Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review

Morita, Shinya; Shinoda, Kazunobu; Tamaki, Satoshi; Kono, Hidaka; Asanuma, Hiroshi; Nakagawa, Ken; Oya, Mototsugu

doi:10.1016/j.jcv.2016.07.015

Cited by 11 publications

(12 citation statements)

References 30 publications

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“…Unlike the approved antivirals, LEF is thought to act independently of viral DNA replication, instead inhibiting the maturation of virions through inhibition of viral structural protein phosphorylation . In most of the available evidence, a loading dose of 100 mg is given for 3–5 days, followed by a maintenance dose of 20–40 mg/day . However, case reports describe the use of doses up to 80 mg/day, without major adverse effects, and viral clearance with doses as low as 10 mg/day …”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

“…In most of the available evidence, a loading dose of 100 mg is given for 3–5 days, followed by a maintenance dose of 20–40 mg/day . However, case reports describe the use of doses up to 80 mg/day, without major adverse effects, and viral clearance with doses as low as 10 mg/day …”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

“…In addition, LEF may have a role in the treatment of recurrence, as was suggested in a recently published case report describing the use of LEF monotherapy for low‐level VL recurrence in the outpatient setting . A 2016 review of the literature on LEF treatment of patients with GR‐CMV demonstrated a success rate of seven of eight patients (88%) in cases with a peak VL < 10 5 , whereas only 10 of 18 patients (56%) of those with peak VLs > 10 5 had long‐term responses to LEF therapy . Overall, a lower peak VL appears to be a unifying characteristic associated with LEF success.…”

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

“…29 In most of the available evidence, a loading dose of 100 mg is given for 3-5 days, followed by a maintenance dose of 20-40 mg/ day. 30,31 However, case reports describe the use of doses up to 80 mg/day, without major adverse effects, and viral clearance with doses as low as 10 mg/day. 30,32 In some cases, therapeutic drug monitoring is performed to ensure sufficient levels of LEF and its active metabolite, teriflunomide.…”

Section: Leflunomidementioning

confidence: 99%

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Ganciclovir‐Resistant Cytomegalovirus Infection in Abdominal Solid Organ Transplant Recipients: Case Series and Review of the Literature

et al. 2017

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Ganciclovir-resistant cytomegalovirus (GR-CMV) is emerging as a significant infection in the abdominal transplant population. GR-CMV is difficult to manage, and treatment options are limited. We report a descriptive case series of 15 patients who had documented GR-CMV at our center and review the literature on treatment of GR-CMV. The first case in this series was detected in 2012; the majority of cases occurred after January 1, 2014, with approximately 50% occurring in 2015. UL97 and UL54 viral genome mutations were present in 100% and 40% of CMV-infected patients, respectively. GR-CMV infection occurred ≤ 1 year posttransplantation in 11 patients (73%). All patients experienced dose reduction of valganciclovir (the oral prodrug of ganciclovir) before the development of GR-CMV. Initial treatment for GR-CMV included a variety of regimens, all including reduction in maintenance immunosuppression. Of the 6 patients with detectable GR-CMV by polymerase chain reaction (PCR) who were discharged without GR-CMV treatment and had a length of stay (LOS) less than 14 days, 83% were subsequently readmitted for treatment of GR-CMV within 2 months (60% in < 20 days); none received leflunomide. Of six patients with a LOS ≥ 14 days, 80% had CMV PCR below quantification on hospital discharge, and only one patient was readmitted in less than 20 days; 83% received leflunomide. Following GR-CMV, there was a 50% rejection incidence, 27% graft loss, and 20% mortality. For patients with more than three admissions for GR-CMV treatment, 100% had a major complication: 60% rejection, 20% graft loss, and 40% mortality. Common clinical characteristics of patients with GR-CMV included high-risk serostatus, lymphocyte depletion, and history of valganciclovir dose reduction. Overall, outcomes were poor. It appears that hospital readmission rate was reduced when CMV was treated to negativity with an initial treatment regimen of reduced immunosuppression, foscarnet, intravenous immunoglobulins, and leflunomide.

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Section: Discussion and Review Of The Literaturementioning

confidence: 99%

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

Section: Discussion and Review Of The Literaturementioning

confidence: 99%

Section: Leflunomidementioning

confidence: 99%

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Ganciclovir‐Resistant Cytomegalovirus Infection in Abdominal Solid Organ Transplant Recipients: Case Series and Review of the Literature

et al. 2017

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“…Leflunomide was first used in the treatment of ganciclovir-resistant CMV infection in 2004 [16]. Morita et al recently reviewed thirty cases of resistant CMV infection in transplant recipients treated with leflunomide; there were twenty successful treatments, five transient responses, and five failures [17]. Although the success rate was only 66.7%, ganciclovir-resistant CMV infection is a challenging problem in a highly immunocompromised population.…”

Section: Discussionmentioning

confidence: 99%

Leflunomide in the Treatment of a Pseudotumoral Genital Herpes Simplex Virus Infection in an HIV Patient

Roger¹,

Anstead

2017

Case Reports in Infectious Diseases

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The patient is a 52-year-old African American man with a past medical history of HIV infection (on antiretroviral therapy, CD4 count 399 cells/µL, and undetectable HIV viral load) and recurrent genital herpes. While on valacyclovir, the patient presented with four tumorous lesions on the perineum and scrotum. A biopsy specimen stained positively with HSV-1 and HSV-2 immunostains and displayed a lymphoplasmacytic infiltrate. The patient received foscarnet and imiquimod for two weeks with minimal improvement. Based on the previous activity of leflunomide, which has both antiviral and immunomodulatory properties, in cytomegalovirus and herpes simplex infections, leflunomide 20 mg orally twice daily was started. The patient received 23 days of foscarnet, 14 days of topical imiquimod, and 11 days of leflunomide with approximately 80% reduction in the size of the perineal lesion. After nine months on leflunomide there was complete regression of the large perineal lesion and only two small ulcerations remained on the scrotum. Pseudotumoral herpes lesions in HIV patients represent an immune reconstitution event and are poorly responsive to the usual anti-herpes agents. This report demonstrates the successful use of leflunomide in the treatment of an HIV patient with pseudotumoral herpes. Thalidomide has also been used with some success.

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Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus

Sepúlveda

Damonte

2018

Journal of Medical Virology

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The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses.

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Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review

Cited by 11 publications

References 30 publications

Ganciclovir‐Resistant Cytomegalovirus Infection in Abdominal Solid Organ Transplant Recipients: Case Series and Review of the Literature

Ganciclovir‐Resistant Cytomegalovirus Infection in Abdominal Solid Organ Transplant Recipients: Case Series and Review of the Literature

Leflunomide in the Treatment of a Pseudotumoral Genital Herpes Simplex Virus Infection in an HIV Patient

Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus

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