents (e.g., antithymocyte globulin and belatacept), kidney and pancreas recipients, patients with high immunologic risk, delayed graft function, and older recipient age.

Serostatus

The most important risk factor for CMV infection is the serostatus of the donor/recipient pair. KTRs with no previous CMV exposure (R-) who receive an organ from a donor with previous exposure to CMV (D+) are at the highest risk of posttransplant CMV infection and disease. The incidence of CMV disease was reported to be almost 3 times higher in seronegative recipients of seropositive donors compared with seropositive recipient groups.² Patients who are CMV D+/R- are at higher risk of developing both CMV infection and disease compared with patients who are CMV R+, although some studies have reported comparable rates of CMV infection in R+.^1,3

In the absence of preventative strategies, the incidence of CMV infection and disease has been reported to be as high as 60% and 56%, respectively, within 3 months posttransplant.⁴ This is seen particularly in the D+/R- KTR population, with similar rates of CMV infection in the R+ population. Further studies, including a meta-analysis by Raval et al.,³ have found that even with prevention strategies, 25% of KTRs develop CMV infection with older age and D+/R- CMV serostatus as consistent risk factors.¹

Immunosuppressive Regimens and the Risk of CMV

Various immunosuppressive agents are known to increase the risk of CMV infections in kidney transplantation. These include antithymocyte globulin (ATG), tacrolimus, mycophenolate, and belatacept.

ATG is widely used in kidney transplantation as induction therapy as well as to treat acute rejection. It is a polyclonal antibody that leads to immune cell depletion via both complement-dependent and complement-independent lysis of T lymphocytes (CD4 and CD8), leading to profound T-lymphocyte depletion.^5,6 However, because of its associated profound immunosuppression, ATG is associated with a higher incidence of opportunistic infections⁷ and malignancy, specifically posttransplant lymphoproliferative disease.⁸

An anti-CMV immune response is primarily a T-lymphocyte-dependent process; thus, T-lymphocyte depletion will lead to a lack of CMV clearance. The increased risk of CMV with the use of ATG as induction immunosuppression has been reported across multiple studies. Kaminski et al.⁹ found that ATG induction significantly increased the risk of CMV infection, and this risk was more profound in recipients who were R+, particularly in those with evidence of cell mediated immunity (CMI) at baseline, than in recipients who were D+/R-. Recipients who were CMV D+/R- still had the highest risk of CMV infection, but this risk did not increase after ATG induction. However, ATG was associated with an increased risk in KTRs who were R+; the authors hypothesized that this was a result of the severe posttransplantation inhibition of preformed CMV-specific T-cell–mediated immunity.⁹ Luan et al.,¹⁰ found that the use of rabbit-derived ATG for induction was associated with a significant increase in the risk of CMV infection compared with basiliximab, a non-T-cell–depleting antibody. However, the use of rabbit-derived ATG for the treatment of acute rejection was not associated with an increased risk of CMV infection when an additional course of valganciclovir was provided. Higher or multiple doses of ATG are also associated with higher CMV infection rates compared with single doses.¹¹

Mycophenolate mofetil and mycophenolic acid have also been linked with an increased risk of posttransplant CMV infection and disease.³ Other studies have not reported a similar risk of infection but have found that patients treated with mycophenolate mofetil who develop CMV infection more often progressed to CMV disease than those without mycophenolate mofetil treatment.¹² More recent studies suggest lower rates of CMV infection with mycophenolate mofetil use compared with some alternative immunosuppressives such as ATG and belatacept.¹³

Belatacept is a selective T-cell costimulation blocker used for immunosuppression in kidney transplantation. It was developed to improve long-term outcomes in KTRs by providing effective immunosuppression without the toxic effects of calcineurin inhibitors.¹⁴ In BENEFIT,¹⁵ one of the largest randomized controlled studies in kidney allograft recipients, belatacept was associated with higher patient and graft survival and improved renal function compared with cyclosporine. There was also a trend toward lower chronic allograft rejection because of its lower incidence of de novo donor-specific antibodies. However, there was a notable increase in early acute T-cell–mediated rejection, which led to more frequent use of T-cell–depleting agents, increasing the risk of opportunistic infections, specifically Epstein-Barr virus and CMV. It is for this reason that de novo use of belatacept is not preferred; thus, later (≥ 6 months posttransplant) CNI to belatacept conversion strategies may be preferred.¹⁶

Subsequent studies17, 18, 19 have reported that belatacept increases the risk of CMV in KTRs, both in de novo use after kidney transplantation and in patients who converted to belatacept-based regimens. In a large randomized controlled trial of KTRs receiving de novo belatacept therapy, patients at a high risk of CMV treated with a belatacept-based regimen were noted to have a higher incidence of CMV viremia. Chavarot et al.¹⁷ have shown that KTRs who converted to a belatacept-based regimen had a 7-fold higher risk of CMV disease than control patients treated with CNIs. Additionally, the disease manifestations were noted to be more severe, including multiorgan presentations in many patients as well as an increased incidence of atypical presentations such as retinitis and hepatitis.¹⁷ Patients at high risk (D+/R-) have also been found to be at higher risk of prolonged viremia.¹⁹ Despite the recognized increased risk, there is no clear guidance on whether CMV prophylaxis should be offered or resumed in patients on belatacept; thus, additional studies are needed to clarify this important clinical matter. Regardless, heightened awareness of this risk is recommended.

Absolute Lymphocyte Count

The role of peripheral blood absolute lymphocyte count as a predictor of CMV infection has been well described. Lymphopenia has been identified as an independent predictor of and is associated with an increased risk of CMV infection.²⁰ The critical number of lymphocytes has not been definitively established, but in one study, a threshold value of < 610 cells/μl has been suggestive of increased risk.²¹ Another study found that an absolute lymphocyte count < 1100 cells/ml on day 28 after transplantation is predictive of the development of subsequent CMV infection in recipients who are D+/R+ and undergoing preemptive therapy (PET) for CMV prevention.²² Low absolute lymphocyte count at the end of treatment for CMV infection/disease was also found to be a predictor of relapses of CMV disease in a retrospective cohort of heart, liver, and KTRs.²³

Kidney and Pancreas Recipients

CMV infection remains a major infectious complication in simultaneous kidney and pancreas transplant recipients. A study by Schachter et al.²⁴ found a higher incidence and more severe course of CMV infection in this population of recipients compared with KTRs, with more CMV disease, CMV pneumonia, recurrent active CMV infection, higher initial and peak CMV loads, and more need for i.v. antiviral therapy. This was notable despite CMV prophylaxis and is attributed to the use of lymphocyte-depleting agents for induction therapy, as well as a less effective reduction in maintenance immunosuppression at the time of CMV diagnosis because of higher concern for acute cellular rejection in the presence of the pancreas allograft.

Patients With High Immunologic Risk

KTRs with high immunologic risk include patients who are HLA-sensitized, recipients with a positive crossmatch, or recipients with ABO incompatibility. To ensure successful transplantation and improved graft survival, these patients typically require various desensitization protocols or intensified immunosuppression management incorporating the use of rituximab, i.v. Ig, and plasmapheresis, among other therapies. Immunologically high-risk status has been found to be an independent risk factor for CMV reactivation.²⁵ Kijma et al.²⁵ described a higher incidence of CMV reactivation specifically in patients who are highly sensitized and receiving rituximab and i.v. Ig. Choi et al.²⁶ observed that the use of ATG and rituximab, particularly in KTRs with ABO- or HLA-incompatibility, significantly increases the risk of CMV infection.

Impaired Graft Function

Impaired graft function, specifically delayed graft function and allograft rejection,³ are additional factors that have been recognized to increase the risk of CMV infection and disease. Delayed graft function was identified as an independent predictor of CMV disease in a study of 1300 KTRs, with a higher incidence of breakthrough CMV disease and earlier onset of infection after transplant.²⁷ Treatment of acute rejection episodes has also been observed to be independently associated with CMV infection and disease. A retrospective study²⁸ found an incidence of CMV infection/disease of 47% after treatment of acute rejection episodes, with the majority of infections (73%) occurring within the first month. Most of these patients received rabbit-derived ATG in addition to tacrolimus, steroids, and additional immunosuppressive agents, such as mycophenolate or azathioprine.

Advanced Recipient Age

Advanced recipient age (> 65 years) is a consistently identified independent risk factor for both CMV infection and CMV disease after kidney transplantation, as observed in various studies including meta-analyses.^1,29,30 Immunosenescence^31,32 involves a progressive reduction with aging of the human immune system to trigger effective antibody and cellular responses against both vaccinations and infections, leading ultimately to loss of control of infections, including CMV.

Diagnostics

There are numerous tests available for CMV testing; the choice of test depends on whether one is trying to determine the presence of active infection or history of past infection. Serological testing for antibody to CMV using a sensitive and specific assay is indicated to determine the history of CMV but not indicated to identify active infection. Consequently, all potential candidates and donors should undergo CMV IgG testing to assess the risk of recipient posttransplant infection. Although pp65 antigenemia assays were previously used to identify active infection, this test is no longer recommended because of the issues with same-day processing, observer variability, and lower sensitivity in patients with leukopenia, given the need to identify the antigen in white blood cells.³³ Instead, CMV-specific quantitative nucleic acid amplification testing (CMV QNAT) is the preferred diagnostic assay for identification of active infection. CMV QNAT can be performed on either whole blood or plasma; plasma is typically preferred, and most clinical trials have relied on plasma assays. Multiple assays are available and approved in the United States and cleared by the European Union. Although results are typically reported in international units, comparing logarithmic measurements is a more accurate way to assess changes over time; changes of < 0.5 log₁₀ are not generally regarded as significant.³³ Although interlaboratory variability limits the ability to compare results between different laboratories, CMV QNAT³⁴ has become a reliable diagnostic assay, and ultrasensitive QNAT assays allow for earlier detection of infection. CMV monitoring with QNAT should ideally be performed from the same laboratory to limit interlaboratory variability in results. Quantitative results may also reflect the response to treatment, and there has been a correlation of higher DNA levels with more severe disease.³³ There are important limitations of this assay,³⁵ including negative results in some cases of tissue-invasive disease in which the size of the DNA fragment (amplicon) may be larger (e.g., disease involving the gastrointestinal tract) and persistent detection of low-level DNA fragments, which may not be clinically significant. Antivirals (especially letermovir, an inhibitor of DNA terminase) may increase the number of circulating DNA fragments,³⁶ potentially leading to falsely elevated QNAT results. When CMV is suspected and the result of CMV QNAT is negative, tissue biopsy is indicated to definitively exclude the diagnosis.

Definitions of CMV Disease

Consensus definitions for CMV infection and disease, developed by the CMV subgroup for the Transplant-Associated Virus Infections Forum,³⁷ were recently updated. CMV infection is defined as the presence of replication of CMV DNA in the blood, irrespective of symptoms. CMV disease constitutes both end-organ disease and CMV syndrome. CMV syndrome is defined as the presence of replication of CMV DNA in the blood in association with at least 2 of the following clinical signs and symptoms: fever, arthralgias, leukopenia, thrombocytopenia, and significant hepatic transaminase elevation. CMV disease or tissue-invasive disease refers to the presence of clinical signs or symptoms of end-organ disease (e.g., colitis, enteritis, nephritis, and retinitis).

CMV Treatment

Ganciclovir or valganciclovir are the preferred antiviral agents for the treatment of CMV, assuming no concerns about ganciclovir-resistant virus. Additional agents that have activity against CMV include foscarnet, cidofovir, and maribavir; however, these agents are typically limited for use in resistant or refractory disease (Table 1). Valganciclovir is an orally administered prodrug of ganciclovir and is well absorbed from the gastrointestinal tract and rapidly hydrolyzed to ganciclovir in the intestinal wall and liver. Valganciclovir also achieves blood levels that are comparable to i.v. ganciclovir.³⁸

Table 1.

Antiviral agents in kidney transplant recipients

Medication	Ganciclovir	Valganciclovir	Foscarnet	Cidofovir	Maribavir	Letermovir
Mechanism of action	Inhibition of viral DNA polymerase	Inhibition of viral DNA polymerase (oral prodrug of ganciclovir)	Inhibition of viral DNA polymerase	Inhibition of viral DNA polymerase	Inhibition of viral UL97 kinase	Inhibition of viral terminase complex (UL56)
Formulation	i.v.	Oral	i.v.	i.v.	Oral	i.v./oral
Major adverse effects	Myelosuppression	Myelosuppression	Nephrotoxicity, genital ulcers	Marked nephrotoxicity, uveitis	Dysgeusia	GI upset
Renal dose adjustment	Requireda,b	Requiredc,d	Requirede	Requirede	No adjustment required	No adjustment required
Resistance pathway	UL97, UL54	UL97, UL54	UL54	UL54	UL97	UL56
Major drug-drug interactions	Mycophenolate mofetil/ mycophenolic acid (increased myelosuppression)	Mycophenolate mofetil/ mycophenolic acid (increased myelosuppression)	Tacrolimus (additive nephrotoxicity); cyclosporine (additive nephrotoxicity)	Tacrolimus (additive nephrotoxicity); cyclosporine (additive nephrotoxicity)	May increase tacrolimus and cyclosporine levels	Tacrolimus (↑ tacrolimus levels); cyclosporine (↑ letermovir exposure/levels)
Activity against HSV/VZV	Active against HSV and VZV	Active against HSV and VZV	Active against HSV and VZV	Active against HSV and VZV	Not active against HSV and VZVf	Not active against HSV and VZVf
Limitations	Bone marrow suppression	Bone marrow suppression	Marked nephrotoxicity	Marked nephrotoxicity	Avoid with high viral load; not indicated for CNS/retinal disease; low barrier to resistance	Not indicated for treatment of CMV infection/disease owing to low barrier to resistance

CMV, cytomegalovirus; CNS, central nervous system; CrCl, creatinine clearance; GI, gastrointestinal; HD, hemodialysis; HSV, herpes simplex virus; VZV, varicella-zoster virus.

^aGanciclovir treatment dose adjustment for CrCl: CrCl ≥ 70 ml/ min/ 1.73 m², 5 mg/kg q12H; CrCl: 50–69 ml/ min/ 1.73 m², adjust dose to 2.5 mg/kg q12H; CrCl: 25–49 ml/ min/ 1.73 m², adjust dose to 2.5 mg/kg i.v. q24h; CrCl < 25 ml/ min/ 1.73 m², adjust dose to 1.25 mg/kg i.v. q24h; for HD, adjust dose to 1.25 mg/kg i.v. after dialysis on days when dialysis was performed.

^bGanciclovir prevention dose adjustment for CrCl: CrCl: ≥ 70 ml/ min/ 1.73 m², 5 mg/kg q24H; CrCl: 50–69 ml/ min/ 1.73 m², adjust dose to 2.5 mg/kg q24H; CrCl: 25–49 ml/ min/ 1.73 m², adjust dose to 1.25 mg/kg i.v. q24h; CrCl: < 25, adjust dose to 0.625 mg/kg i.v. q24h; for HD, adjust dose to 0.625 mg/kg i.v. after dialysis on days when dialysis was performed.

^cValganciclovir treatment dose adjustment for CrCl: CrCl: ≥ 60 ml/ min/ 1.73 m², 900 mg q12H; CrCl: 40–59 450 mg q12H; CrCl: 25–39 ml/ min/ 1.73 m², 450 mg q24H; CrCl: < 25 mL/ min/ 1.73 m², 450 mg q48H; for HD, 200 mg 3 times/week after dialysis on days when dialysis was performed.

^dValganciclovir prevention dose adjustment for CrCl: CrCl: ≥ 60 ml/ min/ 1.73 m², 900 mg q24H; CrCl: 40–59 ml/ min/ 1.73 m², 450 mg q24H; CrCl: 25–39 ml/ min/ 1.73 m², 450 mg q48H; CrCl: < 25 ml/ min/ 1.73 m², 450 mg twice weekly; for HD, 100 mg 3 times/week after dialysis on days when dialysis was performed.

^eFoscarnet and cidofovir dose adjustment, seek pharmacy expertise for assistance.

^fAdditional prophylaxis against HSV/VZV with valacyclovir or acyclovir.

Selecting between ganciclovir and valganciclovir depends on various factors, including the severity of infection, initial viral load level, the patient’s ability to tolerate and consistently take oral medications, and kidney function. I.V. ganciclovir is typically preferred for patients with significant GI malabsorption, those with very high initial viral DNA levels, and those with severe tissue-invasive disease (including GI disease, pneumonitis, and CNS disease). Valganciclovir is preferred in all other scenarios because of low cost and mitigation of risk associated with vascular access. A randomized clinical trial³⁹ that compared 3 weeks of oral valganciclovir with i.v. ganciclovir for treatment of mild-to-moderate CMV disease reported valganciclovir to be noninferior to ganciclovir.

While on antiviral therapy, monitoring of CBC and renal function is imperative to assess drug toxicity and consideration of renal dose adjustment, respectively. Myelosuppression, specifically leukopenia, is the most significant and common adverse event associated with ganciclovir and valganciclovir. If leukopenia develops, the use of granulocyte colony- stimulating factor can be considered.

Treatment is typically continued for a minimum of 21 days: all symptoms and DNAemia should be resolved before discontinuation of treatment. Weekly CMV load using QNAT should be monitored to ensure sufficient treatment to resolve the infection. In addition to antiviral therapy, reduction of immunosuppression is also a key component of CMV management. There are limited studies exploring the benefit of adding i.v. Ig or CMV-Ig to antiviral treatment of CMV disease; consensus guidelines recommend considering this for patients with life-threatening disease, CMV pneumonitis, and possibly other severe forms of disease, drug-resistant virus, and those with hypogammaglobulinemia (IgG < 400 mg/dl).³³

Resistant and Refractory CMV

Refractory CMV infection occurs when there is a failure to achieve > 1 log₁₀ decline in CMV DNA level in whole blood or plasma or persistent signs and symptoms of CMV disease after at least 2 weeks of appropriate antiviral therapy.³⁷ Resistant CMV infection is defined as refractory CMV infection with detection of a viral genetic mutation that decreases susceptibility to 1 or more antiviral drugs. Risk factors for drug-resistant CMV^40,41 include prolonged subtherapeutic doses of antiviral drugs (underdosing – Young et al.⁴⁰), profound immunosuppression,⁴² D+/R- serostatus,⁴³ and recurrent CMV infection. The options for the treatment of refractory and resistant CMV include maribavir, foscarnet, and cidofovir (Figure 1).

Figure 1.

Management of drug-resistant CMV infection. FOS, foscarnet; GCV, ganciclovir; MBV, maribavir; VGCV, valganciclovir. ∗Avoid the use of maribavir for high DNA levels (e.g., > 50,000 IU/ml [≥ 4.7 log10 IU/ml]).

In suspected drug-resistant infections, resistance testing using a CMV genotypic assay should be obtained to detect specific mutations in the UL97, UL54, and UL56 genes. Viral UL97 kinase gene mutations typically are more common⁴⁴ and appear first, particularly after ganciclovir/valganciclovir exposure, whereas UL54 DNA polymerase gene mutations usually emerge later and confer increased ganciclovir resistance as well as potential cidofovir or foscarnet cross-resistance.⁴⁵ Letermovir resistance often involves the UL56 codon.⁴⁶

The degree of resistance to ganciclovir conferred by CMV UL97 genetic mutations depends on the site of mutation, which could confer either a low-level or high-level resistance. CMV infections with mutations conferring low-level resistance, such as UL97, C592G, and C480F, can be successfully treated with higher doses of ganciclovir.⁴⁷ The most common UL97 genetic mutations that confer high-level ganciclovir resistance are M460V/I, H520Q, C592G, A594V, L595S, and C603W.³³ These require treatment with an alternate agent, such as maribavir, foscarnet, or cidofovir.

Maribavir is an oral benzimidazole L-riboside inhibitor of the CMV UL97 kinase^48,49 that has shown a superior safety profile, specifically less myelosuppression and nephrotoxicity, compared with other antivirals used to treat CMV. The SOLSTICE trial,⁵⁰ a phase 3 randomized trial in solid organ and hematopoietic stem cell transplant recipients, compared maribavir with investigator-assigned therapy for the treatment of refractory CMV infection, with or without resistance. Confirmed plasma viral DNA clearance at study week 8 was achieved by 56% of participants in the maribavir arm versus 24% in the investigator-assigned therapy arm. Of note, a small percentage of patients enrolled had symptomatic CMV infection, including tissue-invasive disease (8%); thus, most patients had asymptomatic CMV viremia. These results led to the approval of maribavir by the US Food and Drug Administration in 2021 for treatment of posttransplant CMV infection/disease that is refractory to treatment with ganciclovir, valganciclovir, cidofovir, or foscarnet and is now recommended in the guidelines as a preferred agent for resistant/refractory cases.³³ Outside of the United States, maribavir is available for primary therapy of CMV that is neither resistant nor refractory.

Based on subgroup analyses showing higher response rates with maribavir with lower starting viral loads, it is recommended to avoid use in high plasma viral load (i.e., > 50 000 IU/ml) to avoid emergence of resistance. In these situations, foscarnet may be used initially to reduce the viral load followed by a switch to maribavir at a lower viral load.

Maribavir resistance is not common, and baseline resistance is not typically seen. Posttreatment emergence of resistance has been described and reported to be as high as 26% based on additional genotypic analysis data from the SOLSTICE trial.⁴⁷ The resistance rate was noted to vary significantly based on treatment response, with maribavir resistance occurring in 48% of nonresponders versus 86% of patients with recurrence during treatment.⁴⁷ The most common mutations conferring maribavir resistance are UL97 F342Y, T409M, H411Y, and C480F.^47,48,51 Ganciclovir and maribavir cross-resistance is not a common phenomenon; however, recent trials^52,53 have identified instances of maribavir-ganciclovir cross-resistance associated with specific mutations. UL97F342Y and C480F, which confer 4.5-fold and 224-fold reduced susceptibility to maribavir, respectively, are associated with 1.5-fold reduced susceptibility to valganciclovir/ganciclovir.

Maribavir is generally well tolerated and has a superior safety profile compared with other anti-CMV therapy, with less myelosuppression and nephrotoxicity.⁴⁸ However, dysgeusia is a common side effect and occurs in up to one-third of patients. Maribavir also has several notable drug interactions, including tacrolimus, which need careful monitoring. Patients with retinal and CNS disease were excluded from the study, so it is not recommended in these scenarios. Additionally, maribavir only has activity against CMV, so additional antivirals with activity against HSV and VZV would need to be initiated if those infections were of concern. Coadministration of maribavir and ganciclovir is contraindicated because of concerns for drug antagonism.

Letermovir has a low barrier for the development of resistance and is neither recommended nor approved for treatment of CMV. Case reports and series of treatment with letermovir either alone or in combination with other antivirals have been reported,^54,55 but there is no current recommendation for its use for treatment.

Role of Cellular Therapies

Adoptive T-cell-based therapy or CMV cytotoxic T-lymphocyte (CTL) therapy is a potential therapy to treat viral infections posttransplantation by reconstituting the CMV-specific T-cell response and thus controlling CMV infections in this patient population. CTLs may be beneficial to patients who are resistant to antivirals or in whom it is difficult to reduce immunosuppression, as it may lead to a greater risk of rejection. CTLs are manufactured from peripheral blood mononuclear cells isolated from unrelated healthy volunteers.⁵⁶ The peripheral blood mononuclear cells are then incubated with specific viral antigens to generate interferon-gamma.^56,57 The most immunodominant CMV antigens used to stimulate the CMV-specific immune response are IE-1 and pp65 proteins. These cells are then cultured in a medium containing cytokines, after which the final product containing interferon-gamma positive CD4 and CD8 T cells is harvested. Several case reports and 1 phase 1 clinical trial58, 59, 60 have been published using CMV-specific CTLs (CMV-CTLs) to treat resistant/refractory CMV in solid organ transplant recipients. In a case series highlighting the use of adoptive T-cell therapy for various viral infections, CTLs used in the 4 cases⁶⁰ of resistant CMV infections led to more than 50% reduction in viral load as well as a significant improvement in acute kidney injury in half the patients. Limitations include length of manufacturing process as it can take 8–12 weeks to generate the CTLs. Additional data are needed demonstrating safety and efficacy of CTL therapy in clinical trials.

Prevention

There are various mechanisms by which CMV evades the host’s immune response to directly downregulate both the innate and adaptive arms of the immune system. These include reducing HLA expression as well as encoding proteins that specifically inhibit presentation of peptides by antigen-presenting cells, thus limiting the activation of CMV-specific T-cell responses.²

Optimal prevention strategies after solid organ transplantation are associated with improved outcomes. Without preventive strategies, approximately 60% of KTRs experience active CMV infection, and approximately 20% develop CMV disease. CMV has been well described to be associated with a myriad of direct and indirect effects. The direct effects include asymptomatic viremia, CMV syndrome, and CMV disease. Indirect effects⁶¹ include increased rates of bacterial, viral, and fungal infections, posttransplant lymphoproliferative disease, increased rates of graft dysfunction and failure, acute rejection,61, 62, 63, 64 allograft glomerulopathy,⁶⁵ transplant and nontransplant vascular disease, diabetes,⁶⁶ and mortality. Given these complications, there has been a significant focus on prevention.

There are currently 2 strategies widely used for CMV prevention—universal prophylaxis or preemptive monitoring. Universal prophylaxis entails providing antiviral prophylaxis to all patients starting within 7–10 days of transplantation. Choices for antiviral prophylaxis include oral agents such as valganciclovir, letermovir, and high-dose valacyclovir. Duration of prophylaxis is determined by risk status and is typically administered for 3 to 6 months for KTRs. The current guidelines³³ recommend 6 months (200 days) of prophylaxis for kidney recipients who are D+/R-, because this duration has shown a reduced risk of CMV disease compared with 100 days,⁶⁷ which is recommended for recipients who are seropositive (R+). Durations beyond 6 months have not shown benefit in kidney recipients and can contribute to increased cost and higher rates of leukopenia. PET entails monitoring of CMV DNA in blood at weekly intervals to detect early viral replication which would trigger initiation of antiviral therapy. The thresholds used for initiating antiviral treatment are not well defined and have varied extensively across various studies, ranging anywhere from any level of DNAemia to > 5000 IU/ml in whole blood.

Current guidelines³³ suggest that preemptive therapy and universal prophylaxis are both comparable methods of CMV disease prevention for high- and intermediate-risk KTRs (Table 2). Early CMV DNAemia is common with PET; however, late CMV infection/disease is seen more often with universal prophylaxis. PET may be more difficult to implement as it requires weekly monitoring but is associated with less drug toxicity than universal prophylaxis. Studies have not clearly shown whether 1 approach is more favorable for prevention of acute rejection and overall graft survival. One retrospective study⁶⁸ found similar allograft outcomes and long-term survival in KTRs at high-risk with both strategies, whereas a large prospective national cohort study of mostly kidney and liver recipients found an increased risk of graft loss with PET.⁶⁹

Table 2.

Characteristics of antiviral prophylaxis and preemptive therapy in patients who underwent renal transplant

Feature	Universal antiviral prophylaxis	Preemptive therapy
Procedure	Antiviral medication given to all patients at risk of CMV for 3–6 mos after transplant	Weekly CMV PCR monitoring with initiation of antiviral therapy with CMV DNAemia detection
Antiviral	i.v. ganciclovir/PO valganciclovir; letermovir	N/A
Efficacy against CMV disease prevention	Good efficacy; very low risk during prophylaxis period	Good efficacy
Late-onset (i.e., after 3–6 mos after transplant) CMV disease	Higher risk (after prophylaxis period)	Lower risk
Cost attributable to:	Medication	Laboratory monitoring
Feasibility	Easy to implement as frequent lab visits are not required	Requires weekly monitoring of labs
Toxicity	Higher rates of myelosuppression	Lower risk of drug toxicity
Acute rejection	Lower risk of acute rejection	Unknown effect on rejection
Resistance	Potential low risk with prolonged exposure	Uncommon
Duration of prophylaxis	Dependent on risk status: High risk (D+/R-) 6 mos Intermediate risk (R+) 3 mos Low risk (D-/R-) 3 mos	12 wks after transplant

CMV, cytomegalovirus; D+/R-, donor-seropositive/recipient-seronegative; D-/R-, donor-seronegative/recipient-seronegative; DNAemia, DNA viremia; N/A, not applicable; PCR, polymerase chain reaction; PO, oral; R+, recipient-seropositive.

Adapted from Kotton et al.²⁵

Valganciclovir is the preferred antiviral for prophylaxis based on efficacy data compared with oral ganciclovir in patients who underwent transplant and are at high risk.⁷⁰ For KTRs having high and intermediate risk, the recommended dose is 900 mg daily with the dose adjusted for renal function. Extending the duration of valganciclovir prophylaxis to 200 days showed a reduction in the incidence of late-onset CMV disease with overall similar safety and tolerability compared with 100 days^67,71 and is thus recommended for KTRs at high risk. “Mini-dosing” of valganciclovir is used by certain centers in an attempt to improve tolerability and entails using half the recommended dose for prophylaxis. There are many published studies^72,73 on low-dose valganciclovir prophylaxis; however, most do not incorporate data on renal function, thus making it unclear if patients received the appropriate renally adjusted dose of valganciclovir. Additionally, a higher incidence of breakthrough infections has been shown^74,75 in those receiving low-dose prophylaxis compared with standard doses, and thus the guidelines specifically do not recommend low-dose valganciclovir prophylaxis.

Although highly effective for CMV prophylaxis, use of valganciclovir is often limited by myelosuppression leading to early discontinuation of CMV prophylaxis. Myelosuppression in this setting is often multifactorial; concomitant medications, especially mycophenolate and to a lesser extent, trimethoprim-sulfamethoxazole, have been commonly implicated. This may lead to dose reduction of immunosuppressive agents (especially antiproliferative agents including mycophenolate) to counter leukopenia/neutropenia, and this potentially increases the risk of rejection. This led to interest in the use of letermovir, an inhibitor of the CMV DNA terminase complex that is not associated with bone marrow suppression and was initially approved by the US Food and Drug Administration for the prevention of CMV in adult CMV-seropositive allogeneic stem cell transplant recipients. In a randomized controlled trial conducted by Limaye et al.⁷⁶ letermovir was compared with valganciclovir for prophylaxis in adult KTRs who were CMV-seronegative and received an organ from a CMV-seropositive donor. Letermovir administered at 480 mg daily for up to 200 days was found to be noninferior to valganciclovir for prophylaxis of CMV disease in these patients. In those receiving letermovir, there were significantly lower rates of leukopenia and neutropenia and thus less discontinuation of prophylaxis. There were also no letermovir-associated resistance mutations identified in the patients who had developed CMV disease/infection, compared with 12.1% in the valganciclovir arm that did develop valganciclovir-associated mutations. Thus, development of resistance to letermovir appeared unlikely to emerge when used for prophylaxis. Letermovir was subsequently approved by the US Food and Drug Administration in June 2023⁷⁷ for prophylaxis in adult KTRs at high risk of CMV, specifically recipients who were D+/R-, and has been included as an option for prophylaxis in the international CMV guidelines.³³

Important considerations for letermovir include its lack of activity against HSV and VZV; thus, patients need to receive concomitant valacyclovir or acyclovir for prophylaxis against those herpes viruses. Because of its inhibition of CYP3A4, letermovir is also associated with significant drug-drug interactions, necessitating dose modifications of concomitant medications. Coadministration with tacrolimus leads to increased plasma concentration of tacrolimus and thus requires careful and close monitoring of tacrolimus levels to prevent toxicity. When used with cyclosporine, close monitoring of cyclosporine levels as well as a 50% reduction of letermovir dose is recommended owing to increases in cyclosporine plasma concentrations. Subsequent studies have detailed real-world experience using letermovir as prophylaxis in kidney transplantation including improved rates of leukopenia, stable maintenance dosing of mycophenolate without need for frequent dose reductions and less use of granulocyte colony-stimulating factor.^77,78 Additionally, the high cost of letermovir limits its widespread use for primary prophylaxis, particularly in resource-limited regions. Secondary prophylaxis is not generally recommended after completion of treatment for CMV infection. However, it may be instituted on a case-by-case basis depending on individual patient-specific risk factors, e.g., high-risk serostatus, low absolute lymphocyte count, negative CMV CMI assay, or recent enhanced immunosuppression.

Immunosuppression management plays a critical role in preventing CMV infections in transplant recipients. There is emerging data suggesting that patients receiving mammalian target of rapamycin inhibitors (mTORs), such as sirolimus and everolimus, are at a low risk of CMV disease/infection. There are various proposed mechanisms as to how mTORinhibitors may exhibit a protective role against CMV infection and disease. They are known to inhibit T-cell proliferation through inhibition of the cell cycle as well as possess various antiviral properties that aid in improving the quality and functionality of memory T cells in response to viral stimuli.⁷⁹

Several prospective studies including randomized clinical trials80, 81, 82 have been conducted over the past 5 years to evaluate the role of mTOR inhibitors in the management of CMV. Tedesco et al.⁸¹ compared the incidence of CMV infection and disease in de novo KTRs receiving an mTOR inhibitor-based or mycophenolate-based regimen in combination with tacrolimus. All patients were treated with a preemptive approach to CMV prevention and only 5% to 6% of the population was CMV high risk (D+/R-). The authors found that patients treated with everolimus had a reduced incidence of first CMV infection/disease at 12 months as well as overall lower rates of recurrent CMV. Based on these studies, there may be a role for switching patients who have recurrent CMV from an antiproliferative agent to mTOR, assuming the patient is at low risk for rejection and there are no other contraindications to this approach.³³

Ig for the Prevention of CMV

Ig preparations (both i.v. Ig and CMV-specific Ig) were studied in early trials of CMV prevention and reported to have some benefit when compared with placebo.⁸³ Older trials combining ganciclovir and Ig for CMV prevention in thoracic transplantation may have shown some benefit for cardiac and lung transplant recipients with reduced rates of bronchiolitis obliterans, transplant arteriopathy, and CMV and improved survival.⁸⁴ However, these studies do not reflect current management which includes more prolonged antiviral prophylaxis and the current consensus guidelines do not recommend the routine use of Ig preparations for prevention of CMV. However, they may be considered in select circumstances in combination with antivirals.³³

CMV Vaccine

Given the impact of CMV on transplant outcomes, there has been significant interest in developing an effective CMV vaccine to prevent CMV. A number of platforms have been studied, including the original live attenuated Towne strain vaccine, adjuvanted DNA plasmid-based, adjuvanted glycoprotein B, nonreplicating viral vector, modified vaccinia Ankara triplex vaccine, chimeric peptide adjuvanted vaccine, and more recently, an mRNA vaccine. Although these have been well tolerated with some evidence of immune responses, at this time there are no prospective controlled trials that support the use of vaccination for prevention of CMV in KTRs. Current clinical trials are ongoing in patients who underwent liver and stem-cell transplantation.

Immune Monitoring and CMV-CMI Specific Assays

The CMV guidelines note that lymphopenia and hypogammaglobulinemia may predict risk for CMV and can be monitored.³³ Additionally, assays for assessing CMV-specific T-cell responses can help predict the risk of CMV infection or disease. Various assays are available; however, widespread implementation in routine clinical practice is limited by lack of access and cost of testing, as well as differences in assay interpretations. The most common assays measure interferon-gamma release from T cells in response to CMV-specific antigens using an enzyme-linked immunosorbent assay, such as QuantiFERON-CMV,⁸⁵ or an enzyme-linked immunosorbent spot-based assay technique, such as T-Track CMV or T-Spot. Flow cytometry uses intracellular cytokine staining to create a CMV T-cell immunity panel.

A 2024 study by Solera et al.,⁸⁵ determined that QuantiFERON-CMV-guided prophylaxis was more beneficial in patients with R+ serostatus receiving ATG than those who were D+/R-. In the D+/R- group, the test had limited utility because of very low rates of positivity, and thus, almost all patients in this subgroup received 6 months of prophylaxis. In the R+/ATG induction subgroup, the test had greater utility and there was apparent delineation of patients who were immune or nonimmune at all points tested which allowed for individualization of prophylaxis durations. In another study by Paez-Vega et al.,⁸⁶ 150 kidney recipients who were R+ were randomized to fixed duration versus immune-guided prophylaxis using the QuantiFERON-CMV assay starting at 30 d posttransplant. The incidence of CMV viremia and disease was similar in the 2 arms, but the CMI-guided arm was able to discontinue prophylaxis earlier with a resultant lower incidence of neutropenia (9.2% vs. 37.8%; P < 0.001).

Manuel et al.⁸⁷ assessed the enzyme-linked immunosorbent spot-based assay assay in kidney and liver transplant recipients with D+/R- serostatus and those with R+ serostatus receiving ATG and found similar rates of CMV infection between individuals receiving fixed durations of prophylaxis versus immune-guided duration. The CMI-guided group had a shorter duration of prophylaxis (145.5 d fixed duration vs. 113.7 d in the CMI-guided group; P < 0.001). These assays were generally more predictive in individuals who were seropositive before transplant.

Given these results, the guidelines³³ recommend considering the use of CMV-specific CMI to individualize antiviral prophylaxis posttransplant, as well as predict late CMV reactivation after prophylaxis in recipients who are CMV-seropositive. Various studies have demonstrated that early discontinuation of prophylaxis based on CMI testing is possible and does not lead to a higher incidence of infection or disease. By personalizing the prophylaxis and management of CMV, excess treatment, cost, and toxicity may be avoided. Where available, CMV-CMI assays may provide a useful adjunct to CMV management.

Conclusion

Despite significant advances, the risk of CMV infection remains a challenge in KTRs. The updated CMV consensus guidelines³³ offer new recommendations with regard to diagnostics, prevention, and treatment of CMV infection in solid organ transplant recipients. Novel antiviral agents as well as CMV-specific immune assays allow for individualizing strategies for prevention and treatment.

Disclosure

EAB has received research support from Takeda and Merck and honorarium from Takeda. SI has no conflict of interest to disclose.