Protzer U, Goergen B, Hopf U, Neuhaus P, König V, Meyer zum Büschenfelde K H, Gerken G
1st Medical Department, Johannes Gutenberg University of Mainz, Germany.
J Med Virol. 1996 Oct;50(2):135-44. doi: 10.1002/(SICI)1096-9071(199610)50:2<135::AID-JMV6>3.0.CO;2-B.
Orthotopic liver transplantation (OLT) is a possible treatment for acute or chronic liver failure due to hepatitis B virus (HBV) infection, but reinfection of the graft can be a serious complication. The aim of this study was to monitor HBV markers, to analyse pre-core-/core-mutations as well as to identify the viral population causing reinfection after OLT, and to investigate the emergence or disappearance of these mutants in patients receiving immunosuppressive treatment. Fifty-four pre-and posttransplant serum samples of 17 patients were analysed. All patients underwent OLT for HBV-related liver disease and had HBV-DNA before and after OLT. Total DNA was extracted from all sera and a 240 bp fragment comprising the pre-core region of HBV was amplified by polymerase chain reaction (PCR). Pre-core mutants of HBV were determined by direct sequencing of these PCR products and by sequencing of PCR clones. Eight of 17 patients were infected with pre-core wildtype HBV before OLT (group A). Seven of eight patients of group A were reinfected by pre-core wildtype HBV after OLT. In one of eight patients in addition to wildtype HBV a mutant strain (nt. 1899 G-->A) was detected. Nine of 17 patients were infected with pre-core mutant HBV before OLT (group B). Six of nine patients of group B were reinfected with the same mutant population; in one, an additional pre-core mutation emerged; two patients lost pre-core mutant HBV (nt. 1896 and 1899 G-->A). In one of the latter two, a pre-core start-codon mutant (nt. 1816 G-->T), not detectable before OLT, emerged, in the other a nt. 1897 G-->A stop-codon mutant persisted. Five patients of each group were followed-up for more than 24 (25 to 58) months on immunosuppressive therapy. In all five patients of group A, pre-core wildtype of HBV persisted during long-term follow up. Two of five patients of group B were infected stably with a stop-codon HBV-mutant nt. 1896. In three patients, the nt. 1896 stop-codon mutant disappeared during immunosuppressive therapy. However, in one of the latter three, an HBV stop-codon mutant nt. 1897 persisted. In conclusion, most patients who underwent OLT for HBV-related disease were reinfected with the same virus population that existed before OLT. In rare cases, new mutants emerged after OLT or preexisting mutants were lost. During long-term follow-up on immunosuppressive therapy, in the majority of patients pre-core mutants disappeared and wildtype HBV became the predominant virus strain.
原位肝移植（OLT）是治疗乙型肝炎病毒（HBV）感染所致急慢性肝衰竭的一种可行方法，但移植肝再感染可能是一种严重并发症。本研究旨在监测HBV标志物，分析前核心/核心区突变，确定OLT后导致再感染的病毒群体，并研究这些突变体在接受免疫抑制治疗患者中的出现或消失情况。分析了17例患者移植前后的54份血清样本。所有患者均因HBV相关肝病接受OLT，且在OLT前后均有HBV-DNA。从所有血清中提取总DNA，通过聚合酶链反应（PCR）扩增包含HBV前核心区的240 bp片段。通过对这些PCR产物直接测序以及对PCR克隆测序来确定HBV的前核心突变体。17例患者中有8例在OLT前感染前核心野生型HBV（A组）。A组8例患者中有7例在OLT后被前核心野生型HBV再感染。8例患者中的1例除野生型HBV外还检测到一种突变株（nt.1899 G→A）。17例患者中有9例在OLT前感染前核心突变型HBV（B组）。B组9例患者中有6例被相同的突变群体再感染；其中1例出现了额外的前核心突变；2例患者失去了前核心突变型HBV（nt.1896和1899 G→A）。后2例患者中的1例出现了OLT前未检测到的前核心起始密码子突变（nt.1816 G→T），另1例nt.1897 G→A终止密码子突变持续存在。每组5例患者接受免疫抑制治疗随访超过24（25至58）个月。A组所有5例患者在长期随访中前核心野生型HBV持续存在。B组5例患者中有2例被终止密码子HBV突变体nt.1896稳定感染。3例患者中，nt.1896终止密码子突变体在免疫抑制治疗期间消失。然而，后3例患者中的1例，HBV终止密码子突变体nt.1897持续存在。总之，大多数因HBV相关疾病接受OLT的患者被OLT前存在的相同病毒群体再感染。在罕见情况下，OLT后出现新的突变体或原有突变体消失。在免疫抑制治疗的长期随访中，大多数患者前核心突变体消失，野生型HBV成为主要病毒株。
