title: 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 acyclovir-resistant 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.
authors.affiliation: Institute of Pathology, Department of General Pathology, University of Heidelberg, Heidelberg, Germany. thomas.longerich@med.uni-heidelberg.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Christoph
authors.initials: C
authors.lastname: Eisenbach
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Kremer
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.forename: Burkhard
authors.initials: B
authors.lastname: Helmke
authors.forename: Jens
authors.initials: J
authors.lastname: Encke
authors.forename: Thomas
authors.initials: T
authors.lastname: Kraus
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
mesh_terms: D000212:Acyclovir / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use; D001483:Base Sequence; D001706:Biopsy; D017931:DNA Primers; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D020803:Encephalitis, Herpes Simplex / Q000601:surgery*; D006561:Herpes Simplex / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000601:surgery*; D016031:Liver Transplantation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012008:Recurrence; D018139:Simplexvirus / Q000235:genetics* / Q000302:isolation & purification
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D004279:DNA, Viral; D000212:Acyclovir