Screening for hepatitis B virus to prevent viral reactivation — who and when?

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Abbreviations

HBV

hepatitis B virus

TNF‐α

tumor necrosis factor‐α

Reactivation of hepatitis B is characterized by a significant rise in hepatitis B virus (HBV) replication (>2 log increase in HBV DNA level from baseline) in a person with previously stable or undetectable levels. Over the last two decades, a growing body of knowledge has accumulated on the risk of hepatitis B virus (HBV) reactivation in patients receiving immunosuppressive therapy. The widespread use of immunosuppressive agents for diverse clinical indications, the potential for adverse outcomes following HBV reactivation in this setting, the availability of sensitive and specific assays for HBV, and the ability to effectively prevent episodes of HBV reactivation with preventive antiviral therapy justify implementation of routine screening programs for HBV in patients for whom immunosuppressive therapy is indicated.

Why Should We Screen for Hepatitis B Prior to Receipt of Immunosuppressive Therapy?

Globally, chronic HBV infection is the leading cause of liver‐related morbidity and mortality. Worldwide, more than 2 billion people have been infected with HBV, of whom, approximately 400 million are chronically infected.1 The prevalence of HBsAg (the serological marker of chronicity) varies significantly among different geographic regions, with the highest rates reported in Asia and sub‐Saharan Africa (Fig. 1). In the United States, HBV is largely an immigrant disease, with more than 90% of cases imported from countries of intermediate or high HBV prevalence.2

Figure 1.

Global prevalence of HBV (adapted from: Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley A, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. Centers for Disease Control and Prevention. MMWR Recomm Rep. 2008;57[RR‐8]:1‐20).

Only a small proportion of patients previously exposed to HBV will likely receive immunosuppressive, cytotoxic, or immunomodulatory medications for treatment of malignant, autoimmune, and chronic inflammatory diseases or to prevent rejection following solid‐organ transplantation. However, treatment with such medications increases the risk of HBV flares, particularly among those with chronic HBV infection (HBsAg positive ± HBeAg), and can also lead to HBsAg seroreversion and recrudescence of hepatitis in individuals with resolved infection (HBsAg negative, anti‐HBc positive ± anti‐HBs). Indeed, a systematic review of 550 HBsAg‐positive patients who received immunosuppressive therapy without antiviral prophylaxis highlights the issue. Thirty‐seven percent of subjects experienced reactivation, one‐third of subjects developed a flare of hepatitis, 13% experienced liver failure, and 6% died. Use of prophylactic lamivudine reduced the rate of hepatitis flares by 79% to 100%, and there were no cases of decompensation or death.3

Risk factors for HBV reactivation include younger age, male sex, HBsAg and DNA positivity, and duration and intensity of the immunosuppressive regimen, as well as the type of underlying malignancy.4 Combining several of these risk factors (viral, type of malignancy, and immunosuppressive regimen) can be useful for stratifying patients into high, intermediate, and low risk for reactivation (Fig. 2). In addition to the adverse liver consequences, HBV reactivation can lead to interruption of treatment for the underlying disease, resulting in increased morbidity and mortality. Timely screening for HBV infection followed by prophylactic treatment with antiviral medications when indicated can significantly reduce the risk of viral reactivation with its associated adverse outcomes.3

Figure 2.

Risk factors for HBV reactivation.

Who Should Be Screened?

In 2008, the Centers for Disease Control and Prevention (CDC) updated and expanded its guidelines for testing for chronic hepatitis B and recommendations for public health evaluation and management for chronically infected persons and their contacts.5 These guidelines now include a recommendation to screen all patients scheduled to receive immunosuppressive medications. The European Association for the Study of the Liver and Asian–Pacific Association for the Study of the Liver also recommend universal HBV screening prior to initiation of immunosuppressive therapy,6, 7 whereas the American Association for the Study of Liver Diseases, American Society of Clinical Oncology, and the National Comprehensive Cancer Network,8, 9, 10 recommend screening patients at high risk for HBV infection. Although a targeted approach would likely be more cost‐effective than universal screening, such an approach may lead to failure to identify chronically infected or previously exposed subjects and has been generally difficult for health care professionals to comply with. Prospective studies are needed to establish the advantages of one screening approach over the other in this clinical setting. However, until such evidence becomes available, it remains prudent to screen all patients prior to receipt of immunosuppressive therapy.

In the last decade, novel therapeutic agents have been introduced for the treatment of malignant, autoimmune and chronic inflammatory diseases. These include biologic agents such as tumor necrosis factor‐α (TNF‐α) inhibitors and small molecules such as tyrosine‐kinase inhibitors. The former have gained widespread use in the fields of gastroenterology, rheumatology, and dermatology. Although not traditionally classified as immunosuppressants, TNF‐α inhibitors have nevertheless been associated with clinically significant HBV reactivations, presumably by interfering with innate and adaptive immune system control of viral replication.11 All patients without malignancy who require long‐term but less intense immunosuppression should therefore be screened for HBV infection and preferably vaccinated prior to initiation of therapy if found to be negative for markers of active infection (HBsAg) or past infection (anti‐HBc).

What Tests Should Be Used for HBV Screening?

Testing for hepatitis B infection in high‐risk groups should be performed with a US Food and Drug Administration (FDA)‐licensed or FDA‐approved serological assay for HBsAg according to the manufacturer's recommendations. Initially reactive specimens should be confirmed with a licensed confirmatory test. The CDC recommends testing patients for HBsAg, anti‐HBc, and hepatitis B surface antibody before they receive immunosuppressive therapy.5 These three tests allow for defining of the HBV phenotype and determining the risk of reactivation and the need for prophylaxis. The interpretation of HBV serology is shown in Table 1. Western professional societies recommend inclusion of anti‐HBc in the screening tests,6, 10 but Asian professional societies do not.7 Whether to include anti‐HBs and HBV DNA testing among anti‐HBc‐positive subjects is controversial because of the lack of prospective data on their role as an aid to decision making, but is supported by expert opinion. HBsAg‐negative/anti‐HBc‐positive subjects who are anti‐HBs negative or have detectable HBV DNA are assumed to have a higher risk for reactivation than their counterparts who are anti‐HBs positive and HBV DNA negative and, therefore, should receive preventive antiviral therapy.

Table 1.

Screening Tests and Results

Test	Significance	Action
HBsAg	HBV infection	Prophylaxis indicated
Anti‐HBs alone	Immunity to HBV	None
Anti‐HBc +/‐ anti‐HBs	Exposure to HBV	‐If HBsAg ‐ve, low risk for standard chemotherapy ‐If BMT or Rituximab consider prophylaxis

When Should Screening Be Done?

Patients requiring immunosuppressive therapy should be screened for HBV infection prior to initiation of therapy. Unfortunately, low rates of HBV screening have been reported in cancer patients and especially among those known to be at high risk for HBV infection.12 Collaborative effort should be made by professional societies, policy makers, and health care providers to increase compliance with current CDC recommendations on HBV screening. A recent study demonstrated the feasibility of using computerized physician order entry to facilitate the screening and identification of patients at high risk of HBV reactivation prior to treatment with biological drugs.13

Conclusions

HBV reactivation has become a serious health problem with the growing use of immunosuppressive therapies. HBV screening can significantly reduce morbidity and mortality associated with this condition and is therefore recommended in all patients before initiating immunosuppressive therapy. A greater effort should be made to improve currently low screening rates in patients at risk for HBV reactivation.