Clinical reactivation after liver transplantation with an unusual minor strain of hepatitis B virus in an occult carrier

Abstract

Hepatitis B virus (HBV) DNA is detectable in a number of liver transplant candidates who are negative for hepatitis B surface antigen (HBsAg). After liver transplantation (LT), such patients may have molecular and/or serologic evidence of HBV replication. However, clinical disease from reactivation of occult HBV infection after LT has not been described. We report a patient who underwent LT for cryptogenic cirrhosis and had to be retransplanted twice for hepatic artery thrombosis. The patient was negative for HBsAg and positive for anti-hepatitis B core (HBc) and anti-HBs before all LT procedures and developed acute hepatitis B shortly after receiving the third graft. The HBV strain isolated at that time exhibited an unusual in frame insertion of a CAG motif within the HBV polymerase (HBV INSϩ ). HBV INSϩ was detected retrospectively as a minor species in pretransplantation sera and the explanted native liver by insertion-specific polymerase chain reaction. This case in an occult HBV carrier shows that clinically apparent, endogenous reinfection of the graft may occur with minor HBV variants that are not detectable in pretransplantation samples by standard diagnostic procedures. This has implications for the analysis of sources of acute hepatitis B in patients after LT Hepatitis B after liver transplantation (LT) greatly affects patient outcome. In principle, 2 modes of infection are possible: (1) endogenous reinfection in patients who were transplanted for hepatitis B, and (2) exogenous or de novo infection, mostly as a result of nosocomial transmission of hepatitis B virus (HBV) through the liver allograft, blood products, and other exogenous sources. Although the prevalence of de novo infection with HBV is only 3.5% 1 and has a good prognosis in most cases, endogenous reinfection is frequent and may lead to severe hepatitis. 2 A prerequisite for endogenous reinfection after LT is the presence of active hepatitis B before transplantation. The incidence of reinfection after LT depends on the level of pretransplant viremia and the prophylactic measures taken. [3][4][5][6] Few cases of reinfection have been described in patients with serologic signs of previous hepatitis B. [7][8][9] These patients were negative for hepatitis B surface antigen (HBsAg) and positive for anti-hepatitis B core antigen (HBc), but negative for anti-HBs. In recipients who are positive for both anti-HBs and anti-HBc antibodies before LT, to our knowledge, clinically apparent reinfection has not been described yet. By definition, these patients have resolved hepatitis B and can be divided into 2 clinically important groups in the transplantation setting. First, the vast majority of these individuals are negative for serum HBV DNA by polymerase chain reaction (PCR). In the second group, serum HBV DNA can be detected by PCR and these patients are referred to as occult HBV carriers. The outcome of LT in such carriers has yet been investigated in only few studies. None of the study patients experienced clinically apparent reinfection with H...

The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients

“…To detect HBV sequences in our samples, we aligned all short reads from whole-genome sequencing against a comprehensive list (n = 73) of HBV reference genomes (genotype A-I and a strain of Woolly Monkey HBV) (Supplemental Table 2; Zöllner et al 2006;Mulyanto et al 2011). HBV sequences were not detected in samples from the HBV-negative individual but were clearly present in both tumor and nontumor liver samples from the HBV-positive patients (Fig.…”

Occult hepatitis B virus infection

“…The virological and clinical reactivation of the occult HBV infection has been repeatedly observed in several different clinical conditions including hematological malignancies, HIV infection, hematopoietic stem cell transplantation, and organ transplantation (Table 3). In this context, it is of note that occult HBV infected patients undergoing OLT may present re-infection of the new liver [109], and occasionally this event may be followed by virological and clinical re-activation [110]. Moreover, the availability of new, potent immunosuppressive drugs -like the anti-CD20, the anti-CD52 and the anti-TNF monoclonal antibodies, recently introduced in the therapeutic schedules of various clinical settings -seems to have further increased the risk of HBV reactivation in cryptically infected individuals that may present very severe clinical sequels [111][112][113][114][115].…”

Update on donor-derived infections in liver transplantation

“…The persistence of viral DNA in donor hepatocytes is the likely source. [36][37][38][39][40][41] In the absence of prophylaxis, surface antibody-negative recipients are more likely to subsequently develop allograft hepatitis. Recipient anti-HBV surface antibodies may control viral replication, 42 but the transmission of viral hepatitis can be mitigated with the use of antiviral prophylaxis such as lamivudine or entecavir with or without supplemental hepatitis B immune globulin.…”