We present a case of CMV CRN with ganciclovir resistance that was successfully managed with letermovir and leflunomide.

Viral retinitis is a rare but vision-threatening disease. Acute retinal necrosis (ARN) is typically caused by HSV or VZV and classically presents in immunocompetent individuals. It is characterized by rapidly progressive retinitis with significant intraocular inflammation, the latter of which is thought to stem from an intact host immune response [15]. In contrast, CMV retinitis is seen in severely immunocompromised patients and is typified by slowly progressive retinal necrosis and minimal intraocular inflammation. The more recently described CMV CRN that is seen in “partially” immunocompromised people seems to share some features of both these entities: the chronic/subacute course of CMV retinitis with the associated intraocular inflammation and occlusive retinal vasculitis present in ARN [8].

Case reports of CMV CRN have described a variety of potential etiologies for the underlying mild immunocompromised state. These include: immunosenescence from aging, presence of diabetes mellitus, and the use of non-cytotoxic immunosuppressive agents, such as prednisone, anti-metabolites, and calcineurin inhibitors [8,9,10,11,12,13,14]. At this time, it is not clear if certain immunosuppressive agents may lead to a higher risk of CRN than others. Our patient was receiving treatment with abatacept, a biologic fusion protein that inhibits T-cell activation, along with low-dose methotrexate and prednisone at the time of CRN onset.

In the setting of immunosuppression for the treatment of a systemic autoimmune disease, initial treatment of CMV CRN could potentially consist of modification or discontinuation of these treatments to allow for immune restoration [12]. This is not always possible however, and systemic and/or intravitreal anti-viral treatments have regardless been utilized in the previously reported cases [8,9,10,11,12,13,14]. Ganciclovir, an inhibitor of CMV DNA polymerase, is commonly used as the first-line anti-viral agent in treating CMV infections. However, ganciclovir resistance develops in 40–50% of patients, particularly in the setting of chronic treatment, the need for multiple treatment courses, and inadequate absorption of oral ganciclovir. Ganciclovir resistance is typically due to mutations in the CMV phosphotransferase (UL97) or polymerase (UL54) genes [6, 16]. While our patient did not undergo CMV genetic analysis to confirm a resistance-conferring mutation, there was progression of retinitis despite two weeks of therapy, which, in the absence of genetic data, is considered refractory CMV [17].

With ganciclovir resistance, consideration can be given to switching to systemic foscarnet or cidofovir, however cross-resistance between ganciclovir and these two drugs is relatively high and both can be associated with significant side effects and toxicities [5, 6, 18]. Intravitreal anti-viral injections can be effective and avoid systemic toxicities. In our case, for example, multiple intravitreal foscarnet injections were successfully utilized to treat active retinitis that was not responding to intravitreal and oral ganciclovir. However, due to their short duration of action [19] and the subsequent need for frequent re-injection, intravitreal anti-viral injections are difficult to utilize chronically for prophylactic treatment.

Leflunomide, via its active metabolite teriflunomide, is an anti-metabolite that inhibits B- and T-cell replication and has been found to be effective in the treatment of inflammatory disease, particularly rheumatoid arthritis, for which it appears to have similar efficacy as methotrexate [20]. The anti-CMV properties of leflunomide arise from interference with viral capsid assembly, so there does not appear to be cross-resistance with the traditional anti-viral agents which inhibit CMV DNA replication [18, 21,22,23]. Prior studies have reported success with the use of leflunomide at doses of up to 100 mg daily in treating ganciclovir-resistant CMV viremia and CMV retinitis [18, 22,23,24]. GI side effects and transaminitis are the most common potential toxicities. In our case, leflunomide 20 mg daily was tolerated and appeared to provide benefit for both CRN and rheumatoid arthritis.

Letermovir is a newer anti-CMV medication that was approved in 2017 in the United States for the treatment of CMV infection following HSCT. Letermovir acts via inhibition of the CMV viral terminase complex (UL56), also a different mechanism of action than traditional anti-virals [25, 26]. It has been found to be effective in the treatment of CMV anterior uveitis and drug-resistant CMV retinitis with minimal side effects and without the need for routine laboratory monitoring [6, 16, 25, 26]. There is evidence from in-vitro studies that UL56 mutations conferring letermovir resistance can emerge quickly, although there are only few cases of this being found in clinical practice [6, 27].

The local immunosuppression induced by the STA injection, in conjunction with the patient discontinuing leflunomide and letermovir shortly after the injection, likely also contributed to the re-activation of retinitis. Clinicians should be cautious in utilizing local corticosteroid injections in the setting of CMV CRN, and it would seem prudent to continue systemic anti-viral prophylaxis if injections are utilized to treat secondary inflammation such as CME.

While a recently described disease, the incidence of CMV CRN may increase in the future as the use of non-cytotoxic immunosuppressive therapies that result in relatively mild immunosuppression also increases. Treatment with ganciclovir is effective but frequently leads to resistance, as in our case. In this situation, combination use of letermovir and leflunomide, particularly in the setting of rheumatoid arthritis where leflunomide can also have an anti-inflammatory effect, can be considered. The use of multiple anti-viral therapies with different mechanisms of action may also lead to decreased risk of resistance, as has been demonstrated in other chronic viral infections [28].

A limitation of this case report is the lack of CMV genetic analysis in our patient to identify a resistance-conferring mutation.