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Jonggi Choi, Young-Suk Lim, Characteristics, Prevention, and Management of Hepatitis B Virus (HBV) Reactivation in HBV-Infected Patients Who Require Immunosuppressive Therapy, The Journal of Infectious Diseases, Volume 216, Issue suppl_8, 15 October 2017, Pages S778–S784, https://doi.org/10.1093/infdis/jix178
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Abstract
Hepatitis B virus (HBV) reactivation becomes a challenging issue with increasing use of immunosuppressive agents and cytotoxic chemotherapy for varied medical conditions, including cancer. The spectrum of HBV reactivation in the setting of immunosuppression may vary from asymptomatic reactivation to liver failure leading to death. HBV reactivation can hamper the course of planned therapies and diminish the effects of therapies; thus, it adversely affects the prognosis of the original disease and the survival of the patients. There is mounting evidence that HBV reactivation can be prevented and managed if patients are screened to determine their risk for HBV reactivation and are treated prophylactically before therapy with immunosuppressive agents or cytotoxic chemotherapy is initiated. In this article, we review the diagnostic criteria and clinical outcomes of HBV reactivation, discuss how immunosuppressive therapy may influence the risk of HBV reactivation, and outline strategies to prevent HBV reactivation.
The natural course of hepatitis B virus (HBV) infection is determined by the interaction between viral replication and host immune response. Even in patients with evidence of serological recovery, HBV can be detected in the hepatocytes and peripheral blood mononuclear cells [1]. Therefore, individuals with a history of HBV infection who are receiving immunosuppressive therapy are at risk of HBV reactivation, as well as patients with chronic hepatitis B (CHB). Such reactivation can be asymptomatic or can cause hepatitis (characterized by an increase in serum aminotransferase levels). In severe cases, it can lead to hepatic failure and/or death. In addition, reactivation of HBV may result in discontinuation of immunosuppressive therapy, which may delay the treatment of the underlying disease. This review discusses the pathophysiology, clinical manifestations, diagnosis, risk stratifications, management, and prevention of HBV reactivation in patients receiving immunosuppressive therapy.
PATHOPHYSIOLOGY AND PHASES OF HBV REACTIVATION
HBV infection can be classified as acute or chronic, depending on the persistence of HBV surface antigen (HBsAg). CHB is defined as the persistence of HBsAg for >6 months. To understand the phase and status of HBV infection, it is necessary to correctly interpret serologic markers of HBV. HBsAg and antibody to HBV core antigen (anti-HBc) are currently recommended as serologic markers in screening for HBV reactivation [2–4]. The serum HBV DNA level may be required to assess the replicability of HBV. CHB is indicated by HBsAg and anti-HBc positivity and/or detectable HBV DNA. Past or remote HBV infection is indicated by HBsAg negativity and anti-HBc positivity and/or by anti-HBs positivity with undetectable HBV DNA.
Patients with CHB and patients with a previous history of HBV infection are at risk of reactivation because HBV can remain in the covalently closed circular form after recovery from acute HBV infection, thereby providing a source of HBV reactivation in the future. HBV replication in the liver or in mononuclear cells is controlled by HBV-specific CD4+ helper T cells, CD8+ cytotoxic T cells, and cytokines. Weakened host immunity by immunosuppressive therapy may allow HBV to replicate actively.
Depending on HBV replication, host immune status, and inflammatory activity in the liver, HBV reactivation can be described in 3 phases [5]. In the first phase, with decreased host immunity, HBV replicates vigorously and maintains high levels of serum HBV DNA. However, the degree of inflammation is generally low as host immunity is also suppressed. Consequently, alanine aminotransferase (ALT) levels are not elevated, and patients rarely present with symptoms. Serologically, in the first phase, the serum HBV DNA level can be increased in patients with CHB or detected in patients with CHB in whom HBV DNA was previously undetectable in serum. In patients with past or remote infection (ie, HBsAg-negative, anti-HBc–positive patients), serum HBV DNA can be detected or HBsAg negativity can be converted to HBsAg positivity (known as seroreversion). In the second phase, once host immunity begins to recover, it will actively eliminate HBV, which sometimes leads to severe inflammation accompanied by elevated ALT levels and manifestation of symptoms [5]. Hepatocellular injury may occur at this stage, ranging from mild hepatitis to hepatic failure. Since this second phase results from the reconstitution of the host immune system, it occurs after the completion of immunosuppressive therapy; however, this may occur between chemotherapy cycles [6]. In the third phase, inflammation ceases either spontaneously, by administering antiviral treatment, or by withholding immunosuppressive therapy.
DEFINITION OF HBV REACTIVATION
Although there have been many studies regarding HBV reactivation, various definitions of reactivation have been used, and no unified terminology has yet been established. Traditionally, hepatitis was defined as an ALT level that increased by ≥3-fold to >100 IU/L, and HBV reactivation was defined as a >10-fold increase in the HBV DNA level or the appearance of HBV DNA in patients with previously undetectable HBV DNA. In 2013, the American Association for the Study of the Liver Disease proposed the following standardized nomenclature for HBV reactivation in patients receiving immunosuppressive therapy [4, 7]. HBV reactivation was defined as exacerbation of CHB or reactivation of past HBV infection after initiation of immunosuppressive therapy. Exacerbation of CHB was defined as HBsAg positivity plus a ≥2-log increase in the HBV DNA level in individuals positive for HBV DNA at baseline, an HBV DNA level of >100 IU/mL in individuals in whom HBV DNA was undetectable at baseline, or an HBV DNA level of ≥100000 IU/mL in individuals who did not undergo HBV DNA testing at baseline. Reactivation of past HBV infection was defined as reappearance of HBsAg in individuals who were previously negative for HBsAg, appearance of HBV DNA in HBsAg-negative individuals, or detection of HBV DNA in individuals in whom HBV DNA was previously undetectable.
One thing to consider is a differential diagnosis of HBV reactivation with other possible conditions presenting similar clinical features, such as toxic hepatitis due to an immunosuppressive regimen, coinfection with other viruses, or other liver diseases. Therefore, an accurate diagnosis of HBV reactivation requires the correct interpretation of HBV serologic findings and results of relevant laboratory tests.
CLINICAL MANIFESTATION OF HBV REACTIVATION
The clinical manifestations of HBV reactivation span a wide spectrum, from no symptoms to acute liver failure leading to death. Although no unified terminology has been introduced to describe the clinical pictures of HBV reactivation, asymptomatic flare in the HBV DNA level, biochemical hepatitis, clinical hepatitis, and acute liver failure describe most clinical pictures of reactivation based on its severity. Asymptomatic flare in the HBV DNA level represents high-level or reappearance of HBV DNA without an elevated ALT level or symptoms. Biochemical hepatitis refers to evidence of an elevated ALT level, when the patient is asymptomatic. Clinical hepatitis can present with various symptoms, such as fatigue, malaise, and jaundice, with elevated HBV DNA and ALT levels. Severe progression or improper management of HBV reactivation can lead to acute liver failure. Consequently, HBV reactivation may disrupt planned immunosuppressive therapy, resulting in progression of underlying disease. A prospective study of 41 patients with breast cancer who were receiving chemotherapy showed premature termination of chemotherapy or a delay in the treatment schedule in 71% with HBV reactivation but only 33% without reactivation [8].
FACTORS DETERMINING HBV REACTIVATION
Viral Factors
HBV replication status prior to the commencement of immunosuppressive therapy is an important risk factor for HBV reactivation. HBsAg-positive patients with a high level of HBV DNA are more likely to develop HBV reactivation than those with low-level HBV DNA and are also associated with a high risk of reactivation after completion of antiviral prophylaxis [9]. Generally, patients with CHB (ie, those who are HBsAg positive) are more likely to develop HBV reactivation than patients with past or remote HBV infection (ie, HBsAg-negative, anti-HBc–positive patients). In a study of 100 patients with lymphoma receiving chemotherapy, HBV reactivation occurred in 48% of HBsAg-positive patients, 4% of HBsAg-negative, anti-HBc–positive patients, and 0% of HBsAg-negative, anti-HBc–negative patients; the rates of liver failure were 7% in HBsAg-positive patients, 2% in HBsAg-negative, anti-HBc–positive patients, and 0% in HBsAg-negative, anti-HBc–negative patients [10]. In a prospective study of 244 HBsAg-negative patients treated with chemotherapy for lymphoma, HBV reactivation developed in 3% [11].
Host Factors
Young age and male sex have been found to be risk factors for HBV reactivation [12], but another study reported old age as a risk factor [9]. The effect of age and sex on the risk of HBV reactivation thus remains unclear.
Underlying Diseases
Hematologic Malignancies
HBV reactivation has been well studied in patients receiving chemotherapy for hematologic malignancies, especially non-Hodgkin lymphoma [10, 13, 14]. An early study reported a high incidence of HBsAg positivity among patients with non-Hodgkin lymphoma [15], suggesting that HBV may play a role in the carcinogenesis of lymphoma. However, it is still unclear whether lymphoma confers a higher risk for HBV reactivation than other cancers or whether high reactivation rates in patients with lymphoma are due to the high intensity of cytotoxic chemotherapy. In patients receiving immunosuppressive treatment for acute or chronic leukemia and multiple myeloma, HBV reactivation has been reported with an incidence of 3%–61%, depending on chemotherapy regimen and the host’s HBV-associated serologic findings [16].
Solid Tumor
Breast cancer is associated with a 25%–40% incidence of HBV reactivation [8, 17]. Anthracycline and corticosteroids, which are shown to increase HBV replication, are commonly used in chemotherapy for breast cancer (41%), resulting in a higher rate of HBV reactivation as compared to other solid cancers (7%–29%) [18].
Hematopoietic Stem Cell Transplantation (HSCT)
Performance of HSCT for treatment of hematologic malignancy requires stronger immunosuppression and a longer duration of immunosuppressive therapy. In addition, unique conditions, such as engraftment, posttransplantation immunosuppression, and reconstitution of immune system, should be considered in the risk of HBV reactivation. In 33 HBsAg-positive patients receiving HSCT, 19 (57.6%) developed HBV reactivation, and 1 died of liver failure [19]. In a retrospective study with 137 HBsAg-negative, anti-HBc–positive patients who underwent HSCT, the HBV reactivation rate was 10%, and reactivation occurred at a median of 19 months after HSCT. In this study, treatment with rituximab was associated with an increased risk of HBV reactivation [20].
Solid Organ Transplantation
Patients who have undergone solid organ transplantation need long-term immunosuppression, which exposes the patients to an increased risk of HBV reactivation. The reported incidence of HBV reactivation among renal transplant recipients ranged from 50% to 90% in HBsAg-positive patients [21] and from 0.9% to 5% in HBsAg-negative, anti-HBc–positive patients [22]. A case series of HBV reactivation was also reported in recipients of other organ transplants, including lung, pancreas, or heart [23]. HPB reactivation after liver transplantation may be regarded as different category than that occurring after other types of organ transplantation. Because a considerable number of liver transplantations for treatment of cirrhosis or hepatocellular carcinoma (HCC) involve HBV-infected individuals, such patients are at risk of HBV reactivation and graft loss. This special setting is beyond the scope of this review, and guidelines by the American Association for the Study of the Liver Disease provide a more detailed review and recommendations [24].
HCC
The incidence of HBV reactivation in patients with HCC varies from 4% to 67% [25]. Many cases of HCC involve patients with liver cirrhosis, whose livers have a limited functional reserve. Therefore, HBV reactivation can negatively affect morbidity and mortality by deteriorating remnant liver function or by interrupting planned therapy. Indeed, HBV reactivation can occur during various anticancer treatments for HCC, such as hepatectomy, local ablation, systemic chemotherapy, radiation therapy, and transarterial chemoembolization (TACE) [26]. Although TACE is a local modality treatment, it does have systemic effects, such as those associated with the establishment of an arteriovenous shunt or peritumoral microcirculation [27], and it is therefore a risk factor for HBV reactivation [26]. In 83 HBsAg-positive patients with HCC who were treated with TACE, 28 (33.7%) had HBV reactivation, and 3 died of hepatic decompensation [26]. Of 109 HBsAg-negative patients treated with TACE, 12 (11%) showed HBV reactivation [27]. Of the 12 patients with HBV reactivation, 4 developed clinical hepatitis, and 1 experienced hepatic decompensation [27].
Rheumatologic Disease
Reported incidences of HBV reactivation in patients with rheumatologic disease, particularly rheumatoid arthritis, were 12.3% in HBsAg-positive patients [28] and 3%–5% in HBsAg-negative, anti-HBc–positive patients [29]. Because of wide use of tumor necrosis factor α (TNF-α) inhibitors and other biological agents, HBV reactivation in this setting has been frequently reported [30].
Inflammatory Bowel Disease
HBV reactivation rates in patients with inflammatory bowel disease range from 0.6% to 36% for HBsAg-positive patients and from 1.6% to 42% for HBsAg-negative, anti-HBc–positive patients [31]. In earlier studies, HBV reactivation was reported in patients receiving traditional immunosuppressants and/or corticosteroids. Since the introduction of TNF-α inhibitors and other biologic agents, HBV reactivation has been reported through case series, with hepatic failures in some of the cases [32, 33].
TYPES OF IMMUNOSUPPRESSIVE THERAPY
Systemic Chemotherapy
Theoretically, most chemotherapeutic agents can induce HBV reactivation, as they suppress host immune system. However, the actual impact on HBV reactivation varies depending on the degree of immunosuppression, concomitant use of other immunomodulatory agents, and chemotherapy regimen (ie, dose, cycle, and interval). Anthracyclines, such as doxorubicin, daunorubicin, epirubicin, and idarubicin, have been associated with a risk of HBV reactivation [8, 17]. According to the American Gastroenterological Association 2015 guidelines, anthracyclines were classified as conferring a moderate risk for HBV reactivation in HBsAg-negative, anti-HBc–positive patients and a high risk in HBsAg-positive patients [2, 34].
Traditional Immunosuppressive Agents
Traditional immunosuppressant agents, such as azathioprine, 6-mercaptopurine, and methotrexate, have long been used in rheumatic diseases, inflammatory bowel disease, and other autoimmune diseases. Only a small number of cases of HBV reactivation in these settings have been reported. According to the American Gastroenterological Association 2015 guidelines, these traditional immunosuppressants are regarded as having a low risk of HBV reactivation (<1%) [34].
TNF-α Inhibitors
TNF-α inhibitors are approved for the treatment of inflammatory bowel disease, psoriasis, and rheumatoid arthritis. In a retrospective study of 80 patients with Crohn disease treated with infliximab, 2 of 3 experiencing HBV reactivation developed severe hepatitis, and 1 died [32]. A large case series of 257 patients receiving TNF-α inhibitors for various diagnoses reported that HBV reactivation occurred in 37% of patients who were HBsAg positive, whereas only 5% of HBsAg-negative, anti-HBc–positive positive patients experienced reactivation. In this case series, 5 patients developed acute liver failure, and 4 subsequently died [35]. TNF-α inhibitors are considered to have a low-to-moderate risk of HBV reactivation [34]. Etanercept and adalimumab can be considered to confer a likelihood of HBV reactivation similar to that of infliximab, given that these drugs have the same target as infliximab. In a prospective study of 67 HBsAg-negative, anti-HBc–positive patients treated with TNF-α inhibitors for rheumatoid arthritis (25 with infliximab, 23 with etanercept, and 19 with adalimumab), there was no HBV reactivation during treatment, with a mean follow-up of 42.5 months [36].
Other Biological Agents
Tyrosine kinase inhibitors, such as imatinib and nilotinib, have recently been introduced for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. There have been few available data regarding the association between these agents and the risk of HBV reactivation. An anti-CD52 agent, alemtuzumab, which is approved for use in refractory chronic lymphocytic leukemia, stem cell transplantation, and solid organ transplantation, is reported to cause HBV reactivation [37, 38].
Corticosteroids
Among the most commonly used immunomodulatory agents are corticosteroids. Corticosteroids not only suppress cytotoxic T-cell function, but also induce direct activation of corticosteroid-responsive HBV genes, thereby increasing HBV replication and reactivation [39, 40]. In a randomized trial of 50 HBsAg-positive patients with non-Hodgkin lymphoma, patients were randomly assigned to receive conventional chemotherapy with or without prednisone. A significantly higher rate of HBV reactivation was observed in patients treated with prednisone (73%), compared with patients treated with prednisone-free regimen [41].
There is a gray zone stratifying the risk in patients receiving corticosteroids, because the regimen, particularly the doses and intervals, varies widely depending on the indication and the response to treatment. In addition, corticosteroids have commonly been used with other immunosuppressive therapies as a component of the regimen. When stratifying the risk of HBV reactivation, the dose and duration of corticosteroid exposure should be considered first. Current guidelines suggest <10 mg of prednisone (or the equivalent) for low doses, 10–20 mg for moderate doses, and >20 mg for high doses [2]. Regarding the duration of corticosteroid treatment, long-term use refers to use for >4 weeks, whereas short-term use refers to use for <1 week [2, 34]. Table 1 summarizes the risk of HBV reactivation with respect to the dose and duration of corticosteroid use. With regard to other administration routes of corticosteroids, such as topical use, inhalation, or intraarticular injection, available data are too limited to draw firm recommendations.
2015 American Gastroenterological Association Guidelines on the Risk for and Prevention of Hepatitis B Virus (HBV) Reactivation, by Immunosuppressive Agent and HBV Surface Antigen (HBsAg) and Antibody to HBV Core Antigen (Anti-HBc) Status
| Immunosuppressant Type(s) . | Agent(s) . | HBsAg-Positive, Anti-HBc–Positive Patients . | HBsAg-Negative, Anti-HBc–Positive Patients . | ||
|---|---|---|---|---|---|
| Reactivation Risk . | Recommendations . | Reactivation Risk . | Recommendations . | ||
| B-cell–depleting agents | Rituximab, ofatumumab | High | Prophylaxis | High | Prophylaxis |
| Anthracycline derivatives | Doxorubicin, epirubicin | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| TNF-α inhibitors | Etanercept, adalimumab, certolizumab, infliximab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Cytokine inhibitors and integrin inhibitors | Abatacept, ustekinumab, natalizumab, vedolizumab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Tyrosine kinase inhibitors | Imatinib, nilotinib | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Corticosteroids | |||||
| Duration, ≥4 wk | |||||
| Moderate/high dose | … | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| Low dose | … | Moderate | Prophylaxis or close monitoring | Low | Usual care |
| Duration, ≤1 wk | … | Low | Usual care | Low | Usual care |
| Traditional immunosuppressants | Azathioprine, 6-mercaptopurine, methotrexate | Low | Usual care | Low | Usual care |
| Immunosuppressant Type(s) . | Agent(s) . | HBsAg-Positive, Anti-HBc–Positive Patients . | HBsAg-Negative, Anti-HBc–Positive Patients . | ||
|---|---|---|---|---|---|
| Reactivation Risk . | Recommendations . | Reactivation Risk . | Recommendations . | ||
| B-cell–depleting agents | Rituximab, ofatumumab | High | Prophylaxis | High | Prophylaxis |
| Anthracycline derivatives | Doxorubicin, epirubicin | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| TNF-α inhibitors | Etanercept, adalimumab, certolizumab, infliximab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Cytokine inhibitors and integrin inhibitors | Abatacept, ustekinumab, natalizumab, vedolizumab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Tyrosine kinase inhibitors | Imatinib, nilotinib | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Corticosteroids | |||||
| Duration, ≥4 wk | |||||
| Moderate/high dose | … | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| Low dose | … | Moderate | Prophylaxis or close monitoring | Low | Usual care |
| Duration, ≤1 wk | … | Low | Usual care | Low | Usual care |
| Traditional immunosuppressants | Azathioprine, 6-mercaptopurine, methotrexate | Low | Usual care | Low | Usual care |
Data are from [34].
aTotal daily dose of prednisone (or equivalent): low dose, <10 mg; moderate dose, 10–20 mg; high dose, >20 mg.
2015 American Gastroenterological Association Guidelines on the Risk for and Prevention of Hepatitis B Virus (HBV) Reactivation, by Immunosuppressive Agent and HBV Surface Antigen (HBsAg) and Antibody to HBV Core Antigen (Anti-HBc) Status
| Immunosuppressant Type(s) . | Agent(s) . | HBsAg-Positive, Anti-HBc–Positive Patients . | HBsAg-Negative, Anti-HBc–Positive Patients . | ||
|---|---|---|---|---|---|
| Reactivation Risk . | Recommendations . | Reactivation Risk . | Recommendations . | ||
| B-cell–depleting agents | Rituximab, ofatumumab | High | Prophylaxis | High | Prophylaxis |
| Anthracycline derivatives | Doxorubicin, epirubicin | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| TNF-α inhibitors | Etanercept, adalimumab, certolizumab, infliximab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Cytokine inhibitors and integrin inhibitors | Abatacept, ustekinumab, natalizumab, vedolizumab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Tyrosine kinase inhibitors | Imatinib, nilotinib | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Corticosteroids | |||||
| Duration, ≥4 wk | |||||
| Moderate/high dose | … | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| Low dose | … | Moderate | Prophylaxis or close monitoring | Low | Usual care |
| Duration, ≤1 wk | … | Low | Usual care | Low | Usual care |
| Traditional immunosuppressants | Azathioprine, 6-mercaptopurine, methotrexate | Low | Usual care | Low | Usual care |
| Immunosuppressant Type(s) . | Agent(s) . | HBsAg-Positive, Anti-HBc–Positive Patients . | HBsAg-Negative, Anti-HBc–Positive Patients . | ||
|---|---|---|---|---|---|
| Reactivation Risk . | Recommendations . | Reactivation Risk . | Recommendations . | ||
| B-cell–depleting agents | Rituximab, ofatumumab | High | Prophylaxis | High | Prophylaxis |
| Anthracycline derivatives | Doxorubicin, epirubicin | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| TNF-α inhibitors | Etanercept, adalimumab, certolizumab, infliximab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Cytokine inhibitors and integrin inhibitors | Abatacept, ustekinumab, natalizumab, vedolizumab | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Tyrosine kinase inhibitors | Imatinib, nilotinib | Moderate | Prophylaxis or close monitoring | Moderate | Prophylaxis or close monitoring |
| Corticosteroids | |||||
| Duration, ≥4 wk | |||||
| Moderate/high dose | … | High | Prophylaxis | Moderate | Prophylaxis or close monitoring |
| Low dose | … | Moderate | Prophylaxis or close monitoring | Low | Usual care |
| Duration, ≤1 wk | … | Low | Usual care | Low | Usual care |
| Traditional immunosuppressants | Azathioprine, 6-mercaptopurine, methotrexate | Low | Usual care | Low | Usual care |
Data are from [34].
aTotal daily dose of prednisone (or equivalent): low dose, <10 mg; moderate dose, 10–20 mg; high dose, >20 mg.
Anti-CD20 Antibodies (Rituximab)
B-cell–depleting agents, such as anti-CD20 antibodies, are considered to carry the highest risk of HBV reactivation. Rituximab and ofatumumab represent this class of drugs, but rituximab has been more extensively studied in the setting of hematologic malignancies. A study of 46 HBsAg-negative, anti-HBc–positive patients with lymphoma showed that 24% who were treated with rituximab had HBV reactivation, whereas none who were treated without rituximab experienced reactivation [42]. A meta-analysis of cases in a Food and Drug Administration (FDA) safety report demonstrated that rituximab-based therapy showed an increased risk of HBV reactivation (pooled odds ratio, 5.7), compared with immunosuppressive therapy without rituximab [14]. So far, 109 cases of fatal HBV-related liver failure associated with rituximab or ofatumumab was reported in a postmarketing data from the FDA Adverse Event Reporting System. Now it is recommended that all patients who plan to receive anti-CD20 agents should be screened for HBsAg and anti-HBc. Interestingly, HBV reactivation may occur ≥12 months after rituximab use [43], which confers prolonged immunosuppression and recovery by rituximab. Thus, it is recommended that antiviral prophylaxis be administered at least 12 months after completion of rituximab.
PREVENTION OF HBV REACTIVATION
Screening Strategy
Prior to initiation of immunosuppressive therapy, screening for HBV is essential to prevent HBV reactivation. The purpose of HBV screening is to identify patients at risk of HBV reactivation and initiate treatment with antiviral agents to prevent reactivation. One study reported that <20% of patients with HBV-associated risk factors were screened at the onset of chemotherapy [44]. Although a consensus has made regarding the need for HBV screening in patients who plan to receive immunosuppressive therapy, there is controversy as to whether universal screening is a better approach than risk-based screening. While the risk-based approach focuses more on the cost-effectiveness aspects of HBV screening, universal screening might be better because of the serious consequences of HBV reactivation and the lower effectiveness of the risk-based approach in real practice. In HBV-endemic areas or countries, a universal screening strategy might be more beneficial, considering the high prevalence of HBV infection, low awareness for HBV infection, and availability of highly efficacious prophylaxis with minimal toxicity. As discussed earlier, screening by serologic testing should include tests for HBsAg and anti-HBc, and serum HBV DNA screening may also be necessary in patients with CHB.
Risk Stratification of HBV Reactivation
Table 1 summarizes HBV treatment recommendations, by risk of HBV reactivation, in various clinical settings.
Low-Risk Patients
Low-risk patients may receive usual medical care.
Moderate-Risk Patients
Moderate-risk patients can be treated with antiviral prophylaxis or monitored closely. When monitoring, follow-up with HBV serologic testing should be performed on a regular basis of 3–6 months. Once there is evidence of HBV reactivation, treatment with antiviral agents should be initiated immediately.
High-Risk Patients
Patients in this category should be treated with prophylactic antiviral therapy before or concurrently at the initiation of immunosuppressive treatment with entecavir or tenofovir.
Based on the risk for HBV reactivation, Table 2 summarizes screening and monitoring strategies for prevention of reactivation.
Screening and Monitoring Strategies for Prevention of Hepatitis B Virus (HBV) Reactivation in the Setting of Immunosuppressive Therapy
| Variable . | Comments . |
|---|---|
| Screening | |
| Target population | Persons at high or moderate risk for HBV infectiona |
| Test targetsb | HBsAg, anti-HBc; HBV DNA if HBsAg is detected |
| Timing | Before initiating immunosuppressive therapy |
| Monitoring | |
| Test targets | HBsAg, ALT, HBV DNA |
| Timing | Every 3 moc until at least 6 mo after completion of immunosuppressive therapy (consider monitoring until 12 mo after completion of treatment if anti-CD20 agent is used) |
| Variable . | Comments . |
|---|---|
| Screening | |
| Target population | Persons at high or moderate risk for HBV infectiona |
| Test targetsb | HBsAg, anti-HBc; HBV DNA if HBsAg is detected |
| Timing | Before initiating immunosuppressive therapy |
| Monitoring | |
| Test targets | HBsAg, ALT, HBV DNA |
| Timing | Every 3 moc until at least 6 mo after completion of immunosuppressive therapy (consider monitoring until 12 mo after completion of treatment if anti-CD20 agent is used) |
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to HBV core antigen; HBsAg, HBV surface antigen.
aUniversal screening may beneficial in an area where HBV is endemic.
bThe role of antibody to HBV surface antigen for screening in the setting of immunosuppressive therapy is unclear.
cMonitoring interval can be shortened to 1–2 mo, depending on the presence of HBV reactivation.
Screening and Monitoring Strategies for Prevention of Hepatitis B Virus (HBV) Reactivation in the Setting of Immunosuppressive Therapy
| Variable . | Comments . |
|---|---|
| Screening | |
| Target population | Persons at high or moderate risk for HBV infectiona |
| Test targetsb | HBsAg, anti-HBc; HBV DNA if HBsAg is detected |
| Timing | Before initiating immunosuppressive therapy |
| Monitoring | |
| Test targets | HBsAg, ALT, HBV DNA |
| Timing | Every 3 moc until at least 6 mo after completion of immunosuppressive therapy (consider monitoring until 12 mo after completion of treatment if anti-CD20 agent is used) |
| Variable . | Comments . |
|---|---|
| Screening | |
| Target population | Persons at high or moderate risk for HBV infectiona |
| Test targetsb | HBsAg, anti-HBc; HBV DNA if HBsAg is detected |
| Timing | Before initiating immunosuppressive therapy |
| Monitoring | |
| Test targets | HBsAg, ALT, HBV DNA |
| Timing | Every 3 moc until at least 6 mo after completion of immunosuppressive therapy (consider monitoring until 12 mo after completion of treatment if anti-CD20 agent is used) |
Abbreviations: ALT, alanine aminotransferase; anti-HBc, antibody to HBV core antigen; HBsAg, HBV surface antigen.
aUniversal screening may beneficial in an area where HBV is endemic.
bThe role of antibody to HBV surface antigen for screening in the setting of immunosuppressive therapy is unclear.
cMonitoring interval can be shortened to 1–2 mo, depending on the presence of HBV reactivation.
Prophylaxis Versus Preemptive Therapy
Prophylactic antiviral therapy refers to treatment commenced prior to or concurrently with the initiation of immunosuppressive treatment, whereas preemptive therapy indicates starting antiviral therapy as soon as serologic or laboratory clues of HBV reactivation (ie, detection or increased level of HBV DNA or increased level of ALT) are evident during close monitoring. A meta-analysis of 14 studies reviewing HBsAg-positive patient with cancer who were receiving chemotherapy demonstrated that patients who received prophylactic lamivudine treatment had a lower rate of HBV reactivation (4% of patients), liver failure (0%), and mortality (2%) than patients who did not receive prophylaxis (37% for reactivation, 13% for liver failure, and 7% for mortality) [45]. A randomized study of 52 HBsAg-positive patients treated with chemotherapy for non-Hodgkin lymphoma also showed a lower incidence of HBV reactivation in the prophylactic lamivudine group (12% of patients), compared with the preemptive lamivudine group (56%) [13]. Another randomized study comparing prophylactic entecavir with preemptive entecavir treatment in patients with lymphoma who were receiving rituximab-containing chemotherapy showed a lower rate of HBV reactivation in the prophylactic entecavir group (2.4% of patients), compared with the preemptive entecavir group (17.9%) [46]. A randomized trial of 73 HBsAg-positive patients with HCC who were treated with TACE compared prophylaxis with lamivudine and deferred therapy and showed a higher HBV reactivation rate (29.7%) among patients who received deferred therapy, compared with patients who received prophylaxis (2.8%) [47]. These studies demonstrate that prophylactic antiviral therapy is more efficacious than preemptive treatment in HBsAg-positive patients and HBsAg-negative, anti-HBc–positive patients.
Choice of Antiviral Agents
Currently, 5 nucleos(t)ide analogues are available for the treatment of CHB. Of these, lamivudine and entecavir have been studied in the setting of immunosuppression. Considering the high rate of resistance to lamivudine, lamivudine is no longer considered preferable for the prevention of HBV reactivation. Entecavir or tenofovir disoproxil fumarate should be considered as first-line treatment, as these agents have high antiviral potency and a lower rate of resistance even after long-time use. Indeed, a study of 123 patients with lymphoma showed that, compared with lamivudine, prophylactic entecavir had a lower rate of HBV reactivation (0% vs 12.4%), hepatitis (5.9% vs 28.0%), and disruption of chemotherapy (5.9% vs 20.2%) [48].
Duration of Prophylactic Antiviral Therapy
Little is known about when prophylactic antiviral therapy can be ceased safely. In a retrospective study of 46 HBsAg-positive patients with hematologic malignancies, the cumulative probability of HBV reactivation was reported to be 33% when lamivudine prophylaxis was stopped 3 months after completion of chemotherapy [49]. In addition, HBV reactivation can occur 3–6 months after completion of immunosuppressive therapy and, when rituximab is used, as late as 17 months after completion [50]. A retrospective study of 127 HBsAg-positive cancer patients who received antiviral prophylaxis reported the cumulative incidence of HBV reactivation at 1 and 2 years after withdrawal of prophylaxis to be 14.3% and 22.4%, respectively. In this report, 74.1% of patients with HBV reactivation had lymphoma, of whom approximately half received rituximab-containing chemotherapy. Therefore, current guidelines recommend that use of antiviral therapy for 6 months after completion of immunosuppressive therapy may be sufficient for preventing HBV reactivation; however, for patients using anti-CD20 agents, antiviral prophylaxis for 12 months is recommended [2, 3].
SUMMARY
HBV reactivation can occur in patients with CHB during immunosuppressive therapy, as well as in patients with past HBV infection during or after immunosuppressive therapy, leading to symptoms ranging from asymptomatic fares in the HBV level to liver failure. Screening for HBV reactivation should be encouraged for patients who plan to receive immunosuppressive therapy, and risk stratification for reactivation, based on host and viral factors, as well as the duration and type of immunosuppressive therapy, should precede treatment initiation. Prophylactic antiviral therapy is generally more efficacious than preemptive therapy in high-risk patients and in some moderate-risk patients. Entecavir or tenofovir is the preferred antiviral agent for prophylaxis, owing to its high potency and low rate of resistance. Antiviral prophylaxis should be maintained for at least 6 months after completion of immunosuppressive therapy or for 12 months in patients receiving immunosuppressive anti-CD20 agents.
Notes
Acknowledgment. We thank Joon Seo Lim, PhD, of the Scientific Publication Team at Asan Medical Center, Seoul, Korea, for providing proofreading assistance.
Financial support. This work was supported by the Korean National Health Clinical Research Project (grant HC15C3380) and the Korean Health Technology Research and Development Project (grants HI14C1061 and HI17C1862), Ministry of Health and Welfare, Republic of Korea; and by the Proteogenomic Research Program, through the National Research Foundation of Korea, funded by the Korea government.
Supplement sponsorship. This work is part of a supplement sponsored by the Hepatitis Research Center at the National Taiwan University Hospital.
Potential conflicts of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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