Effect of Entecavir Versus Tenofovir on HBV DNA Level in Peripheral Blood Mononuclear Cells

Overview

Liver disease associated with persistent hepatitis B virus (HBV) infection remains an important public health problem with significant morbidity and mortality. In spite of the existence of an effective vaccine, worldwide approximately 260 million people are chronic HBV surface antigen (HBsAg) carriers and current treatment with interferon and/or nucleoside analogues (NA) is not able to achieve a complete cure. The key obstacle to HBV eradication is the persistence of HBV DNA in the nuclei of infected hepatocytes, either integrated into the host genome or as a covalently closed circular DNA (cccDNA) episomal form. While HBV integration is rare and its clinical implications still require investigation, cccDNA plays an essential role in the long-term persistence of HBV infection and can often be detected even following NA therapy and HBsAg seroconversion. Since quantification of cccDNA in infected hepatocytes requires invasive liver biopsy, more accessible tissues, such as serum or peripheral blood mononuclear cells (PBMCs) have been investigated in different patient populations.

Some reports have shown that cccDNA in serum is a marker of off-treatment virological relapse, whereas others have not found cccDNA in the serum of chronic hepatitis B patients. Some investigators speculate that PBMCs support HBV replication only partially, with linear and circular relaxed HBV DNA but not cccDNA formed in these cells, while others have detected cccDNA in PBMCs and/or plasma in a variable proportion of patients with chronic and occult HBV infection. Although hepatocytes are recognized as the main target of HBV infection, HBV and other members of the hepadnaviral family, such as woodchuck hepatitis virus (WHV), have significant lymphotropic properties. Hepadnaviral infection of lymphoid cells is an important mechanism by whitch virus escapes immune recognition and lymphoid reservoirs, particularly those harbouring drug-resistant HBV, may be the key to develop antiviral resistance. Positive detection rate of HBV-DNA in neutrophils of chronic hepatitis B patients was 30.95%, After treatment of adefovir, the positive rate of HBV-DNA in neutrophils of chronic hepatitis B patients was 9.52% acting as asource of extrahepatic occult infection. In liver transplant recipients, HBV in peripheral blood mononuclear cells has been implicated in graft reinfection with a specific lymphoid cell derived viral variant. Additionally HBV intrauterine infection was primarily caused by maternal to fetal peripheral blood mononuclear cells transport in the second trimester of pregnancy. The goal of treatment for chronic hepatitis B is to prevent liver disease progression and improve survival by long-term suppression of hepatitis B virus replication in a sustained manner. A functional HBV cure, defined as a sustained hepatitis B surface antigen loss or seroconversion based on assays with a lower limit of HBsAg detection of 0.05 IU/mL, is a rare event in the natural history of chronic hepatitis B that is associated with a reduced risk of HCC. Complete HBV cure is defined as an elimination of cccDNA together with durable HBsAg loss and undetectable serum HBV-DNA. Although liver biopsy is needed to measure intrahepatic cccDNA activity, serum biomarkers that reflect cccDNA levels are needed instead. Such as HBV RNA, hepatitis B core-related antigen, and/or quantitative HBsAg have been investigated. Quantification and ratio of large and middle proteins of HBsAg also showed specific patterns across different phases of hepatitis B that would predict the viral activity. Entecavir (ETV) or tenofovir disoproxititis fumarate (TDF) are recommended as first line therapy in the treatment of naïve chronic hepatitis B because of their higher antiviral potency and higher genetic barriers than other antiviral agents. In reality, ETV and TDF showed high virological responses of up to 93% and 100%, respectively, and a rare genotypic resistance of only 1.2% and 0%, respectively, during the 5- year follow-up in a cohort study. In a study evaluating Dynamic changes of HBV-DNA in serum and peripheral blood mononuclear cells of chronic hepatitis B patients, concluded that HBV-DNA exists in PBMCs even after 48 weeks of lamivudine treatment that may reinfect hepatocytes again and cause the relapse of hepatitis. Coffin., et al 2011; suggested that hepatitis B virus in lymphoid cells may be more resistant to antiviral therapy leading to a differential rate of HBV variant secretion in serum or plasma. Furthermore, HBV quasispecies diversity in liver correlated with antiviral drug resistance and this may have implications for the emergence of dominant resistant HBV variants over time.