Hepatitis B core‐related antigen to detect hepatitis B virus (HBV) reactivation in heart transplant recipients with past HBV infection: A pilot study

Abstract

Hepatitis B virus (HBV) reactivation in immunosuppressed HBsAg−/anti-HBc+/HBV-DNA− patients has been described in various clinical settings. We recently analyzed this phenomenon in 11 heart transplant recipients with markers of prior HBV infection (anti-HBc+/±anti-HBs+/HBVDNA−, thereafter referred to as "past HBV"), searching HBV-DNA by high-sensitivity qualitative nested PCR in sera obtained before transplant and for a median period of 30 months after transplant. 1 A definite HBV reactivation (HBV-DNA detectable in serum with standard, commercially available methods) was observed in only one of these 11 past HBV recipients. In contrast, virological events of uncertain significance (VEUS, ie, intermittently positive HBV-DNA only with high-sensitivity qualitative nested PCR) were observed in five of the remaining 10 recipients. The single patient with definite HBV reactivation was treated with entecavir before ALT elevation, while the other subjects were only followed up and none of them developed clinical signs of liver injury. 1 Although the clinical significance of such VEUS appeared to be negligible in our patients, they could imply persistence of covalently closed circular HBV-DNA (cccDNA) within hepatocytes. Recently, cccDNA was found to correlate with a novel serological marker of HBV infection, named hepatitis B core-related antigen (HBcrAg). HBcrAg derives from denatured hepatitis B e antigen (HBeAg), HBV core antigen and a core-related protein (p22cr). SerumHBcrAg levels correlate mostly with serum HBV-DNA 2 and cccDNA, but also with quantitative HBsAg (QT-HBsAg). 3 Thus, HBcAg could be used to monitor intrahepatic viral status 2 in different phases of the natural history of HBV infection 4 and to early detect HBV reactivation after discontinuing antiviral therapy or when immune suppression occurs. 5 However, no data are available regarding the significance of HBcrAg in solid organ transplant recipients with past HBV infection.Accordingly, we designed this study to assess whether HBcrAg levels could be used as a measure of HBV reactivation after heart transplant.Our aims were to study the dynamics of this novel marker of HBV replication in such immunosuppressed past HBV-infected patients and assess its possible correlation with QT-HBsAg and HBV-DNA detected by high-sensitivity PCR. AbstractHepatitis B core-related antigen (HBcrAg) has been proposed as a new marker of hepatitis B virus (HBV) replication. We analyzed HBcrAg dynamics in 15 heart transplant recipients with active or prior HBV infection and correlated it with quantitative (QT)-HBsAg and HBV-DNA pre-and post-transplant. Serum HBcrAg was detected in HBsAg/HBV-DNA-positive subjects but not in recipients with past HBV infection. HBcrAg levels correlated with QT-HBsAg in pre-and post-transplant samples.In prior HBV infection, HBcrAg levels were unrelated to HBV-DNA positivity. In heart transplant recipients with prior HBV infection, HBcrAg does not correlate with viral replication and cannot be applied to detect HBV reactivation during follow-up. ...

Outcome of nucleos(t)ide analog cessation in patients with treatment for prevention of or against hepatitis B virus reactivation

“…The levels of hepatitis B core‐related antigen and anti‐HBs are known to be useful for predicting HBV reactivation, and are surrogate markers for cessation of NA in patients being treated for HBV reactivation 19–21 . Previously, it was reported that HBV DNA did not rise to the level of quantification after cessation of NA in the patients with anti‐HBs ≥10 mIU/ml at the time of NA cassation 17 .…”

Essentials in the diagnosis of postoperative myocardial lesions similar to or unrelated to rejection in heart transplant

“…In certain cases, histological diagnosis is difficult to establish in a viral infection that is associated with inflammation and necrosis, especially when there are no microorganisms directly associated with the infection. Sometimes it is difficult to differentiate a virus-induced lesion from an acute rejection (26,27). In these instances the results of the initial biopsy (with differential diagnosis difficulties) are compared with the results of subsequent biopsies, performed after specific treatment for the infection have already been administered.…”

Reactivation of hepatitis B virus infection – an important aspect of multifaceted problem

“…To date, there is no single generally accepted term for a condition that occurs after the resolution of acute or chronic hepatitis B and is characterized by a special set of serological viral markers: negative HBsAg and positive anti-HBc class IgG (in combination with anti-HBs or not). To describe subjects with such a serological profile, when no certain data on the disease history are available, different definitions are used in the literature: “previous HBV infection”[ 22 ], “past exposure to hepatitis B”[ 23 ], “past HBV infection”[ 24 ], “resolved HBV infection”[ 25 ], and even “anti-HBc alone”[ 26 ]. In case of a sustained HBsAg loss and undetectable level of HBV DNA, combined with the absence of clinical or histological signs of active viral infection in an individual who was previously HBsAg-positive, the term “resolved chronic hepatitis B” is proposed[ 27 ].…”