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What’s New in CMV Prevention and Therapy for Transplant Patients?
BY SHMUEL SHOHAM, MD, FIDSA
Infection and disease caused by the human cytomegalovirus (CMV) remains a challenge in transplant recipients. Two new drugs, letermovir (Prevymis, Merck) and maribavir (Livtencity, Takeda) are now available for prevention and treatment, respectively, of CMV disease. This article reviews the clinical role of these drugs.
Overview
Prevention and treatment of CMV disease is a fundamental part of supportive care for recipients of hematopoietic stem cell transplant (HSCT) and solidorgan transplant (SOT). Prevention is mainly by chemoprophylaxis during times of highest risk, such as in the first several months after transplantation and at times of intensification of immunosuppression. CMV serology is helpful for identifying patients at higher risk for clinically significant CMV infection. In HSCT, there is a higher risk for clinically significant CMV infection in recipients who are CMV-seropositive. In SOT, the highest risk is in CMV-seronegative recipients receiving organs from CMV-seropositive donors.
Until recently, the drug of choice for prevention of infection has been valganciclovir, which is the oral prodrug of ganciclovir. Ganciclovir administered intravenously is used when oral therapy is not feasible. Oral ganciclovir is no longer used as it has low bioavailability and is associated with poorer outcomes than other therapies.
Treatment of CMV (as opposed to prophylaxis) is given when the level of viremia exceeds a certain numerical threshold (preemptive therapy), when there is viremia with symptoms compatible with CMV infection (CMV syndrome), and when there is evidence for tissue-invasive CMV disease. Treatment is usually with either IV ganciclovir or oral valganciclovir, at doses higher than those used for prophylaxis.1
The main toxicity with valganciclovir and ganciclovir, which henceforth will be referred to as (val)ganciclovir, is bone marrow suppression.2 This predominantly manifests as leukopenia but also can
be present with thrombocytopenia or anemia. Bone marrow toxicity from (val) ganciclovir can be particularly challenging in HSCT recipients, especially earlier in the transplant process when the donor stem cells have not yet fully engrafted. This side effect has largely curtailed use of (val)ganciclovir chemoprophylaxis during such periods in HSCT recipients. Bone marrow suppression may also be an issue at later stages of the HSCT process and in SOT recipients with limited bone marrow reserves owing to their underlying conditions and incomplete recovery from the transplant procedure. Additionally, transplant recipients are often treated with other medications, such as mycophenolate, that may deplete their bone marrow reserves. Management of cytopenia arising from (val)ganciclovir use often requires growth factor (granulocyte colonystimulating factor) support and/or discontinuation of the antiviral agent.
Ganciclovir is a guanosine analog that inhibits the CMV DNA polymerase. To become active, ganciclovir must be phosphorylated by the viral enzyme phosphotransferase. This enzyme is a product of the CMV UL97 gene and mutations in that gene confer resistance to ganciclovir. This, in turn, can lead to CMV that proves refractory to ganciclovir. Of note, refractory CMV may not be genotypically resistant. Risk factors for CMV resistance include extensive exposure to ganciclovir, suboptimal ganciclovir levels in the setting of intensive immunosuppression and high viral loads.2 Neither cidofovir nor foscarnet requires this viral phosphorylation step to be active and hence are not affected by UL97 mutations. Mutations in the CMV UL54 gene, which encodes for a viral DNA polymerase, can lead to resistance to ganciclovir, cidofovir, and foscarnet or none of these.3
Until recently, the main treatments available for refractory or ganciclovir-resistant CMV were foscarnet and cidofovir. The efficacy and safety of both drugs are suboptimal. Additionally, the FDA has only granted them an indication for retinitis. The main toxicities with
CMV disease: CMV infection with signs and foscarnet are renal impairsymptoms (includes CMV syndrome and ment and electrolyte abnortissue-invasive CMV disease). malities. The predominant CMV syndrome: detection of CMV in blood (eg, by polymerase chain reaction [PCR] test) and 2 or more of the following: fever, malaise or fatigue, leukopenia, atypical lymphocytosis, thrombocytopenia, or elevated liver aminotransferases (defined only for solid-organ transplant recipients). toxicities with cidofovir are renal impairment and uveitis. In a study including 39 transplant recipients treated with foscarnet for ganciclovir-resistant or -refractory CMV infection, virologic failure occurred in one-third and renal dysfunction occurred in one-half of foscarnet recipients.6 In a CMV end-organ disease: sites of infection study including 16 transplant include GI tract, liver, retina, lungs, and central recipients receiving cidofovir, nervous system. 50% failed to clear CMV virePreemptive treatment: administration of an antiviral drug to a patient with CMV viremia while still asymptomatic, with the goal of preventing progression to CMV disease. Usually based on sequential monitoring of an early detection test such as quantitative CMV PCR. mia. Side effects were common, with nephrotoxicity occurring in 37.5% of recipients and uveitis in 25%.7 The development of maribavir as an alternative drug is a major advance Prophylaxis: administration of an antiviral drug in management for such to patients at risk for CMV. patients. The clinical role of Clinically significant CMV infection: CMV disease or CMV viremia leading to preemptive maribavir in such instances is reviewed later in this article. treatment. Letermovir CMV serology: measurement of CMV Letermovir is approved immunoglobulin G antibody levels. by the FDA for prophylaxis in CMV-seropositive HSCT recipients. The approved dose is 480 mg daily (oral or IV) through 100 days posttransplant. Letermovir’s mechanism of action is by interference with DNA cleavage/packaging/maturation within the CMV virion.8 This is facilitated by inhibition of the viral terminase enzyme complex (UL51, UL56, and UL89). Letermovir is not active against other herpesviruses (eg, herpes simplex virus [HSV] and varicella zoster virus [VZV]), for which purpose (val)acyclovir needs to be coadministered in patients who require prophylaxis for HSV and VZV. Because the hurdle to development of resistance is generally low, the main use of letermovir is for prevention of infection as either primary or secondary prophylaxis— including the maintenance phase of therapy when viral load is very low. The most common side effects of letermovir are gastrointestinal (GI). It is not associated with the bone marrow toxicities of (val)ganciclovir or the renal and electrolyte toxicities of foscarnet. More challenging are the various drug interactions. Letermovir is a moderate inhibitor of the cytochrome enzyme CYP3A and hence can increase levels of drugs metabolized through that
me ma t r g nia, a vi ro CMV, cytomegalovirus; GI, gastrointestinal; HSCT, hematopoietic stem cell transplant.
pathway (eg, cyclosporine, tacrolimus, and sirolimus). It is also an inducer of CYP2C9 and 2C19, and can decrease levels of drugs metabolized through those pathways (eg, voriconazole). Of note, coadministration of letermovir with cyclosporine (but not tacrolimus or sirolimus) leads to increased levels of letermovir. However, all of these interactions are relatively manageable with alteration of doses and monitoring of drug levels of the immunosuppressants or voriconazole.
Several trials have examined the efficacy of letermovir as prophylaxis in HSCT recipients. Marty et al conducted a blinded randomized controlled trial of letermovir versus placebo in CMV-seropositive HSCT recipients. In that trial, letermovir therapy was associated with fewer episodes of clinically significant CMV infection or requirement for premature discontinuation of therapy by 24 weeks after transplantation (122/325 patients [37.5%] vs 103/170 [60.6%]; P<0.001).9 An evaluation of all-cause mortality in that trial showed letermovir prophylaxis to be associated with lower risk for mortality at 24 weeks. (hazard ratio [HR], 0.58; 95% CI, 0.35-0.98; P=0.04).10 Postmarketing surveillance of HSCT recipients receiving letermovir as prophylaxis also showed lower rates of CMV reactivation in the first 100 days after transplant compared with historical controls (20% vs 72%; P<0.001). Similarly, the rate of clinically significant CMV infection was lower in the letermovir group versus controls (4% vs 59%; P<0.001).11 In a retrospective study, use of letermovir in CMV-seropositive HSCT recipients significantly decreased mortality with an adjusted hazard ratio of 0.62 (95% CI, 0.40-0.98). The improvement in survival was most marked in recipients of T cell–depleted transplants.12 Similarly, the impact of letermovir on HSCT mortality was evaluated in retrospective analyses. In a study comparing 114 HSCT recipients who received letermovir prophylaxis for a median of 92 days with 571 patients without prophylaxis, the incidence of clinically significant CMV and mortality at 6 months were significantly reduced (44.7% vs 72.4%; P<0.001 and 80.4% vs 73.0%; P=0.033).13
Use of letermovir as a prophylaxis strategy in HSCT recipients with acute graft-versus-host disease (GVHD) was evaluated in several retrospective studies. For example, an analysis of 119 patients showed letermovir prophylaxis was associated with decreased development of clinically significant CMV infection (HR, 0.08; 95% CI, 0.03-0.27; P<0.001), nonrelapse mortality (P=0.04), and improved overall survival (P=0.04).14
Increasingly, letermovir is used off-label in solidorgan transplant recipients, and there is an ongoing randomized double-blind trial of letermovir versus valganciclovir prophylaxis in kidney transplant recipients (MK8228-002). This is often in patients who have had difficulty tolerating (val)ganciclovir but still require primary prophylaxis, maintenance, or secondary prophylaxis therapy after control of significant disease. Letermovir was used in a series of 37 lung and 4 heart transplants for primary and secondary prophylaxis. In that study, median duration of letermovir prophylaxis was 282 days (interquartile range, 131-433 days). The rates of adverse effects requiring letermovir discontinuation and of breakthrough CMV infection were 12% and 2.4%, respectively.15 In a study of solid-organ transplant recipients who were converted from valganciclovir to letermovir prophylaxis, there was no significant difference in the rate of CMV breakthrough between patients on letermovir (8.7%) and valganciclovir (13.5%) (P=0.7097).16 In a study of 28 lung transplant recipients treated with letermovir for ganciclovir-resistant or -refractory CMV infection, 23 patients (82.1%) had a rapid response with subsequent clearing of the virus. Among the 5 nonresponding patients, 3 were discovered to have mutations conferring resistance at the viral terminase enzyme (UL56Gen: C325Y).17 In addition, Aryal et al reported that 3 of 8 (37.5%) SOT patients receiving letermovir for prophylaxis developed CMV viremia during prophylaxis.18 A key parameter for treatment failure is viral load. Thus, care must be taken to ensure viral load at the time of letermovir initiation is low enough to avoid risk for development of resistance and treatment failure. For example, in a study of 21 HSCT and 27 SOT recipients with CMV infection who were treated with letermovir, the key parameter for success was viral load. Whereas viral load improved or remained stable (<1 log rise in viral load) in 35 of 37 letermovir recipients initiated on therapy when viral load was less than 1,000 IU/mL, this was only the case in 6 of 10 patients whose viral load exceeded 1,000 IU/mL at initiation of letermovir.19 In another study, risk factors for breakthrough infection among patients receiving letermovir prophylaxis were low-grade CMV replication (21-149
Table. Medication for Prevention and Treatment of CMV in Transplant Recipients
Drug Target ➔ Activity Safety and Adverse Effects Uses Ganciclovir/ valganciclovir DNA polymerase viral replication Cytopenias Prevention and treatment of CMV infection
Maribavir UL97 protein kinase viral assembly Dysgeusia, GI upset, drug interactions Treatment of resistant/ refractory CMV. In future this may also include uncomplicated CMV in HSCT
Letermovir Terminase enzyme viral maturation GI upset, drug interactions Prevention and possibly treatment with viral load <1,000 copies/mL
Cidofovir DNA polymerase viral replication Renal and ocular toxicity Treatment of resistant/ refractory CMV infection
Foscarnet DNA polymerase viral replication Renal and electrolyte toxicity Treatment of resistant/ refractory CMV infection
CMV, cytomegalovirus; GI, gastrointestinal; HSCT, hematopoietic stem cell transplant.
IU/mL), both at the time of letermovir initiation or during prophylaxis, and development of acute GI GVHD.20
Maribavir
Maribavir is approved by the FDA for the treatment of post-transplant CMV infection that is refractory to treatment with other anti-CMV agents, such as (val)ganciclovir, cidofovir, or foscarnet. The approved dose is 400 mg twice daily. Maribavir’s mechanism of action is through inhibition of UL97 protein kinase and impairment of viral DNA assembly. As with letermovir, maribavir is not active against other herpesviruses (eg, HSV and VZV), for which (val)acyclovir needs to be coadministered if prophylaxis against HSV and VZV is needed. Of note, because CMV UL97 protein kinase is needed to activate ganciclovir, the combination of maribavir and ganciclovir actually results in antagonism of the latter drug’s antiviral activity.21
The main side effects of maribavir are taste disturbances (dysgeusia) and GI upset. Dysgeusia occurs frequently, but most often has not led to discontinuation in clinical trials of maribavir. The drug is metabolized by the CYP3A4 system and is a weak inhibitor of that enzyme complex. Hence, coadministration with maribavir leads to increased levels of calcineurin inhibitors (cyclosporin and tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus). For example, maribavir 400 mg twice daily increased tacrolimus trough concentrations by 57%.22
Several trials have assessed the efficacy of maribavir for treatment of CMV infection. Maertens et al compared maribavir and valganciclovir as preemptive therapy in a phase 2, open-label trial of adult HSCT and SOT recipients with CMV reactivation (plasma CMV DNA level, 1,000-100,000 DNA copies/mL). Participants received maribavir at doses of 400, 800, or 1,200 mg twice daily or the standard dose of valganciclovir for up to 12 weeks. The study included 117 participants in the maribavir group and 39 in the valganciclovir group. Clinical outcomes at 6 weeks were similar in both groups (79% and 67% of patients; risk ratio, 1.20; 95% CI, 0.95-1.51). Responses to treatment were also similar among the various maribavir dose groups. The authors concluded that maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of HSCT or SOT. A higher incidence of GI adverse events—notably dysgeusia—and a lower incidence of neutropenia were found in the maribavir group.23
Maribavir was also tested as therapy in a phase 2 trial including 120 HSCT and SOT recipients with CMV that had proven refractory or resistant to available antivirals ([val]ganciclovir, foscarnet, and cidofovir). Patients with refractory or resistant CMV infections having plasma CMV DNA levels of 1,000 copies/mL or higher were randomized (1:1:1) to twice-daily, doseblinded maribavir 400, 800, or 1,200 mg for up to 24 weeks. In that study, 80 of 120 (67%) patients achieved undetectable CMV DNA levels within 6 weeks of treatment, with similar outcomes among all the dosing groups. Among the 25 patients in that study who developed recurrent infections while on treatment, 13 developed mutations conferring maribavir resistance. As with the preemptive therapy study, GI side effects, specifically dysgeusia, were the most common adverse events related to therapy (78/120; 65%) and led to maribavir discontinuation in 1 patient. The authors concluded that maribavir at a dose of 400 mg or higher twice daily was active against CMV infection in transplant recipients who were refractory or resistant to other antivirals.24
The results of this phase 2 trial led to a randomized, open-label phase 3 trial of maribavir (n=235) at a dose of 400 mg twice daily, compared with investigator-assigned therapies (n=117; [val]ganciclovir, foscarnet, cidofovir) for 8 weeks, for treatment of refractory or resistant CMV in HSCT and SOT recipients. Significantly more patients in the maribavir group achieved
clearance of CMV viremia at the end of the 8-week treatment period (55.7% vs 23.9%; adjusted difference [95% CI], 32.8% [22.80%-42.74%]; P<0.001) and also CMV clearance plus symptom control during followup out to 16 weeks were significantly more frequent in the maribavir group (18.7% vs 10.3%; adjusted difference [95% CI], 9.5% [2.02%-16.88%]; P=0.01). As would be expected, maribavir was associated with less acute kidney injury than foscarnet (8.5% vs 21.3%) and less neutropenia than (val)ganciclovir (9.4% vs 33.9%).25
Maribavir was also evaluated for CMV prophylaxis, but results have been mixed and it is not approved for that indication. The lack of efficacy for prophylaxis may be explained by inadequate dosing in some of the early clinical trials. In a phase 2 prophylaxis study involving HSCT recipients, Winston et al compared maribavir at various doses (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) with valganciclovir. Plasma CMV DNA was lower in each of the respective maribavir groups (7% [P=0.001]; 11% [P=0.007]; 19% [P=0.038]) compared with placebo (46%), and antiCMV therapy was used less often in patients receiving each respective dose of maribavir (15% [P=0.001]; 30% [P=0.051]; 15% [P=0.002]) than in those receiving placebo (57%).26 However, in a study of high-risk liver transplant recipients (CMV donor positive/recipient negative serology), maribavir at 100 mg twice daily was compared with oral ganciclovir for prevention of CMV disease. CMV infection as measured by presence of viremia, antigenemia, or CMV disease occurred in 60% of maribavir versus 20% of ganciclovir recipients (P<0.0001) at 100 days and at 6 months (72% vs 53%; P=0.0053) after transplantation. The authors concluded that at a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease.27 Moreover, in a phase 3 prophylaxis study of HSCT recipients who had engrafted, outcomes with maribavir (100 mg orally twice per day) were similar to placebo. The incidences of CMV viremia and disease within 6 months were 28% versus 30% and 4% versus 5%, respectively. The authors concluded that compared with placebo, maribavir prophylaxis did not prevent CMV disease when started after engraftment.28
Conclusion
While (val)ganciclovir remains the cornerstone for treatment of CMV in both HSCT and SOT and for prophylaxis in SOT recipients, the arrival of letermovir and maribavir as therapeutic options is a major advance in the field. Letermovir is approved by the FDA for prophylaxis in CMV-seropositive HSCT recipients and maribavir is approved as treatment of CMV infection refractory to (val)ganciclovir, cidofovir, or foscarnet. The main side effects of both drugs are GI in nature, with maribavir causing dysgeusia in a substantial percentage of patients. Neither letermovir nor maribavir is associated with the bone marrow suppression seen with (val)ganciclovir or with the renal and electrolyte toxicities seen with foscarnet and cidofovir. As more data and clinical experience accumulate, it is expected that the primary roles for these 2 drugs will expand to include a broader range of patients for whom (val) ganciclovir is proving too toxic.
References
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Agents Chemother. 1987;31(3):452-454. 3. Limaye AP. Ganciclovir-resistant cytomegalovirus in organ transplant recipients. Clin Infect Dis. 2002;35(7):866-872. 4. Fisher CE, Knudsen JL, Lease ED, et al. Risk factors and outcomes of ganciclovir-resistant cytomegalovirus infection in solid organ transplant recipients. Clin Infect Dis. 2017;65(1):57-63. 5. Emery VC, Griffiths PD. Prediction of cytomegalovirus load and resistance patterns after antiviral chemotherapy. Proc Acad Sci
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CMV-seropositive recipients of allogeneic hematopoietic cell transplantation. Clin Infect Dis. 2020;70(8):1525-1533. 11. Anderson A, Raja M, Vazquez N. Clinical “real-world” experience with letermovir for prevention of cytomegalovirus infection in allogeneic hematopoietic cell transplant recipients.
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Chemother. 2006;50(10):3470-3472. 22. Pescovitz MD, Bloom R, Pirsch J, et al. A randomized, double-blind, pharmacokinetic study of oral maribavir with tacrolimus in stable renal transplant recipients. Am J Transplant. 2009;9(10):2324-2330. 23. Maertens J, Cordonnier C, Jaksch P, et al. Maribavir for preemptive treatment of cytomegalovirus reactivation. N Engl J Med. 2019;381(12):1136-1147. 24. Papanicolaou GA, Silveira FP, Langston AA, et al. Maribavir for refractory or resistant cytomegalovirus infections in hematopoietic-cell or solid-organ transplant recipients: a randomized, dose-ranging, double-blind, phase 2 study. Clin Infect Dis. 2019;68(8):1255-1264. 25. Avery RK, Alain S, Alexander BD, et al. Maribavir for refractory cytomegalovirus infections with or without resistance posttransplant: results from a phase 3 randomized clinical trial.
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Am J Transplant. 2012;12(11):3021-3030. 28. Marty FM, Ljungman P, Papanicolaou GA, et al. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet
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Dr. Shoham reported research grants from Ansun, Ciara, Emergent Biosolutions, F2G, Gilead, Merck, Shire, and Zeteo, and being a paid advisor for Adagio, Adamis, Celltrion, Immunome, Intermountain Health, and Karyopharm.
About the author
Shmuel Shoham, MD, FIDSA, is a professor of medicine at Johns Hopkins University School of Medicine, in Baltimore, Maryland.
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