The treatment of CMV in pediatric SOT recipients (Table 2), whether for asymptomatic viremia or CMV disease, is largely derived from the adult literature. Cautious reduction in immune suppression and treatment with antiviral agents remain the mainstay for treatment of CMV infection in children. Although oral ganciclovir may be appropriate as an initial choice in asymptomatic viremia or mild/moderate disease, it is no longer widely available in the United States. IV ganciclovir is the preferred agent in more severe CMV disease or if there is a concern for impaired GI absorption (3, 28). Other antiviral agents such as foscarnet and cidofovir are considered second or third-line options, mainly reserved for use in cases of ganciclovir resistance due to their highly nephrotoxic potential. Data is emerging regarding newer antiviral agents, letermovir and maribavir, in both prevention and treatment of refractory CMV infection in the adult and pediatric SOT literature. Duration of treatment for CMV disease is dependent on resolution of clinical symptoms treatment guidelines. Following completion of treatment, many centers will provide secondary prophylaxis for 1–3 months to reduce the risk for recurrence, although not currently supported by high quality evidence (3).

Ganciclovir was the first antiviral approved for the treatment of CMV infection in 1989. Ganciclovir and its oral pro-drug valganciclovir, compete with deoxyguanosine triphosphate for binding to viral DNA polymerase, thereby inhibiting viral DNA synthesis (29). Several studies have demonstrated efficacy of ganciclovir and valganciclovir for the treatment of CMV in adult SOT recipients, and this is largely extrapolated to the pediatric SOT population (30–32). Hematologic toxicities such as leukopenia, neutropenia, thrombocytopenia, and anemia are well-known and reversible adverse effects of ganciclovir and valganciclovir (33). These agents are recommended to be used with caution in patients with pre-existing cytopenias, and use should be avoided when ANC < 500 cells/ml, platelet count is <25,000/ml, or hemoglobin <8 g/dl. However, disseminated CMV can itself suppress the bone marrow, and granulocyte-colony stimulating factor (G-CSF) may be used to manage bone marrow suppression in patients requiring prolonged treatment with ganciclovir or valganciclovir.

FDA-approved dosing for both ganciclovir and valganciclovir in the pediatric population has undergone scrutiny in recent years. In 2009, valganciclovir received pediatric approval for the prevention of CMV in kidney and heart transplant recipients using an FDA approved dosing algorithm of 7 x BSA x CrCl (calculated from the modified Schwartz formula) (29). In 2010, the FDA issued a safety alert cautioning valganciclovir overexposure in pediatric patients with low body weight, low body surface area, and below normal serum creatinine levels as the labeled dosing algorithm did not account for these patient factors (29). With this alert, valganciclovir labeling was revised to include a maximum creatinine clearance of 150 ml/min/1.73 m² and a maximum dose not to exceed 900 mg. Overall this has led to alternative weight-based and BSA-based dosing strategies and an overall lack of consensus amongst providers (34). A national survey published in 2018 found that only 25% of transplant centers in the United States that participated in the survey utilized the FDA-approved dosing algorithm, many of them using modified variations of the formula or different dosing strategies alltogether (34). Several small, single-center pediatric studies have gone on to support the findings that the FDA-approved dosing algorithm leads to supratherapeutic levels (AUC12/24 > 60 mcg*h/ml) in the majority of pediatric patients (35, 36), whereas weight based dosing demonstrated subtherapeutic exposure (36, 37), however, more recent large pediatric data suggests that this may not impact clinical outcomes of prevention of CMV viremia (38). Another small retrospective study found no difference in the development of CMV viremia by weight-based vs. FDA-labeled dosing; however, the incidence of neutropenia was higher in those who received FDA-labeled dosing (39). Finally, there are several, recent population pharmacokinetic model-based studies which have looked at IV ganciclovir dosing algorithms in pediatric patients and found that standard dosing of ganciclovir 5 mg/kg daily (prevention dose) or every 12 h (treatment dose) are projected to achieve subtherapeutic ganciclovir concentrations, particularly in younger patients <2 years old. These findings led to the development of a new dosing algorithm (3x BSA x CrCL), which has been reviewed by the European Medicine Agency (EMA) and added to ganciclovir prescribing information in Europe (37).

Ganciclovir and valganciclovir resistance can occur in up to 2%–4% of pediatric patients with CMV infection (28). Pediatric SOT recipients are a unique population due to high likelihood of CMV mismatch (CMV D+/R−) at the time of transplantation (28). The most common gene mutation in patients initially treated with ganciclovir or valganciclovir is the UL97 kinase mutation which occurs in 90% of cases, with the UL54 DNA polymerase gene mutation typically evolving later. Drug resistance should be suspected in patients who develop refractory CMV infection after prolonged antiviral drug exposure and in those failing to respond after at least 2 weeks of appropriate therapy (3, 28).

Treatment of ganciclovir-resistant CMV disease continues to remain a challenge. Apart from cautious reduction in immunosuppression, foscarnet is the first choice for treatment of ganciclovir-resistant CMV infection (3, 40, 41). Both foscarnet and cidofovir are effective against CMV isolates with isolated UL97 mutations, however there may be cross-resistance in the case of UL54 mutations especially with cidofovir. Genotypic assays should be used to guide therapy. Both are highly nephrotoxic, which remain the main concern with their use. Brincidofovir, a synthetic oral analogue of cidofovir with good oral bioavailability and reduced nephrotoxicity, although promising in preclinical studies, had disappointing results in phase 3 clincal study (42).

Maribavir is a CMV enzyme pUL97 kinase inhibitor that was FDA-approved in November 2021 for the treatment of post-transplant refractory CMV infection in both adult and pediatric patients ≥12 years of age weighing ≥35 kg (43). Maribavir is dosed 400 mg orally twice daily with no dose adjustments for kidney impairment, and lacks bone marrow and kidney toxicity (29). It may be swallowed whole, crushed, or dispersed and administered through a feeding tube if needed, providing administration options often needed in pediatric patients. The most common side effect reported includes dysgeusia. It can potentially increase drug concentrations of substrates of Cytochrome P450 3A4 and/or P-glycoprotein (P-gp), including tacrolimus, cyclosporine, everolimus, and sirolimus. In addition, Maribavir may antagonize the antiviral activity of ganciclovir and valganciclovir, therefore, co-administration is not recommended.

Maribavir's FDA approval was largely based on the SOLSTICE trial (44), a randomized, open-label, multicenter trial with maribavir 400 mg twice daily or investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for 8 weeks in 352 HSCT and SOT recipients with refractory CMV infections. Significantly more patients in the maribavir group achieved CMV viremia clearance at 8 weeks than patients in the IAT group (55.7% vs. 23.9%). A greater proportion of patients with genotypic resistance to IAT achieved viremia clearance at 8 weeks vs. IAT group (62.8% vs. 20.3%). Secondary outcomes including CMV viremia clearance and symptom control was maintained through week 16. Recurrence, however, was common after discontinuation (50% in maribavir and 39% in IAT group) as noted in additional label information (29). Interestingly, non-published label data reported from the SOLSTICE study also showed development of treatment-emergent resistance with pUL97 substitutions that were detected in 58 patients (47 patients who were on-treatment failures and 11 patients who were relapsed). Maribavir had less acute kidney injury compared to foscarnet (8.5% vs. 21.3%) and less neutropenia compared to valganciclovir/ganciclovir (9.4% vs. 33.9%). SOLSTICE trial design intended to include patients age ≥12 years, however, did not in fact enroll any patients under 18. Labelling approval for use in patients 12 years and older (and over 35 kg) largely is derived from population pharmacokinetic modeling.

Maribavir has also been examined for use in preemptive treatment (45). In a dose finding, randomized open-label trial in adult patients with HSCT or SOT, maribavir appeared to have similar efficacy to valganciclovir for clearing CMV viremia at 3 and 6 weeks. It is important to note that 2 patients in this study developed CMV recurrence after initial response to treatment and were found to have developed resistance mutation in the UL97 protein kinase.

Maribavir appears to be an appealing option allowing for potential outpatient management of patients with refractory or resistance CMV while sparring adverse effects like myelotoxicity. More data, however, is needed to evaluate the clinical impact and potential for cross-resistance with increased use of Maribavir.

Letermovir is novel CMV DNA terminase enzyme complex inhibitor (pUL51, pUL56, pUL89) FDA approved for the prevention of CMV infection and disease in adult CMV-seropositive recipients of allogeneic HSCT (29). Letermovir has emerged as an attractive therapeutic option given its unique mechanism of action for potential use in multi-drug resistant CMV and due to its lack of hematologic and kidney toxicities. Letermovir is not currently approved for use in SOT or in the pediatric population, and most recent guidelines do not support routine use at this time (3, 28). Letermovir, however, has been used off-label for both treatment and secondary prophylaxis of CMV infections in SOT, mostly in cases of multi-drug resistant CMV. Case reports and case series in the SOT population have shown mixed results (46–50) and emergence of resistance and treatment failure have been reported (46, 51). In a large multicenter series, letermovir was examined for patterns of off-label use in the management of CMV infection in 47 patients and included patients down to 15 years of age (50). The most common indications for letermovir use were intolerance to other agents, resistance, and preference for use of an oral agent. In most patients treated with letermovir, low levels of viremia (<1,000 IU/ml) were achieved prior to transition to letermovir. Viral suppression was maintained; however, the authors comment that it is unknown whether the treatment success was due to letermovir or other factors such as immune suppression reduction or spontaneous viral clearance. Success rates were lower for patients with higher viral loads (>1,000 IU/ml). There is currently an ongoing, phase II trial examining the safety and efficacy of letermovir and will include children (age ≥12 years) (NCT03728426).

Doses utilized in case reports and case series have ranged from 240 mg daily (when co-administered with cyclosporine) to 960 mg daily (47–51). FDA recommended dose for prevention of CMV in HCST is 480 mg daily, highlighting the need for more formal treatment dose studies. Most common adverse effect reported in clinical trials is gastrointestinal toxicity (diarrhea, nausea, vomiting), others include peripheral edema, fatigue and headache. Letermovir is a moderate inhibitor of cytochrome P450 3A4 and an empiric tacrolimus dose reduction of 30% in addition to therapeutic drug monitoring has been suggested (52). Cyclosporine may also increase the concentration of letermovir; therefore, initial letermovir dosing should be 240 mg daily when used concomitantly.

Cytomegalovirus immune globulin (CMVIG) or IVIG has been used as an adjunctive therapy and may be considered for use in patients with life-threatening disease or those with treatment resistant CMV (3, 28). Much of the evidence in SOT is limited to small uncontrolled trials and case series conducted prior to modern antiviral era (53–55). Newer evidence has found that the use of CMVIG as rescue therapy (in addition to antiviral therapy and immune suppression reduction) appears to be effective at controlling viral replication in the thoracic transplantation (56–59). Based on the lack of controlled studies, treatment with CMVIG in the adult and pediatric patient population remains limited to resistant infection or complicated cases (59). There is no consensus on the optimal dose and frequency, and pediatric doses range from 100 to 400 mg/kg with varying published frequencies (29). Infusion reactions and high cost or accessibility can often be limiting factors for use.

Adoptive transfer of CMV viral specific T-cells (VST) is an emerging therapeutic option for treatment of refractory and resistant CMV (3, 28). It aims to restore virus-specific T cell immunity facilitating reduction in CMV viral loads and improvement or resolution of CMV disease. CMV specific T-cells can be donor-derived (allogenic) or isolated from the transplant recipient (autologous). VST therapy has been primarily studied in HSCT population and found to be safe and effective (60–63). Studies in SOT population are limited, especially among the pediatric population. A prospective phase I clinical trial included 13 SOT recipients (4 kidney, 8 lung, 1 heart) with ganciclovir-resistant CMV infection showed that 11 of the 13 patients (84%) responded with complete resolution or reduction in viremia, end-organ disease, and/or cessation or reduction of antiviral drug use (64). Several other case reports using allogenic VST therapy in kidney (65) and liver (16 year old) (66) and autologous therapy in lung (67) transplant recipients have shown promising results. VST therapy in the pediatric HSCT population has been successfully reported in a recipient with drug resistant CMV retinitis (68). There are several ongoing studies in adult and pediatric patients to evaluate VST therapy in the management of CMV in SOT recipients (NCT04331275, NCT03950414, NCT02532452, NCT02779439). It is important to note that isolation of VST is time and labor-intensive, limited to a few specialized facilities or treatment centers. There has been increased interest in development of “off the shelf” third party banked cells to help overcome this process (28).