Risk of hepatitis B virus reactivation in cancer patients undergoing treatment with tyrosine kinase-inhibitors

Abstract

This editorial commented on an article in the World Journal of Gastroenterology titled “Risks of Reactivation of Hepatitis B Virus in Oncological Patients Using Tyrosine Kinase-Inhibitors: Case Report and Literature Analysis” by Colapietro et al. In this editorial, we focused on providing a more comprehensive exploration of hepatitis B virus reactivation (HBVr) associated with the usage of tyrosine kinase inhibitors (TKIs). It includes insights into the mechanisms underlying HBV reactivation, the temporal relationship between TKIs and HBV reactivation, and preventive measures. The aim is to understand the need for nucleos(t)ide analogs (NAT) and serial blood tests for early recognition of reactivation and acute liver injury, along with management strategies. TKIs are considered to be an intermediate (1%-10%) of HBVr. Current guidelines stipulate that patients receiving therapy with high or moderate risks of reactivation or recent cancer diagnosis must have at least tested hepatitis B surface antigen, anti-hepatitis B core antigen (HBc), and anti-hepatitis B surface antibody. Anti-HBc screening in highly endemic areas means people with negative tests should be vaccinated against HBV. Nucleoside or nucleotide analogs (NAs) like entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) form the basis of HBV reactivation prophylaxis and treatment during immunosuppression. Conversely, lamivudine, telbivudine, and adefovir are generally discouraged due to their reduced antiviral efficacy and higher risk of fostering drug-resistant viral strains. However, these less effective NAs may still be utilized in cases where ETV, TDF, and TAF are not feasible treatment options.

Key Words: Hepatitis B virus; Reactivation; Chronic hepatitis B; Tyrosine-kinase inhibitor; Immunomodulators; Immunosuppressant; Nucleoside analogue; Hemato-oncology

Core Tip: Hepatitis B virus reactivation (HBVr) remains a major concern in patients treated with Immunosuppressants and immunomodulators in oncological settings. Patients harboring either overt or occult HBV infection may encounter HBV reactivation during immunosuppressive therapy. The likelihood of HBV reactivation is linked to the patient’s immune status and the initial condition of HBV infection. Depending on the risk, reactivation can be classified as low (< 1%), intermediate (1%-10%), and high (> 10%), It is important to administer nuclei(t)side analogs of high genetic barriers before and during antineoplastic treatment to prevent reactivation. The safety and effectiveness of immunomodulators are investigated. However, during treatment, clinical monitoring of liver enzymes and HBV DNA is required, and a prospective study is needed to determine appropriate antiviral therapy.

INTRODUCTION

Reactivation of hepatitis B virus (HBV) refers to the resurge of HBV replication in individuals who have previously cleared the virus or have had chronic HBV infection but with inactive disease[1]. According to the World Health Organization, worldwide, more than two billion people are estimated to have been infected with HBV, while around 296 million are infected with chronic HBV. Tyrosine kinase inhibitors (TKIs), such as Bcr-Abl multi-kinase inhibitors (dasatinib, imatinib, and nilotinib), are used for various solid and hematological diseases, including chronic myelogenous leukemia, gastrointestinal tumors, and lung cancer. Bruton’s tyrosine kinase (BTK) inhibitors are increasingly being utilized in the treatment of chronic lymphoma. Since these agents block the signaling of B cell antigen receptors and reduce the proliferation of malignant B cells, BTK inhibitors can activate HBV[2]. The reactivation of the hepatitis B virus (HBV) associated with various categories of drugs and certain drugs or doses is observed in patients classified as either positive hepatitis B surface antigen (HBsAg) or negative HBsAg/anti-hepatitis B core antigen (HBc) positive. Anti-CD20 monoclonal antibodies, including Obintubuzumab and Rituximab, carry a significant risk of reactivating HBV, with incidences ranging from 30% to 60% in individuals who are HBsAg-positive and exceeding 10% in those who are HBsAg-negative or anti-HBc-positive[1,3]. Anthracycline chemotherapy drugs like doxorubicin, daunorubicin, and epirubicin also carry a high risk, with rates between 15% and 30% for HBsAg-positive patients and greater than 10% for HBsAg-negative or anti-HBc-positive patients. Steroids administered at moderate or high doses for four weeks or longer present a moderate risk for HBsAg-negative or anti-HBc-positive patients but a relatively high risk for HBsAg-positive patients. In contrast, low doses for shorter durations pose lower risks[4]. TKIs like imatinib, dasatinib, and nilotinib carry varying levels of risk, generally ranging from high to moderate, but present a low risk for HBsAg-negative or anti-HBc-positive patients. Immune checkpoint inhibitors such as nivolumab and pembrolizumab pose a high risk for patients with positive HBsAg, with uncertainty regarding those with negative HBsAg or positive anti-HBc patients. Proteasome inhibitor bortezomib presents a moderate risk for both HBsAg-positive and HBsAg-negative or anti-HBc-positive patients, typically falling within the 1%-10% range[5]. According to the most recent guidelines, every patient receiving im-munosuppressive therapy needs to get an HBV screening. Prompt preventive antiviral medication and hepatitis B virus reactivation (HBVr) serological monitoring are part of the management for individuals with low-risk (< 1%) HBVr. For patients with moderate (1%-10%) or high-risk (> 10%) HBVr, management includes antiviral prophylaxis, which must be continued for 18 months after immunosuppressive therapy is stopped[6]. The uncertainties include the risk of new and emerging immunosuppressive and immunomodulators, as well as the exact duration of antiviral treatment. Clinical practitioners need to be vigilant about the possibility of HBVr in individuals on immunosuppressive medication, especially in areas with low endemicity. The management of these patients can be enhanced by putting into practice screening and management programs based on the guidelines proposed, which can improve the adverse outcomes.

PATHOGENESIS OF HBV REACTIVATION

HBV is a member of the hepadnaviridae family. The HBV genome is partially double-stranded circular DNA and is contained in an icosahedral capsid covered by lipid bilayers with three different surface proteins. HBV is transmitted by vertical transmission, sexual contact, blood, and contaminated needles from an infected person. Upon entering the host hepatocytes, the HBV inserts double-stranded DNA (dsDNA) into the nucleus, and the viral polymerase reconstructs dsDNA into long circular DNA (cccDNA)[7]. This cccDNA acts as a model for viral replication and can persist for decades, despite the elimination of host-acute HBV infection and related bacterial reduction (elimination of HBsAg and development of anti-HBc). Despite advances in treatment, it is still difficult to fully eradicate HBV genomic material, including cccDNA. In hepatocytes, even a single copy of cccDNA can cause detectable viremia during reactivation, disrupting the delicate balance between the immune system and viremia.

The presence of cccDNA can cause the reactivation of HBV in any situation, compromising the balance between host immune systems and viral replication. This disturbance can be driven by two causes: A weakening of the host’s immune control by immunosuppression and an increase in HBV viral replication. Any form of immunosuppression interferes with the host immune control of virus replication and can lead to the reactivation of HBV[8]. Clinically, reactivation of HBV due to TKIs is characterized by five different stages[9,10]. The first stage is asymptomatic with elevated viral markers and detectable levels of HBV DNA or a recurrence of HBsAg. Following this, serum HBV DNA levels continued to increase, along with elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, suggesting either HBV reactivation-related hepatitis or a hepatic flare. While many patients remain asymptomatic, some may experience constitutional symptoms and jaundice. The subsequent phase involves either spontaneous or treatment-induced improvement, often characterized by decreased ALT and AST levels after antiviral therapy[11]. However, a few patients progress to a fourth stage marked by impaired hepatic synthetic function, abnormal clotting profiles, and elevated serum bilirubin levels. Fortunately, most patients eventually reach a fifth stage where they recover from HBV reactivation after stopping immunosuppressive therapy and starting antiviral treatment. Nonetheless, severe cases of liver injury may necessitate liver transplantation.

TEMPORAL RELATION BETWEEN HBV REACTIVATION AND THE USAGE OF TYROSIN KINASE-INHIBITORS

The likelihood of HBV reactivation depends on the type of immunosuppressive drugs administered. The intensity of immunosuppression depends mainly on the type, dose, and duration of the immunosuppression therapy. Based on the type of immunosuppressive therapy, the risk of reactivation can be broadly categorized into high risk (≥ 10%), moderate risk (between 1%-10%), and low risk (< 1%)[12]. In the clinical practice guidelines, TKI was classified as a moderate-risk class (1%-10%) of HBV reabsorption. According to the American Society of Clinical Oncology, it is recommended to start antiviral therapy before TKI therapy if HBsAg is positive.

Both large and small-scale studies have demonstrated that TKIs are linked to a heightened risk of HBV reactivation. A recent meta-analysis identified four studies in 268 patients with TKIs. In three studies of 196 HBsAg+ patients, of whom 189 did not receive NA-prophylaxis, the cumulative incidence of HBVr and HBVr-associated hepatitis was 11% and 8%[13-15]. A nationwide case-control study in Taiwan of 733691 patients with HBV found that the use of Bcr-Abl TKI was independently associated with the reactivation of HBV [adjusted hazard ratio (aHR): 1.56; 95% confidence interval (95%CI): 1.11-2.20][16]. Currently, TKIs such as dasatinib, imatinib, nilotinib, and ponatinib are the standard treatments for CML. A study conducted in Taiwan involved 142 adults with CML to assess the rate of HBV reactivation during TKI therapy. The study included patients treated with dasatinib (48 patients, 33.8%), imatinib (43 patients, 30.3%), nilotinib (37 patients, 26.1%), ponatinib (1 patient, 0.7%), and those who received more than two TKIs (13 patients, 9.2%). The mortality rate among 19 patients was 26.3%, and HBV reactivation occurred between 3 and 51 months after starting TKI therapy[17].

HBV reactivation and HBV-related hepatitis incidences among TKI users are not significantly lower compared to those receiving chemotherapy. In a retrospective hospital-based cohort study, researchers investigated HBV reactivation risk in lung cancer patients treated with TKIs. Among the 1960 individuals positive for anti-HBc and undergoing systemic therapy, the 3-year cumulative occurrences of HBV reactivation were similar between those receiving chemotherapy and those treated with TKIs (15.0% vs 21.2%; P = 0.680). The incidences of HBV-related hepatitis were also comparable (15.0% vs 9.3%; P = 0.441). Moreover, among HBsAg-negative TKI users (521 patients), the 3-year cumulative incidence of HBV reactivation was only 0.6%. Multivariable regression analysis identified HBsAg positivity as the sole independent risk factor for HBV reactivation in TKI users, with a hazard ratio of 53.8 (95%CI: 7.0-412.9; P < 0.001)[18].

PREVENTIVE STRATEGIES

Preventing HBVr is crucial, as it is avoidable. Early identification of high-risk patients and prompt initiation of appropriate treatment or vigilant monitoring are vital, as delayed detection or failure to administer prophylaxis can result in severe liver damage and irreversible liver failure, even with subsequent antiviral therapy. Guidelines for diagnosing and treating HBV infection in patients receiving immunosuppressive therapy have been released by several well-known international gastroenterology and hepatology organizations, including the American Gastroenterological Association (AGA), the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), and the Asian Pacific Association for the Study of the Liver (APASL)[19-22]. While there may be slight variations, these guidelines concur on fundamental strategies for preventing HBVr. These tactics include understanding the need to screen patients before starting immunosuppression, estimating the risk of HBVr based on serological status and type of immunosuppressive regimen, and adjusting management strategies accordingly, which may include close monitoring in addition to preventive care or antiviral prophylaxis.

Screening

Most guidelines recommend that all patients receiving immunosuppressive drugs, including HBsAg and anti-HBc, be checked for HBV infection, and that if either is positive, HBV DNA tests be performed. Screening typically involves detecting HBsAg and anti-HBc in the blood, although mutations or rare scenarios may lead to false-negative results[23]. For HBsAg-positive patients without baseline hepatitis, a preventive approach through prophylactic NAT before immunosuppressive therapy is recommended, irrespective of HBV DNA status, since reactivation is highly likely. Conversely, HBsAg-negative and anti-HBc-positive patients undergo varied management based on HBV DNA levels and the immunosuppressive regimen (Table 1). Detectable HBV DNA prompts prophylactic NAT, while undetectable DNA necessitates assessing reactivation risk, with high-risk groups receiving prophylactic NAT and moderate or low-risk groups undergoing pre-emptive treatment with HBV DNA monitoring. HBV vaccination should be contemplated for patients who are negative for HBsAg, anti-HBs, and anti-HBc, as the presence of anti-HBs antibodies could potentially guard against reactivation. The immunization should be given before therapy and, if at all feasible, within three months following the conclusion of therapy. This window of time should be between 0 and 1 to 6 months, or, in the event of an emergency, between 1 and 2 to 12 months[24]. However, isolated cases of reactivation have been reported even in patients who test positive only for anti-hepatitis B surface antibody, underscoring the necessity for careful monitoring and prompt initiation of antiviral therapy when warranted. Overall, a comprehensive screening and management algorithm is essential for effectively mitigating the risk of HBV reactivation in patients undergoing anticancer therapy for hematological malignancies.

Table 1 Risk-based approach to hepatitis B virus reactivation management.

Patient category	Risk of HBV reactivation	Recommended approach
HBsAg-positive patients without hepatitis at baseline	High	Prophylactic NAT before immunosuppressive therapy
HBsAg-negative and anti-HBc-positive patients	Varies; depends on HBV DNA level and immunosuppressive regimen	If HBV DNA detectable: Prophylactic NAT; if HBV DNA undetectable: Assess risk of reactivation; high-risk groups receive prophylactic NAT, moderate/low-risk groups undergo pre-emptive treatment with HBV DNA monitoring
HBsAg-negative/anti-HBc-negative/anti-HBs-negative	Moderate	Consider HBV vaccination; the presence of anti-HBs is associated with a lower risk of reactivation
HBsAg-negative/anti-HBc-negative/anti-HBs-positive	Rare	Monitor closely; occasional reports of reactivation despite anti-HBs positivity

HBV: Hepatitis B virus; HBVr: Hepatitis B virus reactivation; NAT: Nucleos(t)ide analog therapy; HBsAg: Hepatitis B surface antigen; HBc: Hepatitis B core antigen; HBs: Hepatitis B surface antibody.

Pre-exposer prophylaxis

Tailored management based on risk stratification is crucial for preventing HBV reactivation through antiviral prophylaxis. Prophylactic antiviral therapy is recommended for all HBsAg-positive patients at moderate to high risk of HBV reactivation. Similarly, HBsAg-negative patients in high-risk groups should also receive antiviral prophylaxis.

The prevention approach includes monitoring coupled with preemptive therapy or antiviral prophylaxis, customized based on the HBV disease status and the specific immunosuppressive regimen[6]. For patients with resolved HBV infections receiving low- or intermediate-risk medication regimens, or for chronic hepatitis B (CHB) patients receiving treatment with low-reactivation-risk medications, preemptive therapy monitoring is advised. Alternatively, individuals who have recovered from HBV infection and face a heightened risk of reactivation, or CHB patients undergoing medication regimens with intermediate or high risks, might contemplate antiviral prophylaxis[9]. Every one to three months, monitoring methods include routine liver function tests (LFTs), HBsAg, and HBV DNA evaluations. If HBV reactivation is discovered, nucleos(t)ide analogue (NA) therapy is promptly started.

ANTI-VIRAL REGIMEN

For patients requiring antiviral prophylaxis, NA therapy ideally commences 1 week before immunosuppressive therapy initiation. During antiviral prophylaxis, EASL recommends LFT and HBV DNA monitoring every 3-6 months. After stopping immunosuppressive medication, patients should continue receiving NA for 6-12 months; extended periods (12-18 months) are recommended for those receiving B cell-depleting drugs. Monitoring should extend 12 months after NA therapy cessation, according to EASL and AASLD recommendations. In both preventive measures and treatment, NAs with a strong resistance barrier, such as entecavir, tenofovir alafenamide (TAF), or tenofovir disoproxil fumarate (TDF), are favored. In situations involving resolved hepatitis B during high-risk immunosuppressive therapy, it is recommended to consider lamivudine or NAs with a robust resistance barrier[25,26]. TDF/TAF and entecavir are favored due to their lower likelihood of inducing drug-resistant viruses and higher potential for achieving viral suppression, particularly in long-term treatment scenarios.

Studies have demonstrated that entecavir is linked to a reduced occurrence of HBV-related hepatitis and reactivation in comparison to lamivudine[26]. Other therapies can also be used to prevent reactivation of HBV, including telbivudine and adefovir, but these have lower resistance barriers than entecavir and tenofovir. Guidelines advise maintaining antiviral therapy for 1-18 months post-cancer treatment, coupled with vigilant monitoring for HBV reactivation through LFTs and HBV DNA testing. Prophylactic measures are favored over treatment due to the potential for fatal consequences despite therapy[10]. In cases of lamivudine resistance, salvage therapy with entecavir or tenofovir may be necessary. Close monitoring of liver function is crucial as hepatic failure can still occur despite nucleoside analog therapy, especially when antiviral resistance emerges, potentially leading to acute liver failure[27]. Patients with liver failure linked to HBV reactivation may be candidates for liver transplantation. Overall, early detection, appropriate antiviral therapy, and vigilant monitoring are crucial for managing chronic HBV infection and preventing severe complications.

CONCLUSION

In conclusion, HBV reactivation remains a significant concern in oncological patients undergoing immunosuppressive therapy, necessitating comprehensive screening and appropriate management strategies to mitigate adverse outcomes. Prompt identification of high-risk patients and the initiation of antiviral prophylaxis, along with vigilant monitoring of liver function and HBV DNA levels, are crucial components of effective management. While NAT, particularly with entecavir and tenofovir, plays a pivotal role in preventing HBV reactivation, salvage therapy may be necessary in cases of lamivudine resistance. Looking ahead, proactive consideration of HBV reactivation during new drug (immunomodulator) development and future trials incorporating protocolized monitoring and NA therapy will generate valuable data to refine clinical practice. Continuous updates to HBV reactivation prevention recommendations are imperative to ensure optimal patient care in the evolving landscape of immunosuppressive therapy.