Recurrent herpes simplex virus hepatitis after liver retransplantation despite acyclovir therapy

Abstract

Herpes virus hepatitis (HSV) represents a form of acute necrotizing hepatitis, which most frequently develops in immunocompromised patients. Therapeutic options include high-dose intravenous acyclovir and liver transplantation. We report the first case of recurrent HSV hepatitis after liver retransplantation, which occurred despite continuous administration of high-dose intravenous antiviral therapy. Because explant histology pointed to initial therapy response, we thought that the reason for recurrence might be due to acyclovir resistance. Most acyclovir resistance is caused by inactivating mutations in the herpes virus thymidine kinase gene. HSV infection was detected by histology and proofed by immunohistochemistry. PCR amplification of the herpes virus thymidine kinase gene was performed on histology specimens to demonstrate the course of viral infection in liver tissue. Genotypic resistance testing of the herpes virus was performed by sequencing the thymidine kinase amplicon. In serial biopsy, HSV-DNA sequences were only detectable when histology revealed herpes hepatitis. Whereas the primary explant exhibited the wild-type thymidine kinase gene, a biopsy of the second graft one month after retransplantation, which showed recurrent herpes virus hepatitis, had a single base insertion within a homopolymeric cytosine stretch. This mutation causes a frame shift leading to a premature stop codon and results in a known acyclovirresistant herpes strain. In conclusion, we believe that testing for acyclovir-resistant herpes strains should be considered in high-risk patients in whom viral clearance is not achieved serologically to prevent fatal recurrence of disease by using antiviral drugs such as inhibitors of HSV-DNA polymerase or viral helicase primase inhibitors. H erpes simplex virus (HSV) hepatitis is an infrequent form of viral hepatitis, which occurs mainly, although not exclusively, in immunosuppressed patients and children. [1][2][3][4] In a recent prospective multicenter study, the incidence was well below 1% (1/354) of all cases with acute liver failure and 2% (1/43) of all cases with virus-related acute liver failure. 5 HSV hepatitis occurs with a frequency of 2% in children after liver transplantation. 6 Therapeutic options for manifest HSV hepatitis are high-dose intravenous therapy with acyclovir and liver transplantation. 1,[7][8][9][10] According to a recent Dutch study, the prevalence of acyclovir-resistant herpes simplex virus strains is about 0.3% in immunocompetent patients in contrast to 7% in immunocompromised patients. 11 The following case report describes a 61-year-old man who received an orthotopic liver transplantation for alcoholic liver cirrhosis and who then developed HSV hepatitis in his graft. Despite immediate highdose antiviral therapy, he developed acute liver failure, was retransplanted, and then developed recurrent and fatal HSV hepatitis in his second graft despite continuous antiviral therapy. Case ReportA 61-year-old male caucasian patient was admitted to our university hosp...

Herpes simplex virus hepatitis: An analysis of the published literature and institutional cases

“…It is speculated that the relatively high frequency of acyclovir resistant herpes viruses in immunocompromised patients may be due to an impaired T-cell response. 93 There are limitations of this study. The retrospective design is limited by the accuracy and completeness of the data reported in the literature and from our hospital records.…”

“…Of the 4 who died post-LT, only 1 had recurrent HSV as a potential contributor to death. 93 That being said, the high morbidity and mortality after LT is not insignificant. Lifelong antiviral therapy after LT is likely required to prevent recurrences, as 2 of the patients had recurrent rash within 2 weeks of acyclovir discontinuation.…”

“…The causes of death in the 4 patients are the following: hemothorax (29 days after LT), 92 acute respiratory distress syndrome (11 days after LT), 92 unknown (365 days after LT, Northwestern patient #1, no autopsy), and recurrent HSV and multiorgan failure despite continuous parenteral acyclovir (42 days after LT). 93 The 3 remaining patients survived long-term (mean reported follow-up ϭ 989 days, standard deviation ϭ 1,448 days). Two patients developed HSV rash within 2 weeks of discontinuing acyclovir but neither developed disseminated HSV (Northwestern patient #1).…”

Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management

“…After healing of an infection caused by a TK-negative drug-resistant HSV strain and stopping antiviral therapy, recurrences are most often associated with a drugsensitive strain, although some cases of spontaneous recurrences of ACV-resistant viruses have been reported (1,78,100,113,125,126,142,146,152,153,178,201,205,232,246). Laboratory diagnosis of ACV resistance is required to guide clinicians toward different treatment options in cases of therapy failure.…”

Infectious Diseases and Clinical Complications During Treatment in CLL

“…Herpes esophagitis is common in immunosuppressed patients, but has rarely been reported in immunocompetent individuals, in whom it appears to be a self-limited illness (Canalejo Castrillero et al, 2010). Pneumonia, hepatitis, gasterointestinal involvement and disseminated infection may occur in immunocompromised patients (Longerich et al, 2005;Medlicott et al, 2005;Massler et al, 2011). Multiple herpes virus co-infection (HSV and EBV) may occur in patients with chronic lymphocytic leukemia (Mercadal et al, 2006).…”