Hep, Hep, Hepatitis!


65 year old female with a history of steroid dependent pemphigus vulgaris would like a second opinion on treatment options. Upon review of her medical records, the rheumatologist discovers she has a history of positive hepatitis B core antibody and refers her to hepatology clinic for further workup. Patient denies history of liver disease, and does not recall being told she has hepatitis B. Her recent hepatic functional panel revealed ALT, AST and total bilirubin within normal limits. She denies history of blood transfusion, tattoos, IVDU or new sexual partners. There is no family history of hepatitis B. Her rheumatologist would like to start her on rituximab and would like to know if this can be initiated immediately. 

Which is the correct response?

Correct Answer:

Further evaluation with additional hepatitis b serologies is needed prior to treatment decision

There is not enough information to determine if the patient has active hepatitis B, chronic hepatitis B, or resolved hepatitis B. Prior to initiation of  high risk immunotherapy, further evaluation is needed to determine the patient’s risk for possible HBV reactivation. Keep reading to learn which patients are at high risk and how to approach screening in this population.

What is HBV reactivation?

In patients with chronic HBV (defined as HBsAg+ for at least 6 months and measurable HBV DNA in the blood), reactivation is defined by an increase in HBV DNA above baseline whereas in patients with resolved HBV (defined by HBsAg -  and anti-HBc+), reactivation is defined by either appearance of HBV DNA in the blood or conversion to  HbsAg + state (i.e. reverse seroconversion) (Table 1).

Table 1 - Guideline Specific Definition of HBV Reactivation

Taken from: Terrault NA, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018

Risk factors for reactivation of HBV infection

Patients with serologic evidence of HBV infection, manifested by either a HBsAg + or  anti-HBc +, are at risk of reactivation, particularly if they receive immunosuppressive therapy. This includes those treated for malignancy or an autoimmune disorder, and those undergoing solid or hematopoietic stem cell transplantation (HSCT). 41%-53% of HBsAg +, anti-HBc + patients compared to 8% -18% of HBsAg -, anti-HBc + patients undergoing anticancer therapies had HBV reactivation. Other studies showed that HBV reactivation from anti-rheumatic therapies was 12.3% in HBsAg + and anti-HBc + patients compared to 1.7% in HBsAg -, and anti-HBc + patients.  Therefore, while other risk factors such as male gender and age have been shown to play a role in HBV reactivation, the level of risk is mostly dependent on HBsAg status and the type of immunosuppression used. (Table 2)

Back to the case

After evaluation in clinic, HbsAg, repeat anti-Hbc IgM and IgG, and HBV DNA were ordered to better evaluate the status of HBV in this patient.

Table 2 - HBV reactivation risk stratification for those undergoing immunosuppressive therapy

Taken from: Loomba R, Liang TJ. Hepatitis B Reactivation Associated with Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology. 2017

Approach to screening

Several guidelines endorse testing for active and chronic HBV in any patient needing immunosuppressive therapy. Risk for HBV reactivation can be readily identified by testing for HBsAg and anti-HBc (Figure 1).

Figure 1 - Approach to HBV testing

Taken from: Loomba R, Liang TJ. Hepatitis B Reactivation Associated with Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology. 2017

Back to the case

In the case above, the patient's serologies revealed:

HBV DNA: undetectable

Anti-HBc IgM: non reactive

Anti-HBc total: reactive

HbSAg: non-reactive.

Of note, Hep C, Hep A, and HIV testing was negative

Clinical Manifestations of HBV reactivation

Different degrees of HBV reactivation may occur. Silent HBV reactivation is seen with an increase in HBV DNA levels without an increase in aminotransferase levels. Mild reactivation can occur with a rise in serum aminotransferase levels without jaundice or other symptoms, whereas jaundice and/or symptoms of liver injury is seen in moderate HBV activation. Finally, severe HBV reactivation is marked by features of liver failure, which could lead to death.

Preventing HBV reactivation

In general, antiviral therapy initiated prior to immunosuppressive therapy or concurrently can minimize the risk of HBV reactivation. If antiviral therapy is initiated after a flare of hepatitis has already occurred, it may take several months to control the disease and reduce the viral load.

Initially, lamivudine was the first agent to become available for treatment or prevention of HBV reactivation. While safe and generally well tolerated, resistance to viral variants is often seen after prolonged use. As a result, antiviral drugs such as tenofovir and entecavir have now become the first line agents to treat HBV.

The decision to administer prophylactic therapy depends on the level of risk as determined by serologic status and type of immunotherapy administered (Table 2 and Figure 1). Although there is no data to dictate how long therapy is required, most experts recommend continuing antiviral therapy for the duration of chemotherapy, with some recommending continued therapy for 3 to 6 months after the last cycle of chemotherapy while other favor continuing for up to 12 months (especially when anti-CD20 is used).

For patients receiving lesser degrees of immunosuppression with only anti-HBc +, close monitoring (DNA levels every 1 to 3 months) and initiation of antiviral therapy when HBV DNA is detectable may be appropriate.

Various guidelines propose slightly different nuanced approaches (Table 3).

Table 3: Guidelines specific management approaches to HBV Reactivation

Taken from: Myint A, et al. Reactivation of hepatitis B virus: a review of clinical guidelines. Clin Liver Dis, 2020. 15(4): p 162-167

Back to the case

With findings of anti-HBc + and the need to initiate high risk anti-CD20 therapy, entecavir was initiated for prophylactic HBV therapy.