Combination Treatment With Letermovir and Ganciclovir for Maintenance Therapy of Multidrug-resistant CMV Infection in a Liver Transplant Recipient.

Abstract

We report the case of a liver transplant recipient, cytomegalovirus (CMV) donor-positive (D+), recipient-negative (R−), with primary multidrug-resistant CMV infection treated with a combination therapy of letermovir and (val)ganciclovir (Figure 1). This case illustrates the challenges of treating multidrug-resistant UL97 and UL54 positive CMV infections in solid organ transplant (SOT) recipients. Combination therapy with foscarnet and ganciclovir has been recommended in such cases, based on in vitro data and experts’ opinion.1 However, as illustrated in this case, available treatment options, particularly foscarnet, are associated with significant morbidities. Indeed, our patient developed esophageal (and genital) ulcers attributed to foscarnet, resulting in decreased oral intake and significant weight loss. Similarly, foscarnet-associated renal insufficiency has persisted after treatment discontinuation with his renal function never recuperating to his baseline. For the treatment of his infection and associated complications, the patient had to stay in the hospital for a total of 105 days, with severe debilitation and depression as a result. This further underlines the urgency for new, better tolerated therapeutic options for drug-resistant CMV. Two new CMV-active agents, maribavir and letermovir, have been recently developed for the treatment and prophylaxis of CMV, respectively.2 Both agents have activity against UL97- and UL54-mutated CMV. Maribavir, although on a fast-track status, has not yet been approved for the treatment of CMV infection by regulatory agencies. Letermovir was recently approved for prophylaxis of CMV in allogeneic hematopoietic cell transplant recipients.2 Since then, several groups have reported their experience with the off-label use of letermovir as salvage monotherapy or secondary prophylaxis for resistant and difficult to treat CMV infections in transplant recipients, with already raised concerns about efficacy and resistance development.3–8FIGURE 1.: Data on cytomegalovirus (CMV) infection, laboratory values of relevance, and associated treatments for a liver transplant recipient with primary CMV infection with multidrug-resistant CMV who was treated with letermovir and (val)ganciclovir combination treatment. A 64-y-old patient with alcoholic liver cirrhosis underwent a liver transplant (CMV D + R−). Primary prophylaxis with valganciclovir 900 mg daily was discontinued on posttransplant d (PTD) 150. On PTD, 164 patients developed asymptomatic viral replication with a plasma CMV quantitative PCR (qPCR) positive at 2000 IU/mL and valganciclovir at induction dose (900 mg twice daily) was initiated. However, patient remained viremic with a CMV qPCR fluctuating between 100 and 1000 IU/mL despite remaining on induction dose of valganciclovir. On PTD 273, he was admitted with malaise, fatigue, diarrhea, and fever and a CMV qPCR at 1.32log5 UI/mL, despite good compliance with valganciclovir. CMV serology was at IgG 5.71 U/mL (positive cut off > 1 U/mL). Treatment with induction dose foscarnet was initiated on PTD 273, and mycophenolate mofetil was stopped. Due to a lack of virologic and clinical response, resistance testing was then performed. CMV genotype revealed L595F/L and C603W/C UL97 mutations conferring resistance to ganciclovir, an N408K UL54 mutation conferring resistance to ganciclovir and cidofovir and the presence of a double CMV population wild and mutated Q578H/Q conferring resistance to ganciclovir, cidofovir, and foscarnet. Treatment was modified on PTD 290 with a combination therapy of foscarnet 50 mg/kg twice daily (adapted to the renal function) and ganciclovir 5 mg/kg IV twice daily. Within 14 d of combination treatment, the diarrhea and fever resolved and CMV qPCR decreased to 2.09log3 UI/mL by PTD 304. By 30 d of combination treatment, the CMV viral load further dropped to 5.42log2 UI/mL, but the patient developed painful esophageal and genital ulcers and acute renal failure with electrolyte abnormalities/Fanconi syndrome attributed to foscarnet. A gastroscopy performed on PTD 320 confirmed a severe ulcerative esophagitis without evidence of CMV esophagitis. Considering the persistence and severity of these symptoms and the low CMV viral load at 2.42log2 UI/mL, foscarnet was replaced by letermovir 480 mg once daily intravenously by PTD 360. On PTD 365, treatment was transitioned to orally administered letermovir 480 mg once daily and valganciclovir 450 mg twice daily (adapted to renal function). After 4 mo of letermovir and valganciclovir combination therapy, the viral load was <21 IU/mL, and the CMV IgG titer increased to 18.8 U/mL. Antiviral treatment was discontinued, and mycophenolate mofetil reintroduced by PTD 630, due to complete clinical and virologic response and a robust CMV seroconversion with CMV IgG titer of 204 U/mL. On PTD 740 follow-up, 100 d after discontinuing letermovir and valganciclovir, the patient remains asymptomatic and aviremic. Of note, the patient had a positive T-Track CMV assay (Lophius Biosciences, Germany), which detects the release of interferon-γ by CD4+ and CD8+ T cells after stimulation of peripheral blood mononuclear cells by CMV antigens (pp65 and Ie1) on PTD 132, 160, 172, and 370.This case report describes the introduction of letermovir in combination with (val)ganciclovir when low-grade viremia (at a log2) was achieved. Letermovir was not used alone because of lack of relevant data, including the appropriate therapeutic dose and because of its known low genetic barrier.2 Under this regimen, the patient had a slow but steady resolution of his clinical symptoms and complete virologic response. Whether valganciclovir was still active at this point, despite documented resistance mutations, remains unclear. Of note, combination maintenance therapy with letermovir was started when the CMV viral load was already too low and coincided with an immunologic response, as documented by a robust CMV IgG titer. Of note, CMV-specific cellular immune function was documented by a positive T-Track CMV assay (Lophius Biosciences, Germany) test as early as posttransplant day 132, suggesting that a combination of sufficient CMV-humoral and cellular immune function is required for the adequate control of this virus. Until more data and maribavir become available, this case suggests that letermovir could be considered as adjunct maintenance therapy combined with (val)ganciclovir for the treatment of drug-resistant CMV infection in high-risk SOT recipients with CMV viral loads <log3. Whether letermovir can be administered alone or in combination with (val)ganciclovir for the treatment of CMV infection to achieve optimal outcomes without the emergence of letermovir-resistant virus remains unclear. This case does not answer this very question. However, it may serve as the basis to stimulate the discussion within the Transplant Infectious Disease community for accelerated and targeted efforts that may definitively answer this question in the context of a prospective clinical trial.