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

Abstract

In this editorial we comment on the article published in the recent issue of the World Journal of Gastroenterology. We focus specifically on the problem of occult hepatitis B virus (HBV) infection, that is a result of previous hepatitis B (PHB) and a source for reactivation of HBV. The prevalence of PHB is underestimated due to the lack of population testing programs. However, this condition not only complicate anticancer treatment, but may be responsible for the development of other diseases, like cancer or autoimmune disorders. Here we unveil possible mechanisms responsible for realization of these processes and suggest practical approaches for diagnosis and treatment.

Key Words: Occult hepatitis B virus infection, Hepatitis B virus reactivation, Previous hepatitis B, Cancer, Autoimmune disorders

Core Tip: Occult hepatitis B virus (HBV) infection is a result of previous hepatitis B (PHB) and source for reactivation of HBV. This may be a challenge when anti-cancer treatment is provided. However, PHB is a reason of other disorders, like cancer and autoimmune disorders development. We discuss this multifaceted problem from the viewpoint of pathogenetic mechanisms, and possible practical approaches.

INTRODUCTION

Reactivation of hepatitis B virus (HBV) infection in patients receiving chemotherapy for solid tumors is a known phenomenon that attracts the attention of researchers and healthcare practitioners due to the possible complications, need for the change of the treatment strategy for the main disease, and lack of unified approaches. The continuing interest to the problem may be confirmed by the fact that near 150 papers on this topic was published yearly during 10 recent years. Two of them, including a recent Commentary are available for the readers of World Journal of Gastroenterology[1,2].

HBV reactivation may occur decades after hepatitis B is resolved due to impaired or suppressed immune control and persistence of molecular basis for the replication in the form of covalently closed circular DNA (cccDNA). There are three main groups of factors that are associated with higher risks of reactivation: (1) Host factors: male gender, older age, presence of liver cirrhosis and a concurrent disease that requires immune suppression; (2) Viral factors: high baseline viral load, positive hepatitis B e antigen, non-A HBV genotype, coinfection with human immunodeficiency virus (HIV), hepatitis С or D viruses; and (3) Factors of immunosuppression: highest risk is associated with B-cell-depleting agents[3].

A number of drugs that are used for the management of patients with cancer, including tyrosine kinase inhibitors, may also lead to reactivation of resolved HBV infection and this underlines the need for special studies, allowing to identify the risks and provide evidence-based algorithms for the prophylaxis. However, the problem is wider than it looks at first glance.

PREVIOUS HEPATITIS B AND DEVELOPMENT OF OTHER DISEASES

It is well known that HBV has cancerogenic properties. It may lead to hepatocellular carcinoma development, but also is a cause of extrahepatic malignancies[4]. The reported risks vary significantly, and this may be caused by methodological issues. For example, in a number of studies subjects of the main and the control groups were tested only for serum hepatitis B surface antigen (HBsAg), and no analysis for hepatitis B core antibody (anti-HBc) positivity was performed. This could lead to underestimation of risks, because in HBsAg-negative/anti-HBc-positive subjects the odds of cancer development are greater than in those not exposed to HBV[4-8].

According to the current knowledge, natural history of chronic HBV infection is a long-lasting dynamic process that includes V phases[9]. At the final (HBsAg-negative) phase, the commonly used main screening serum marker is cleared out of the blood, and the infection persists either in the form of low-level replication (occult HBV infection), and/or in the form of integrations of viral DNA to the host genome[10].

Duration of exposure to the products of viral gene expression may be crucial for the development of HBV-associated malignancy. It might take several decades from the infection to malignant tumor appearance. Carcinogenic mechanisms of HBV may be realized through direct participation of its X gene and highly conservative HBx protein, which modulates the expression and activity of numerous other genes[11]. Point mutations in the X gene region of HBV and the C-terminal truncation of HBx have been reported responsible for the formation of malignant tumors[12-15]. Due to the fact that in the structure of the HBV genome, the X gene overlaps the C-end of the polymerase gene and the N-end of the core gene, the appearance of mutations and/or deletions in the X gene can disrupt regulation and transcription in both of these genes simultaneously[16,17]. Numerous features confirm participation of HBx in the host immune response, oncogenic signaling pathways, proliferation, apoptosis, inflammation, fibrogenesis and angiogenesis[18].

Integration of HBV DNA and associated production of HBx, leading to genetic instability and insertion mutagenesis[10] may occur not only within the liver, but in other organs[4,19].

Another important issue is the involvement of HBV infection in the pathogenesis of other diseases, including those of an autoimmune nature, with hyperactivation of the immune response after contact with viral antigens[20]. Molecular mimicry, epitope spreading, bystander activation and/or immortalization of infected B cells are possible mechanisms for the development of virus-induced autoimmune reactions in genetically predisposed individuals[21]. It should be born in mind that patients with autoimmune disorders and previous hepatitis B (PHB) are potential candidates for immunosuppressive therapy. This forms a vicious circle, when PHB acts as a trigger or a risk factor for autoimmune disorders or cancer, and at the same time may serve as a source of HBV reactivation when treatment for these diseases is provided (Figure 1)[3].

Figure 1 “Vicious circle” of previous hepatitis B. HBV: Hepatitis B virus.

SUGGESTIONS FOR THE COMMON TERMINOLOGY AND REVISION OF OPTIMAL GOALS OF TREATMENT

Current understanding of the mechanisms by which HBV influence host health requires a change of the terminology used. 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].

Keeping in mind that cccDNA (responsible for new virions synthesis) and fragments of the viral DNA integrated into the host genome (some of them can express viral proteins) are usually preserved after HBsAg clearance, it is not correct to talk about the infection in the past tense. At the same time, hepatitis caused by HBV, which usually implies the presence of inflammatory changes in the liver, has different activity at certain stages of the disease and practically disappears in the final (V) phase (HBsAg-negative). In this regard, the term we propose, “previous hepatitis B” (PHB), which indicates the presence of an integrative infection (with or without occult HBV infection), more accurately reflects the essence of this condition and indicates clinically relevant status in those HBsAg-negative/anti-HBc-positive patients who were not tested for serum HBV DNA, or in whom the result was negative.

It is important that not just current active infection, but previous contact with the virus (PHB) itself may cause damage to liver tissue, development of liver cirrhosis and cancer. Therefore, current approaches for treatment of HBV infection with “functional cure” (defined as sustained HBsAg clearance with or without HBs seroconversion and undetectable HBV DNA in the blood after treatment) as a primary goal seems not to be sufficient. Functional cure may help to reduce the problem of HBV reactivation to some degree, but is not able to stop the expression of oncogenic HBV proteins. Only “sterilizing cure”, with complete elimination of viral DNA fragments from the host genome, may solve the problem of reactivation of HBV infection (when different classes of anticancer and immunosuppressive drugs are used) and cancer development.

Although elimination of cccDNA and integrated fragments of the viral genome is not possible using current treatment options, it should be indicated as the ultimate therapeutic target for the future.

PRACTICAL POINTS

There is an obvious need for several practical measures, including: (1) Wider population screening for HBV markers (not only HBsAg, but also, at least, anti-HBc), especially in endemic regions; (2) Stratification of complex risks of HBV reactivation in subjects with PHB receiving anticancer or immunosuppressive medications in consideration of all factors, including those of host, viral and the type of treatment; (3) Development of integrated system (including those based on the artificial intelligence) for the assessment of personalized risks of cancer of different organs in subjects with PHB; and (4) Implementation of advanced algorithms of screening, follow-up and management of comorbid disorders in subjects with PHB to minimize the risks of HBV reactivation and provide optimal and safe treatment.

CONCLUSION

Previous hepatitis B is a multifaceted problem that includes not only HBV reactivation, but also participation of the virus in pathogenesis of autoimmune disorders and cancer. Subjects with PHB and occult infection may have a potential risk for virus transmission during blood transfusion and transplantation.