Maribavir for cytomegalovirus retinitis: A case series and review of the literature

Abstract

Objective:

Therapy for vision-threatening CMV retinitis is often limited by drug resistance or systemic toxicity. Maribavir, a novel UL97 kinase inhibitor that has been FDA-approved for refractory CMV viremia, is a potential alternative to traditional antiviral therapy but remains understudied for CMV retinitis. The objective of this series is to describe the clinical courses and outcomes of patients with CMV retinitis after initiation of maribavir therapy.

Design:

Retrospective case series.

Subjects:

Six patients (11 eyes) with CMV retinitis from two tertiary uveitis centers. All were immunocompromised due to chemotherapy, immunotherapy, or AIDS and were initially treated with standard therapy (systemic and/or intravitreal ganciclovir, valganciclovir, or foscarnet) before developing drug resistance, toxicity, or intolerance prompting a transition to maribavir as alternative therapy.

Intervention:

Oral maribavir 400 mg twice daily.

Main Outcome Measures:

Time to retinitis quiescence, visual acuity (VA), and adverse effects of therapy.

Results:

4/11 eyes had active retinitis upon initiation of maribavir and all achieved quiescence within 6 weeks. The remaining 7/11 eyes were already quiescent and remained so. VA remained stable or improved in all eyes. Notable clinical courses included (1) rapid decline in aqueous CMV titer and resolution of retinitis in a patient with multidrug-resistant CMV failing intravitreal ganciclovir/foscarnet; (2) a patient with UL54-resistant CMV and bilateral macula-involving retinitis rapidly achieving inactivity and preserved visual acuity on maribavir; and (3) successful substitution of maribavir in patients who were unable to continue conventional antiviral therapy due to drug-induced neutropenia or nephrotoxicity. Maribavir was generally well-tolerated, and only mild adverse effects were reported (dysgeusia, myalgia). Review of the literature identified 2 additional cases of patients with similar clinical courses achieving resolution of retinitis on maribavir.

Conclusions:

In this descriptive case series, patients with multidrug-resistant CMV retinitis or intolerance to traditional antiviral therapy were observed to achieve or maintain quiescence of retinitis following initiation of maribavir. These findings suggest maribavir as a potential novel systemic option for challenging cases of CMV retinitis. Prospective studies are necessary to further characterize the efficacy and safety of maribavir for the treatment of CMV retinitis, as well as optimal duration of therapy after quiescence.

Table of contents statement

This retrospective case series presents the clinical courses of 11 eyes of 6 patients with CMV retinitis treated with maribavir at 2 tertiary uveitis centers. Of these, 4 eyes had active retinitis when maribavir was initiated and all 4 achieved quiescence within 6 weeks; the other 7 eyes were already quiescent and remained so.

Introduction

Cytomegalovirus (CMV) is a widespread herpes virus, infecting an estimated 66–90 % of the adult population worldwide.¹ In immuno-competent individuals, primary infection is often asymptomatic, followed by long-term viral latency as the healthy immune system suppresses viral replication.^2,3 However, among immunocompromised individuals, CMV is a common opportunistic infection associated with significant morbidity and mortality. Patients with solid organ and hematopoietic stem cell transplants are particularly susceptible,⁴ as are those with acquired immunodeficiency syndrome (AIDS) and those on chronic immunosuppressive therapy.

Necrotizing retinitis is the most serious ophthalmic manifestation of CMV infection in immunocompromised individuals, requiring prompt and effective treatment to prevent blinding complications.⁵ Classically, four antiviral agents have been utilized in the management of CMV retinitis: ganciclovir (systemic and intravitreal), its prodrug valganciclovir (systemic), foscarnet (systemic and intravitreal), and cidofovir (systemic, rarely intravitreal).⁶ Though typically highly effective against CMV retinitis, these antivirals may be associated with serious adverse effects such as myelosuppression and renal dysfunction that limit systemic usage, while intravitreal therapy often requires serial weekly dosing that results in substantial treatment burden. Resistant strains of CMV have also begun to emerge in the general population, limiting therapeutic efficacy of these traditional antivirals.⁷

Maribavir is a novel oral antiviral that selectively inhibits CMV-specific UL97 kinase to viral DNA replication.⁸ Because this mechanism differs from that of traditional antivirals, maribavir has demonstrated significant efficacy in the treatment of CMV infection in post-transplant patients that is refractory or resistant to traditional therapies. Maribavir therefore gained approval from the United States Food and Drug Administration (FDA) for refractory CMV in 2021.⁹ However, experience with maribavir in the management of CMV retinitis is limited, and ophthalmic outcomes are not yet well-characterized.

Here, we describe a series of 6 patients with CMV retinitis managed with maribavir at 2 tertiary uveitis centers. We additionally review 4 cases previously reported in the literature, highlighting common trends and outcomes in the use of this novel drug in the treatment of CMV retinitis.

Methods

In this descriptive retrospective case series, we identified consecutive patients with CMV retinitis treated with maribavir between January 2023 and December 2024 at two tertiary referral uveitis centers. Inclusion criteria consisted of: (1) clinical diagnosis of CMV retinitis by a uveitis specialist, (2) confirmatory baseline aqueous humor CMV titers by polymerase chain reaction (PCR), (3) treatment with oral maribavir at any point in clinical course, and (4) at least 4 weeks of ophthalmic follow-up after maribavir initiation.

Patient demographics, baseline clinical findings, treatment course, multimodal imaging findings, and clinical outcomes were abstracted and 4 representative cases described in detail. All patients underwent baseline aqueous viral PCR testing to confirm the diagnosis of CMV retinitis. Patients were monitored with serial dilated funduscopic examination and multimodal imaging at clinician-determined intervals; serum CMV viral load and/or repeat aqueous PCR quantification were obtained when determined to be clinically indicated by the treating physician. Uveitis was graded for all visits using the standardization of uveitis nomenclature (SUN) criteria.

Activity of CMV retinitis was determined clinically by the treating physician. Retinitis was defined as active if there was evidence of retinal whitening with thickening at the lesion margin, enlargement of lesion size, or new lesions on serial examinations. Quiescence of retinitis was defined as consolidation along the borders of active retinitis leading to atrophic chorioretinal scarring in region of prior active retinitis.

Antiviral resistance was defined as detection of established CMV resistance mutations (UL97 and/or UL54) on genotypic sequencing of samples from the aqueous humor or serum. Clinically refractory CMV retinitis (“suspected antiviral resistance”) was defined as persistent or progressive activity necessitating a change or escalation of ongoing antiviral therapy. Recurrent CMV retinitis was defined as reappearance of active retinitis after a period of quiescence.

Conventional therapy was defined as treatment with systemic or intravitreal foscarnet, ganciclovir, valganciclovir, or cidofovir. Maribavir was initiated on the basis of individual clinician judgement for either treatment of active CMV retinitis or maintenance of quiescent CMV retinitis in patients with (1) confirmed antiviral-resistant CMV, (2) retinitis refractory to conventional antiviral therapy (suspected resistance), or (3) intolerance/toxicity to conventional antiviral therapy. Standard dosing of maribavir 400 mg orally twice daily (BID) was implemented in all cases for both induction and maintenance therapy. Time to quiescence of CMV retinitis was defined as the interval from maribavir initiation to the first visit meeting criteria for quiescent retinitis. Treatment duration beyond quiescence was individualized by the treating physician based on clinical judgement. This study was deemed exempt from IRB approval and adhered to the tenets set forth by the declaration of Helsinki.

Results

We identified 11 eyes of 6 patients with CMV retinitis treated with maribavir at any point in their clinical course. Patient demographics and clinical courses are summarized in Table 1. All patients were immunocompromised: 5/6 had a systemic malignancy at the time of initial CMV retinitis diagnosis, and only 1/6 was positive for human immunodeficiency virus (HIV). All but one patient had vision of 20/25 or better in each eye at the initial visit. Prior to maribavir, all eyes had previously received one or more intravitreal injections of foscarnet, and 7/11 eyes (64 %) had additionally received one or more injections of ganciclovir. All patients had previously been treated with systemic valganciclovir, foscarnet, and/or cidofovir prior to initiation of maribavir. Reasons for discontinuing systemic valganciclovir included genotypically confirmed or clinically suspected resistance (5 patients) and neutropenia (1 patient). Reasons for discontinuing systemic foscarnet was discontinued due to genotypically confirmed resistance (2 patients), nephrotoxicity (1 patient), and transition to oral therapy (1 patient). Antiviral resistance was confirmed in 4/6 patients who underwent genotypic CMV-resistance testing for UL97 and/or UL54 mutations in aqueous or serum samples. Of the remaining 2/6 patients, 1 exhibited retinitis that was clinically refractory to conventional therapy, and 1 required transition to maribavir due to toxicity from conventional antiviral therapy.

Table 1.

Clinical courses and outcomes of patients with cytomegaloviral retinitis treated with maribavir.

Case	Age (years)	Sex	Background immunocompromise	Active systemic CMV?	Eye with retinitis	Initial Visual Acuity	Traditional therapy prior to maribavir			Retinitis quiescent after initial therapy?	Retinitis quiescent after maribavir?	Time on maribavir therapy	Time to quiescence on maribavir	Total follow-up after maribavir initiation	Supplemental therapy	Final Visual Acuity
							Type of therapy		Reason for discontinuing
Case 1	25	Male	Chemotherapy (T-cell ALL)	No	OD	20/20	PO	Valganciclovir	Refractory	No	Yes	5 months	6 weeks	18 months	None	20/20
							IV	Ganciclovir	Transition to PO therapy
							IVI	Foscarnet x 5	Refractory
								Ganciclovir x 3	Refractory
					OS	20/20	PO	Valganciclovir	Refractory	No	Yes	5 months	6 weeks	18 months	None	20/20
							IV	Ganciclovir	Transition to PO
							IVI	Ganciclovir x 3	Refractory
								Foscarnet x 5	Refractory
Case 2	81	Female	Chemotherapy (multiple myeloma)	Yes	OD	20/150	PO	Valganciclovir	Aqueous Resistance (UL54)	No	Yes	8 weeks	6 weeks	4 months	None	20/100
							IV	Foscarnet	Aqueous Resistance (UL54)
							IVI	Foscarnet x 5	Aqueous Resistance (UL54)
					OS	HM	PO	Valganciclovir	Aqueous Resistance (UL54)	No	Yes	8 weeks	6 weeks	4 months	None	HM
							IV	Foscarnet	Aqueous Resistance (UL54)
							IVI	Foscarnet x 5	Aqueous Resistance (UL54)
Case 3	25	Male	HIV & chemotherapy (Burkitt lymphoma)	Yes	OS	20/25	PO	Valganciclovir	Aqueous Resistance (UL-97)	Yes	Yes	4 months	N/A	4 months (deceased)	IV letermovir IV cidofovir Anti-CMV IVIG	Unknown
							IV	Foscarnet	Serum
								Cidofovir	Resistance (UL54) Hypotonus uveitis + renal failure
							IVI	Ganciclovir x 2	Aqueous Resistance (UL-97) Serum Resistance (UL54)
								Foscarnet x 8
Case 4	61	Male	Immunomodulatory therapy (dermatomyositis, interstitial lung disease)	Yes	OD	20/25	PO	Valganciclovir	Neutropenia	Yes	Yes	4 weeks	N/A	12 months	None	20/25
							IV	None	N/A
							IVI	Ganciclovir x 1	Resolution of retinitis
								Foscarnet x 4	Resolution of retinitis
					OS	20/25	PO	Valganciclovir	Neutropenia	Yes	Yes	4 weeks	N/A	12 months	None	20/25
							IV	None	N/A
							IVI	Ganciclovir x 1	Resolution of retinitis
								Foscarnet x 5	Resolution of retinitis
Case 5	28	Male	Chemotherapy (T-cell ALL)	No	OD	20/20	PO	Valganciclovir	Serum Resistance (UL97)	Yes	Yes	4 weeks	N/A	15 months	None	20/20
							IV	Foscarnet	Resolution of retinitis
							IVI	Ganciclovir x 1	Resolution of retinitis
								Foscarnet x 1	Resolution of retinitis
					OS	20/20	PO	Valganciclovir	Serum Resistance (UL97)	Yes	Yes	4 weeks	N/A	15 months	None	20/20
							IV	Foscarnet	Resolution of retinitis
							IVI	Ganciclovir x 1	Resolution of retinitis
								Foscarnet x 1	Resolution of retinitis
Case 6	20	Male	Chemotherapy (T-cell ALL)	Yes	OD	20/20	PO	Valganciclovir	Serum Resistance (UL97)	Yes	Yes	4 weeks	N/A	7 months	None	20/20
							IV	Foscarnet	Nephrotoxicity
							IVI	Foscarnet x 2	Resolution of retinitis
					OS	20/25	PO	Valganciclovir	Serum Resistance (UL97)	Yes	Yes	4 weeks	N/A	7 months	None	20/25
							IV	Foscarnet	Nephrotoxicity
							IVI	Foscarnet x 2	Resolution of retinitis

Active retinitis was observed in 4/11 eyes (36 %) at time of maribavir initiation; retinitis was already quiescent the remaining the remaining 7/11 eyes (64 %) and maribavir was initiated for maintenance therapy in these cases. All cases of active retinitis exhibited quiescence of retinitis within 6 weeks of initiating maribavir. All eyes had either stable or improved vision compared to baseline at most recent follow-up. No eye exhibited clinically refractory or recurrent retinitis after initiation of maribavir. No ophthalmic complications were observed after initiation of maribavir. Four representative cases and their treatment courses, highlighting important clinical features and outcomes are described below:

Case 1: response to maribavir therapy

A 25-year-old male with a history of T-cell acute lymphoblastic leukemia (T-ALL) in remission status post chemotherapy presented for management of recurrent CMV retinitis refractory to conventional therapy. One year prior to presentation, he had been hospitalized for CMV viremia and CMV retinitis OU which was treated with intravenous (IV) ganciclovir. He was ultimately transitioned to oral valganciclovir 900 mg BID but developed recurrence of CMV retinitis upon discontinuing valganciclovir. Despite restarting oral valganciclovir 900 mg BID, retinitis remained active over 3 months. He was therefore referred for a second opinion.

Upon initial consultation, his best corrected visual acuity (VA) was 20/20 OU. Dilated funduscopic examination revealed active peripheral retinitis OS > OD adjacent to inactive atrophic scarring. Diagnostic anterior chamber paracentesis OS revealed an aqueous CMV titer of 24,100 IU/mL. Antiviral resistance testing was not performed. He was initially managed with a series of weekly intravitreal foscarnet and ganciclovir injections, receiving a total of 5 foscarnet 2.4 mg injections OU, 2 ganciclovir 2 mg injections OU, and 1 ganciclovir 6 mg injection OU over 5 weeks. He remained on oral valganciclovir 900 mg BID through-out this course. The retinitis nearly resolved OD on this therapy, but remained very active OS with limited improvement (Fig. 1A, B). Repeat anterior chamber paracentesis OS revealed persistent aqueous CMV titer of 20,700 IU/mL.

Fig. 1.

Pseudocolor fundus photographs of the left eye of Case 1. (A) at presentation, on oral valganciclovir 900 mg BID for 3 months; (B) after 5 weeks of intravitreal ganciclovir and foscarnet therapy, with persistently high aqueous CMV titers of 20,700 IU/mL; (C) 1 week after starting oral maribavir 400 mg BID; (D) 2 weeks after starting maribavir, with decline in aqueous CMV titers to 3400 IU/mL; (E) 3 weeks after starting maribavir; and (F) 6 weeks after starting maribavir, with complete regression of retinitis.

Because the retinitis remained refractory to intravitreal foscarnet, intravitreal ganciclovir, and oral valganciclovir, he was ultimately transitioned to oral maribavir 400 mg BID and all other antivirals discontinued. The retinitis exhibited rapid regression and completely resolved over 6 weeks of maribavir therapy (Fig. 1C–F) without requiring further intravitreal injections. Repeat anterior chamber paracentesis OS at week 2 of maribavir therapy revealed dramatic reduction in aqueous CMV titer to 3400 IU/mL. After approximately 5 months of maribavir monotherapy, retinitis remained quiescent OU without recurrence and VA was preserved at 20/20 OU.

Case 2: response to maribavir therapy

An 81-year-old Caucasian female with ongoing treatment for multiple myeloma was referred for management of CMV retinitis OU refractory to conventional therapy. She had previously been treated unsuccessfully with valganciclovir until serological analysis revealed UL-54-mediated resistance 3 weeks prior to referral. She had subsequently received 5 bilateral intravitreal foscarnet injections, as well as 1 week of intravenous foscarnet with reported progression of retinitis.

At our initial evaluation, vision was 20/150 OD and hand motion (HM) OS. There was low grade anterior chamber inflammation and 1+ vitreous cells OU. Fundoscopy revealed 1+ vitreous haze and extensive retinitis involving the macula OU (Fig. 2A, 2B). PCR analysis of an aqueous sample from OS confirmed CMV, and genotypic analysis of the sample revealed UL-54 mutation conferring resistance to foscarnet. Maribavir 400 mg BID was therefore initiated and retinitis rapidly regressed and resolved over 6 weeks of treatment without requiring further intravitreal injections (Fig. 2C, 2D). After a total of 8 weeks of therapy, maribavir was discontinued. Retinitis remained quiescent OU off all antiviral therapy at most recent follow up 2 months later. Vision improved marginally to 20/100 OD and remained HM OS.

Fig. 2.

Pseudocolor fundus photographs of right and left eyes of Case 2 at presentation and follow up. Vitreous haze and extensive active retinitis is seen in the periphery of the (A) right and (B) left eyes at initial presentation. Complete resolution of vitritis and retinitis is observed after 6 weeks of maribavir therapy (C and D).

Case 3: multidrug resistance

A 25-year-old male with a history of HIV infection and high-grade Burkitt lymphoma positive for Epstein-Barr virus presented with several months of progressive blurry vision and floaters OS. He had been hospitalized for CMV viremia 3 months prior and treated with IV ganciclovir 5mg/kg BID prior to transitioning to oral valganciclovir 900 mg BID. He subsequently developed pancytopenia, and valganciclovir was therefore discontinued. Upon initial assessment, VA was 20/25 OS. Dilated fundus examination revealed areas of active retinitis extending from the inferior periphery to the inferior macula OS. Anterior chamber paracentesis was performed OS, revealing a CMV titer of 77,300 IU/mL. He was also found to have an increased serum CMV titer of 189 IU/mL compared to 88 IU/mL 1 week prior.

Oral valganciclovir was restarted at a reduced dose of 900 mg once daily due to concerns for myelosuppression, and he was treated with a series of 2 ganciclovir 2 mg intravitreal injections OS. Aqueous CMV antiviral genotypic sequencing subsequently revealed mixed CMV population with UL97-mediated resistance to ganciclovir. He was therefore transitioned to biweekly foscarnet injections and IV foscarnet 70mg/kg BID. Retinitis slowly resolved, and foscarnet injection interval was decreased until retinitis was quiescent. However, due to rising serum CMV titers and development of UL54-mediated foscarnet resistance on serum genotypic sequencing, he was transitioned off IV foscarnet to IV cidofovir 5mg/kg/week. He subsequently developed hypotony uveitis and renal failure requiring discontinuation of cidofovir. He was therefore transitioned to oral maribavir alongside IV letermovir (a prophylactic CMV-terminase complex inhibitor)¹⁰ to suppress serum viral load and potentially enhance the therapeutic effect of maribavir.¹¹

Symptoms and clinical exam findings improved on maribavir and letermovir, and intraocular pressure returned to normal range over the following 2 weeks. He subsequently received a course of IV anti-CMV immunoglobulin as prophylaxis against viral reactivation. Serum CMV titers continued to fluctuate, necessitating re-initiation of low-dose IV cidofovir (1mg/kg, 3 times per week) to suppress viral load. Retinitis remained quiescent over the following 4 months on combined maribavir, letermovir, and low-dose cidofovir, at which point the patient developed a clinical decline to background comorbidities and ultimately expired.

Case 4: medication toxicity

A 61-year-old male with a history of dermatomyositis and interstitial lung disease controlled on mycophenolate, tacrolimus, and hydroxychloroquine presented with a 1-week history of floaters OS. VA was 20/25 OU and dilated fundus examination revealed small peripheral patches of active retinitis OU. Aqueous PCR revealed a CMV titer of 2600,000 IU/mL. Serum CMV titers were also positive at 846 IU/mL. Intravitreal ganciclovir 2 mg and foscarnet 2.4 mg were injected OU and oral valganciclovir 900 mg BID was initiated.

He subsequently developed severe neutropenia necessitating discontinuation of mycophenolate and valganciclovir. He was subsequently managed with weekly intravitreal foscarnet monotherapy. Retinitis resolved OU over the course of 1 month. He was then transitioned to oral maribavir 400 mg BID. Although he developed mild dysgeusia and muscle aches shortly after starting maribavir, these symptoms were tolerable without requiring termination of therapy. After 1 month on maribavir, he exhibited consistently negative serum CMV titers and evidence of immune reconstitution, so maribavir was discontinued. At final follow up approximately 1 year after initial presentation, VA remained stable at 20/25 OU and retinitis remained quiescent without recurrence or need for further intravitreal injections.

Discussion

Maribavir is a novel oral antiviral medication that is FDA-approved for the treatment of refractory CMV infections in post-transplant patients. Unlike conventional antivirals such as ganciclovir and valganciclovir, which require phosphorylation by the CMV-specific UL97 kinase for activation, maribavir directly inhibits CMV UL97 kinase to suppress DNA synthesis and viral replication without relying on UL97-mediated activation.⁸ Because the most common mechanism of antiviral resistance in CMV involves mutations in the UL97 gene that impair activation of ganciclovir and valganciclovir to reduce efficacy,⁷ maribavir retains antiviral activity against these strains by directly targeting UL97 enzymatic activity.^12,13 By directly targeting the UL97 kinase, maribavir also may retain activity against common viral strains with UL54-mediated resistance to foscarnet and cidofovir.¹³

Maribavir’s unique mechanism of action thus positions it as a potential alternative in the management of multidrug-resistant CMV infections, with clinical trial data supporting its noninferiority or superiority to conventional antiviral therapy for the treatment of systemic CMV infections in post-transplant patients with or without drug resistance.^12,14 Maribavir has also demonstrated efficacy as prophylaxis against CMV reactivation in post-transplant patients with CMV.^15,16 Maribavir is therefore gaining recognition as a potential antiviral option for challenging CMV infections.

Experience with maribavir in the management of CMV retinitis remains limited, and published data to date consists of isolated case reports and small case series. Tsui et al. described the resolution of bilateral retinitis in a lung-transplant patient with documented UL97-mediated ganciclovir resistance.²⁰ One eye was treated with a single dose of intravitreal foscarnet (2.4 mg), while the other achieved inactivity and regression of retinitis with systemic maribavir alone. Similarly, Yanagihara et al. published a short case detailing the rapid resolution of ganciclovir-resistant CMV retinitis in a 16-year-old patient with leukemia after initiating systemic maribavir monotherapy.²¹ Finally, Yao et al. recently reported two patients (4 eyes) with treatment-naïve CMV retinitis who demonstrated rapid regression after initiating a combination of maribavir and weekly high-dose intravitreal ganciclovir; one patient was treated concurrently with oral letermovir, while the other was transitioned to letermovir after achieving quiescence on maribavir.²²

Here, we present the clinical course and outcomes of 6 additional patients (11 eyes) with CMV retinitis who were managed with oral maribavir. All 6 patients exhibited CMV retinitis that was initially managed with a combination of conventional systemic and/or intravitreal therapy. Clinical courses were complicated by genotypically confirmed drug resistance in 4/6 patients, clinically refractory retinitis in 1/6 patients, and drug toxicity limiting the use of conventional antiviral therapies in 3/6 patients. In two patients (Cases 1 and 2), initiation of oral maribavir monotherapy for multidrug-resistant CMV retinitis was followed by rapid regression and quiescence of retinitis, without requiring further intravitreal injections. Another patient (Case 3) achieved quiescence with conventional antiviral therapy but suffered from serious adverse systemic and ophthalmic effects requiring transition to maribavir. His retinitis ultimately remained quiescent on maribavir, although this was alongside adjunctive low-dose prophylactic letermovir to suppress serum viral load, which may have additively contributed to maintaining quiescence.¹¹ In two other patients (Cases 4 and 5), quiescence was maintained on oral maribavir monotherapy without requiring further intravitreal injections. This is significant as CMV retinitis is known to recur in up to 30 % of immunocompromised patients on ganciclovir maintenance therapy.²³ Maribavir therefore may represent a potential oral alternative for long-term maintenance therapy in patients with ganciclovir resistance or intolerance.

Maribavir’s favorable safety profile in post-transplant patients also makes it an attractive option for CMV patients who are intolerant of conventional antivirals due to adverse reactions and systemic toxicity. Conventional systemic antivirals are commonly associated with serious adverse effects such as myelosuppression (ganciclovir, valganciclovir), nephrotoxicity (foscarnet, cidofovir), and ophthalmic complications such as uveitis and hypotony (cidofovir). By contrast, data from recent clinical trials patients suggest that maribavir is well tolerated in post-transplant,^12,15–19 and associated with substantially lower risk of complications such as neutropenia and nephrotoxicity compared to valganciclovir/ganciclovir and foscarnet, respectively.^12,16,17 Such patients treated with maribavir have also been reported to have significantly lower rates of treatment discontinuation due to adverse effects compared to conventional systemic antivirals.¹² Dysgeusia is the most common adverse effect seen in patients treated with maribavir,¹⁹ affecting between 35 % to 90 % of patients undergoing therapy.^12,14–16 Other common adverse effects include gastrointestinal upset (nausea, vomiting, diarrhea) and fatigue.^12,14 However, these effects are typically mild and tolerable, only rarely requiring discontinuation of therapy.^12,14

We observed similar safety and tolerability of maribavir in our limited case series as has been previously reported more broadly in post-transplant patients with CMV. In our series, maribavir was not associated with any serious ophthalmic or systemic complications, even among patients suffering from severe myelosuppression or nephrotoxicity after treatment with conventional antivirals. Maribavir was also generally well-tolerated, with only mild adverse effects such as dysgeusia and headaches reported that did not necessitate a change in therapy. Previously reported cases of CMV retinitis treated with maribavir have similarly reported excellent tolerability and have not encountered safety concerns.^20–22 However, further research is required to confirm the safety of maribavir for the treatment of CMV retinitis in patients who are not post-transplant on a wider scale.

An additional advantage to the use of maribavir in the management of CMV retinitis is the potential for reducing intravitreal injection burden in patients who are not candidates for conventional systemic therapy due to drug resistance or toxicity/intolerance. Conventional management of antiviral-resistant CMV retinitis in these patients often involves a prolonged and intensive series of intravitreal ganciclovir or foscarnet injections on a weekly or biweekly schedule to induce and maintain quiescence. Yet certain patients are unable or unwilling to endure the burden of intensive intravitreal therapy. In our series, both patients initiated on maribavir for active retinitis achieved quiescence despite stopping intravitreal injections, and none of our patients who were quiescent required further intravitreal therapy while on maribavir. Similarly, all previously published cases report reduced reliance on intravitreal injections after initiating systemic maribavir.^20–22

The standard recommended dosage of maribavir in systemic CMV infections is 400 mg administered orally BID for both induction and maintenance therapy.^12,14 This dosing is typically maintained for at least 8 weeks, with ultimate duration of therapy individualized based on clinical and virologic response. Limited pre-clinical evidence suggests the potential for additive interactions between maribavir and systemic foscarnet, cidofovir, or letermovir when administered concurrently.^11,24 However, because maribavir directly inhibits the CMV UL97 kinase, it should not be administered in combination with systemic ganciclovir or valganciclovir as both rely upon CMV-specific UL97 kinase for activation. It is uncertain whether intravitreal ganciclovir or valganciclovir maintain therapeutic efficacy when administered with systemic maribavir, although the two patients reported by Yao, et al. did achieve quiescence of CMV retinitis on combined systemic maribavir and intravitreal high-dose ganciclovir. Finally, clinicians should remain vigilant for the development of UL97 gene mutations conferring maribavir resistance,^25–27 which have been found to emerge earlier and more frequently than with ganciclovir.²⁸

This study has several important limitations inherent to its design as a retrospective, descriptive case series studying an emerging therapeutic agent in a novel clinical context. Consequently, the cohort in this series is small and heterogeneous with respect to prior and concomitant antiviral therapy (systemic and intravitreal), indications for initiation of maribavir, disease activity level at maribavir initiation, and length of follow up. These confounding factors prevent any causal inference regarding the efficacy of maribavir for CMV retinitis and highlight the need for larger-scale, prospective data.

Nevertheless, this case series serves an important role by detailing early clinical experience with maribavir in the management of CMV retinitis in challenging real world clinical contexts. Findings from our 6 patients, alongside those of 4 patients previously reported in the literature, offer an early foundation to support the development of future prospective studies examining the safety and efficacy of maribavir for the treatment of CMV retinitis. Further research is warranted to evaluate the efficacy, durability, and long-term outcomes of maribavir for CMV retinitis, as well as the optimal strategies for integrating this novel therapeutic into clinical practice.