Hepatitis B virus (HBV) reactivation (HBVr) has been an increasingly recognized and appreciated risk of immunosuppressive therapies in rheumatic patients. Despite its potential for significant morbidity and mortality, HBVr is a fully preventable complication with appropriate pretreatment screening and close monitoring of susceptible patients. Better knowledge of the risk for HBVr with the different antirheumatic agents and the establishment of the new-generation oral antivirals in clinical practice has greatly improved the design of screening and therapeutic algorithms. In this review, all available data regarding HBVr in rheumatic patients are critically presented and a screening and therapeutic algorithm is proposed.
Key points
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The risk for hepatitis B virus (HBV) reactivation (HBVr) is high for rheumatic patients with chronic infection treated with high-dose corticosteroids (CS), tumor necrosis factor inhibitors, and rituximab (RTX) without antiviral prophylaxis, whereas it seems to be minimal for patients with past HBV infection.
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HBV serologic screening is required for almost all rheumatic patients before immunosuppressive therapies.
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Prophylactic antiviral therapy with the new-generation antivirals, such as entecavir and tenofovir, is required for all patients starting long-term CS and biologics.
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Patients with past HBV infection receiving high-risk therapy, such as RTX, should be screened and monitored by HBV DNA measurements and treated when HBVr is documented.
Introduction
The risk for hepatitis B virus (HBV) reactivation (HBVr) during immunosuppressive therapy in patients with chronic or less frequently past HBV infection is increasingly recognized today in different disciplines of medicine, including rheumatology. HBVr during immunosuppressive therapy can range from an asymptomatic increase in HBV DNA levels to fatal hepatic failure. Better screening and monitoring of HBV-infected patients, as well as early management of HBV infection with the last-generation oral antivirals, has greatly improved the outcome of HBVr in this setting. Here the authors review the existing literature on HBVr in rheumatic patients and propose a screening and management algorithm for patients at risk.
Introduction
The risk for hepatitis B virus (HBV) reactivation (HBVr) during immunosuppressive therapy in patients with chronic or less frequently past HBV infection is increasingly recognized today in different disciplines of medicine, including rheumatology. HBVr during immunosuppressive therapy can range from an asymptomatic increase in HBV DNA levels to fatal hepatic failure. Better screening and monitoring of HBV-infected patients, as well as early management of HBV infection with the last-generation oral antivirals, has greatly improved the outcome of HBVr in this setting. Here the authors review the existing literature on HBVr in rheumatic patients and propose a screening and management algorithm for patients at risk.
Epidemiology of chronic and past hepatitis B virus infection
HBV is a partially double-stranded DNA virus primarily infecting humans through the parenteral route. Most chronically infected patients have acquired the virus either perinatally (in areas of high endemicity: >7%) or through horizontal transmission during childhood (in areas of intermediate endemicity: 2%–7%). Exposure during adulthood (through unprotected sexual intercourse, intravenous drug use, or occupational exposure) rarely leads to chronic infection (<5%). With the introduction of efficient preventive measures, such as universal vaccination of infants, prevention of perinatal transmission, and vaccination of high-risk adults, several studies have shown a decrease in the incidence of acute HBV infection that is not yet followed by a similar reduction in the sequelae of chronic disease.
The prevalence of chronic HBV infection varies worldwide and is highest in sub-Saharan Africa and East Asia (5%–10%) and lowest in Western Europe and North America (<1%). It has to be noted that even in low endemic areas, such as the United States, the prevalence of chronic HBV infection may be significantly higher in specific groups, such as immigrants and institutionalized and incarcerated individuals. A similar geographic variation has been found in the prevalence of resolved HBV infection, with less than 5% of the population in North America having past exposure to the virus, whereas the respective rate exceeds 50% in areas of high endemicity.
Most studies indicate that the rates of chronic and resolved HBV infection in rheumatic patients follow the patterns of the general population. In 2 recent, large, multiethnic, cross-sectional studies in rheumatoid arthritis (RA) and spondyloarthritis, the prevalence of chronic HBV infection was estimated at 3.0% and 3.5%, respectively, although percentages up to 12% in some participating countries were recorded. Similarly, the prevalence of resolved HBV infection ranged between 13% and 15% in European, 25% to 30% in Japanese, and 50% in Chinese cohorts of patients with RA.
Diagnosis and classification of hepatitis B virus infection
The diagnosis of HBV infection relies mainly on serology (hepatitis B surface antigen [HBsAg], hepatitis B envelope antigen [HBeAg], anti-HBs, anti-HBc [hepatitis B core antibody] and anti-HBe antibodies) and serum HBV DNA levels. Serologic tests are used for the differentiation between acute, chronic, or past (resolved) infection, whereas HBV DNA levels are required for distinguishing active chronic hepatitis from the inactive carrier state in chronically infected patients as well as for the detection of occult infection in resolved HBV infection ( Table 1 ).
| Acute Hepatitis | Chronic Infection | Past (Resolved) Infection | |||
|---|---|---|---|---|---|
| Chronic Hepatitis | Inactive Carrier State | ||||
| HBeAg Positive | HBeAg Negative | ||||
| HBsAg | + | + | + | + | − |
| Anti-HBc (total) | + | + | + | + | + |
| Anti-HBs | − | − | − | − | ± |
| Anti-HBc IgM | + | − | − | − | − |
| HBeAg | + | + | − | − | − |
| Anti-HBe | − | − | + | ± | + |
| ALT | ↑↑↑ (usually >10× ULN) | ↑ | ↑ | Normal | Normal |
| HBV DNA | >20,000 IU/mL a | >20,000 IU/mL | >2,000 IU/mL | Undetectable or <2,000 IU/mL | Undetectable b |
a Usually greater than 10 6 IU/mL.
b In patients with occult infection, HBV DNA can be detected in the liver or in the serum (<200 IU/mL).
More specifically:
- 1.
Acute hepatitis B is characterized by high aminotransferases (alanine aminotransferase [ALT] >10× the upper limit of normal [ULN]) and positive HBsAg and IgM anti-HBc antibodies. These patients are rarely encountered in rheumatology practice.
- 2.
The chronic HBV infection definition requires the presence of HBsAg in the serum for greater than 6 months. Most of these patients (70%–80%) are inactive HBV carriers (normal ALT levels, low or undetectable serum HBV DNA) who rarely develop cirrhosis or its complications, whereas spontaneous clearance of HBsAg gradually occurs (1% per year). Approximately 20% to 30% of chronically infected patients though have active chronic hepatitis B (defined by elevated ALT and HBV DNA levels) and, if left untreated, progress to cirrhosis and hepatocellular carcinoma. Two major subsets of chronic hepatitis B are recognized: HBeAg positive and negative.
- 3.
Past or resolved HBV infection is defined by negative HBsAg and positive anti-HBc (total) antibodies in the serum (with or without anti-HBs antibodies). Approximately 5% to 50% of rheumatic patients worldwide demonstrate this serologic profile. Among these patients, a small subset (<5%) can have occult HBV infection defined by the presence of HBV DNA in the liver and occasionally in low levels in the serum (<200 IU/mL). This group of patients is challenging because they can rarely develop HBVr with immunosuppression.
Pathogenesis and natural course of hepatitis B virus reactivation
Hepatocyte injury during acute or chronic HBV infection manifested by ALT elevation (hepatitis) is immune mediated, as the virus does not have a direct cytopathic effect. Both innate and adaptive immunity mechanisms are involved in this process, including the action of antiviral type I interferons (α and β), natural killer cells, and CD8+ T lymphocytes. Strong immune responses are associated with viral clearance during acute icteric hepatitis in adults, but they can also lead to severe liver injury and fibrosis during the immune active phases of chronic hepatitis B.
In patients with chronic or more rarely past HBV infection, immunosuppressive therapy can lead to HBVr. Three phases have been recognized concerning the natural course of HBVr during immunosuppressive therapy : In the initial phase, immunosuppression leads to increased viral replication (high serum HBV DNA levels) due to its suppressive effect on hosts’ immune responses. This risk seems to correlate with the intensity of immunosuppression and the baseline HBV DNA levels. This phase can be followed in some, but not all, patients by an immune-mediated hepatic injury phase, whereby immune cells recognize and attack the HBV-infected hepatocytes. This process usually occurs after the withdrawal of immunosuppression whereby the immune system reconstitutes itself, but it can also happen during chronic therapy (as is the case in most rheumatic patients). The severity of liver damage is determined by the degree of liver inflammation as well as by the stage of the underlying chronic liver disease (no vs minimal vs severe liver fibrosis). Thus, HBVr can vary from a subclinical elevation of ALT levels (silent HBVr) to fulminant hepatitis with liver failure and even death. In the last phase, resolution of liver damage occurs with normalization of HBV DNA and ALT levels.
Definition of hepatitis B virus reactivation
Despite significant efforts, there is currently no unified consensus regarding the definition of HBVr after immunosuppression in the literature.
Most experts define HBVr by virologic terms as follows:
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An increase in serum HBV DNA levels by greater than 1 to 2 logs 10 IU/mL (if HBV DNA was detectable at baseline) or
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The detection of serum HBV DNA (>100 IU/mL, if HBV DNA was negative at baseline)
In some patients with past (resolved) infection, this can be accompanied by the reemergence of the HBsAg (reverse seroconversion). Hepatitis flares can occur during HBVr and are defined as a 3 or more times the ULN increase in ALT values or an absolute ALT of 100 IU/mL or greater.
Risk for hepatitis B virus reactivation according to antirheumatic treatment
Here the authors present an update of the available data regarding the risk for HBVr during antirheumatic treatment without antiviral prophylaxis in patients with chronic or past HBV infection ( Box 1 ).
Treatment
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Corticosteroids (>4 weeks)
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Methotrexate
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Leflunomide
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Cyclophosphamide
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Biologics
High-risk patients
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Patients with high-risk sexual activity (multiple sexual partners, men who have sex with men, patients with sexually transmitted diseases)
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Sexual partners and household contacts of HBV-infected individuals
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Injectable drug users
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Hemodialysis patients
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Health care workers with exposure to patients’ body fluids
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HIV-infected patients
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Patients from areas with moderate to high HBV prevalence (HBsAg positive ≥2%) and their offspring (if not vaccinated)
Abbreviation: HIV, human immunodeficiency virus.
Corticosteroids
Corticosteroids’ (CS) link to HBVr has been strongly established in the literature, and it seems to be dose and time dependent. Data from several studies and case reports link HBVr in patients with chronic HBV infection to moderate to high doses of CS (≥10 mg/d) given for a prolonged period of time (≥4 weeks). In its most recent guidelines, the American Gastroenterological Association (AGA) estimates this risk to be high (>10%), whereas for patients on chronic (≥4 weeks) low-dosage (≤10 mg/d) CS treatment, it is regarded as moderate (1%–10%). Short-term (<1 week) or intra-articular CS administration is considered a low-risk treatment (<1%).
There are no data regarding the risk for CS-induced HBVr in rheumatic patients with past HBV infection. Recently, the AGA has assigned a moderate risk (1%–10%) for HBVr to patients receiving long-term moderate- to high-dosage CS (>10 mg/d for ≥4 weeks), whereas other experts consider this to be a low-risk (<1%) group.
Non-biological Antirheumatic Agents
Methotrexate
Methotrexate (MTX) is the most widely used antirheumatic agent over the last 3 decades in rheumatology. Taking into account the large number of patients that have received MTX, the number of MTX-induced HBVr cases in the literature has been negligible. In a recent review by Tan and colleagues, only 8 such cases were identified. All but one of these patients were also receiving CS, so their effect cannot be excluded. Furthermore, in a recent retrospective cohort study of 358 Taiwanese RA patients with untreated chronic HBV infection who were taking MTX, no evidence of an increased rate of liver cirrhosis was documented, providing indirect evidence of its safety in this population.
Similarly, only 5 cases of HBVr have been reported in the literature in patients with past HBV infection on chronic MTX treatment (all receiving CS at the same time).
Altogether, these data indicate that MTX is safe in rheumatic patients with chronic or past HBV infection (low risk: <1% according to the AGA). Nevertheless, caution is needed because occasionally MTX can be associated with severe or even fatal outcomes in HBV-infected patients. In a recent analysis of all adverse events reported in the Food and Drug Administration’s Adverse Event Reporting System database among 92 HBV-infected patients with RA receiving antirheumatic drugs, there were 27 fatalities and in 20 of them MTX was used (4 patients with fulminant hepatitis).
Other non-biologics
Although implicated in HBVr when used as combination treatment, cases of HBVr with other non-biologics such as hydroxychloroquine, leflunomide (LEF), sulfasalazine, and azathioprine, when used as monotherapy for treating rheumatic diseases are extremely rare. In a recent case-control study from Japan, among 92 patients with HBVr with rheumatic disease, 12 cases of disease-modifying antirheumatic drugs (DMARDs) other than MTX (4 hydroxychloroquine, 4 LEF, 4 sulfasalazine) were reported. Thus, these agents can be categorized as low-risk treatments too.
Mycophenolate is an immunosuppressive for which there are extremely limited data regarding its potential for HBVr. There have been only 2 cases reported in the literature indicating that most likely this is a low-risk agent too.
Cyclophosphamide (CYC) is being used for the treatment of patients with severe rheumatic diseases, such as systemic lupus erythematosus, vasculitides, systemic sclerosis, and so forth, for decades (usually in combination with medium- to high-dose steroids). In a recent study that reviewed all of the available cases from the literature, Droz and colleagues identified 11 cases of CYC-induced HBVr, which occurred faster than any other immunosuppressive (median time: 8 weeks).
Biological Agents
Tumor necrosis factor inhibitors
Tumor necrosis factor α (TNFα) is an important cytokine for HBV eradication from infected hepatocytes. Low TNFα levels have been associated with dampening of the cytokine cascade, impaired apoptosis and clearance of hepatocytes, and suppression of the cytotoxic CD8+ T-cell responses against HBV.
The association between TNF inhibitors (TNFi) use and HBVr has been well established over the last decade. In a review of all published cases until 2011, Pérez-Alvarez and colleagues reported a 64% reactivation rate among 33 HBsAg-positive patients (21 of 33) treated with TNFi without antiviral prophylaxis, whereas in 3 recent studies from East Asia the respective rate was 29% (17 of 61). Most of the reactivations occurred a few months after starting TNFi (mean: 9.8 months); in most patients (12 of 17, 70%), they were accompanied by a hepatitis flare. Most patients (11 of 17) received antiviral therapy at the time of HBVr and had an uneventful course. Interestingly, 6 patients who exhibited HBVr (5 inactive carriers, 3 with ALT elevation) did well without any antiviral therapy. These data clearly point to an increased risk for HBVr with TNFi in HBsAg-positive patients without antiviral prophylaxis (assigned as moderate: 1%–10% by the AGA).
In patients with past HBV infection, the risk with TNFi is much lower. Lee and colleagues, in a review of all published cases in the literature (n = 468), identified only 8 patients (1.7%) with HBVr. Thus, it is evident that TNFi is a low-risk therapy for this group of patients (<1%).
Rituximab
Rituximab (RTX) is a B-cell–depleting monoclonal antibody increasingly used in various rheumatic diseases (RA, antineutrophil cytoplasmic autoantibody–associated vasculitides, systemic lupus erythematosus, cryoglobulinemic vasculitis, and so forth) as well as in hematologic diseases over the last 15 years.
In HBsAg-positive patients with hematologic diseases treated with RTX-containing regimens without antiviral prophylaxis, the risk of HBVr is very high (30%–60%). Although there is a paucity of data for rheumatic patients (except from rare case reports), one can assume that this is similarly high. Thus, RTX is considered a high-risk agent (>10%) for HBsAg-postive patients.
RTX among all biologics also has the highest reported risk for HBVr in patients with hematologic diseases and past HBV infection. In a recent review of all published studies, Perrillo and colleagues estimated a pooled HBVr rate of 16.9%. It should be noted though that in these studies, RTX was given as part of chemotherapeutic regimens including high-dose CS, which could also have contributed to this high risk. On the other hand, the respective data from rheumatic patients do not point to such an increased risk. In 4 recent prospective or retrospective studies including 190 rheumatic patients treated with RTX (either alone or in combination with DMARDs), there was only one case of HBVr with low-level HBV viremia (0.5%). Collectively, these data indicate that the risk for HBVr is much lower in rheumatic compared with hematologic patients with past HBV infection (>10% according to the AGA). Nevertheless, taking into account that definite cases of RTX-induced HBVr have been reported, close monitoring is required (as is discussed later).
Abatacept
Abatacept (ABA) is a fusion protein that inhibits T-cell activation and has been used over the last decade for the treatment of RA. The risk for HBVr in untreated HBsAg-positive rheumatic patients has been explored in 2 retrospective studies. In the first, all 4 inactive HBV carriers who had received intravenous ABA developed HBVr at a mean time of 10 months. On the contrary, none of 38 inactive HBV carriers treated with ABA for 24 months developed HBVr in a recent Italian study. Although the available data are limited, the AGA categorizes ABA as a moderate-risk agent (1%–10%) for HBVr in HBsAg-positive patients.
As with TNFi, the risk for HBVr in patients with past HBV infection seems to be minimal. Although rare cases of HBVr in such patients have been reported in the literature, in 2 recent studies with 24 patients treated with ABA, no cases of HBVr were noted. Similarly to TNFi, the AGA considers ABA to be a low-risk agent for HBVr (<1%).
Tocilizumab
Tocilizumab (TCZ) is a humanized monoclonal antibody that blocks interleukin-6 (IL-6) signaling by inhibiting its receptor. It is used for the treatment of RA and the systemic form of juvenile idiopathic arthritis. Except from a single case report of an HBsAg-positive Japanese patient with RA who had received TCZ for 5 years without HBVr, there are no data regarding TCZ-induced HBVr in HBsAg-positive rheumatic patients.
For patients with past HBV infection, in 2 studies with 25 patients treated with TCZ, there were only 2 cases (8%) of transient low-level viremia that resolved without antiviral therapy. Thus, there are insufficient data so far for TCZ to appropriately grade the HBVr risk in rheumatic patients with chronic HBV infection, although for past infection the risk seems to be low.
Ustekinumab
Ustekinumab (UST) is a monoclonal antibody that inhibits IL-12 and IL-23 signaling and is currently licensed for the treatment of psoriasis and psoriatic arthritis. There is limited experience with this agent in patients with chronic HBV infection. In a retrospective study from Taiwan, 7 patients with chronic HBV infection (4 inactive carriers, 3 with chronic hepatitis B) were treated with UST for 4 to 39 months without antiviral prophylaxis. Two patients (one inactive carrier and one with chronic hepatitis B) developed HBVr without associated hepatitis (at 4 and 7 months, respectively).
For patients with past HBV infection, there has been a case report of HBVr in a patient with psoriasis treated with UST. Although these literature data are scarce, it is the authors’ opinion that UST should be categorized as having moderate risk for HBVr in chronically infected patients and as low risk for patients with past infection.
Other biologics
There have been no reports of HBVr in patients treated with secukinumab (IL-17 inhibitor) or tofacitinib (Janus kinase 1/3 inhibitor); thus, no risk assessment can be conducted for those drugs. In the latter case, one could extrapolate data from the use of other kinase inhibitors, when used in hematology. HBVr is a known complication of treatment with imatinib and nilotinib.
Screening for hepatitis B virus infection
Since the risk of HBVr was recognized and its potential for preventability was established, the need to identify patients at risk before initiating immunosuppressive therapy became a necessity. Currently available guidelines from different medical societies propose 2 methods of screening, that is, either universal screening for all patients before any form of immunosuppressive treatment or screening only patients who start a moderate- to high-risk immunosuppressive agent.
The cost-effectiveness of such HBV screening has been scarcely studied in the literature. Screening all patients has proven to be cost-effective in lymphoma (before Rituximab – Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone [R-CHOP therapy]) and in early stage breast cancer (before adjuvant chemotherapy). On the other hand, universal HBV screening proved economically favorable only in selected patients with solid tumors. Until today, there is no similar study in rheumatic patients.
Whom to screen?
Screening should be conducted for all patients who are at risk for developing HBVr during immunosuppressive therapy. Obviously all rheumatic patients who are at risk for HBV infection (see Box 1 ) or with any indication of underlying liver disease (elevated ALT, any signs of chronic liver disease including ascites, varices, and so forth) regardless of their treatment schedule should be screened for HBV infection.
In terms of the scheduled antirheumatic therapies, we suggest the following:
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Biologics
Given the increased risk of serious and potentially fatal HBVr in patients treated with biologics, all rheumatic patients starting biologics should be screened for HBV infection.
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CS
HBV screening is also strongly recommended for all patients scheduled for long-term (>4 weeks) treatment with CS (either with low or high doses).
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Non-biological DMARDs
- ○
MTX/LEF : Although the available data show a negligible risk for HBVr in patients either with chronic or past HBV infection treated with MTX or LEF, the authors think that screening is required for all patients (as suggested by the American College of Rheumatology [ACR] in its 2008 guidelines), because, although rare, severe cases of HBVr have been reported with these agents and the possibility of drug-induced hepatotoxicity which could complicate the clinical course of patients chronically infected with HBV still exists.
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Antimalarials, sulfasalazine, azathioprine , and calcineurin inhibitors , have only anecdotally been associated with HBVr (usually when given with CS). HBV screening before these treatments should be individualized based on patients’ risk factors for HBV infection.
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How to screen?
There is universal consensus among different societies and experts that screening with HBsAg and anti-HBc is required for all patients at risk for HBVr.
Whether or not to include anti-HBs in the screening process is still controversial. For patients who have previously been vaccinated, titers of anti-HBs of 10 IU/L or greater are generally considered protective, whereas lower titers may indicate the need for booster vaccination. Also, the presence of anti-HBs in unvaccinated patients could be the only marker of past HBV infection in HBsAg-negative/anti-HBc-negative patients. Cases of HBVr have rarely been reported in these patients ; thus, knowledge of their status could increase vigilance during chronic therapy (especially with high-risk biologics, such as RTX). Furthermore, in patients who are triple negative and especially if they have HBV risk factors, vaccination against HBV should be performed before starting immunosuppressive therapy. For all these reasons, the authors argue that anti-HBs should be included in the initial screening ( Fig. 1 ) because, although it does not add a significant cost, it provides valuable information to the clinician.
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