Today, I review, link to, and excerpt from The Curbsiders‘ #440 Hepatitis B with Dr. Arthur Kim.*

*Gandhi MM, Kim A, Williams PN, Watto MF. “#440 Hepatitis B with Dr. Arthur Kim”. The Curbsiders Internal Medicine Podcast. thecurbsiders.com/category/curbsiders-podcast Final publishing date May 20, 2024.

All that follows is from the above resource.

Transcript available via YouTube

Become a pro in Hepatitis B! Dr. Arthur Kim teaches us how to approach Hepatitis B screening and vaccination in primary care, provides pearls on counseling patients with chronic Hepatitis B infection, and summarizes considerations for Hepatitis B antiviral treatment and monitoring.

Show Segments

• Intro
• Case from Kashlak
• Hepatitis B screening – who should be screened?
• Hepatitis B screening – interpreting test results
• Hepatitis B vaccination
• Stages of Chronic HBV infection
• Counseling patients with chronic HBV about preventing transmission and protecting liver health
• Treatment of chronic HBV infection
• Screening for hepatocellular carcinoma
• Outro

Hepatitis B Pearls

1. Updated CDC guidelines recommend that all adults should be screened for Hepatitis B at least once in their lifetime. Several populations may need repeat testing after initial screening, including those without adequate immunity who have ongoing risk factors and those with a greater than average risk of reactivation (such as patients who are about to initiate immunosuppressive therapy).
2. Hepatitis B screening consists of “triple testing” for Hepatitis B surface antigen, Hepatitis B surface antibody, and Hepatitis B core antibody. Keep an eye out for false HBV core antibody positivity in the setting of IVIG, and false HBV surface antigen positivity in the setting of patients tested immediately after same-day vaccination.
3. Available Hepatitis B vaccination formulations include the traditional three vaccine series, a combination HBV / HAV vaccine, the new PreHevbrio vaccine, and the CpG-adjuvanted vaccine. The CpG-adjuvanted vaccine may offer a promising option for populations who are immunocompromised / have traditionally not responded well to the standard vaccine; it is also increasingly being used for a second vaccine series in patients who did not respond to their initial series.
4. Patients with a new diagnosis of chronic Hepatitis B should be counseled on how to prevent transmission to others, as well as how to protect their liver health.
5. Treatment for Hepatitis B is warranted in patients with cirrhosis, as well as non-cirrhotic patients with evidence of active disease (based on ALT levels and HBV DNA). The preferred treatment regimens for HBV are tenofovir (in the form of tenofovir alafenamide or tenofovir disoproxil fumarate), or entecavir.
6. Hepatocellular carcinoma screening should be conducted every 6 months with abdominal ultrasound +/- alpha-fetoprotein in several subsets of patients with chronic HBV at elevated risk of HCC.

Hepatitis B – Notes

Hepatitis B Screening

Who should be screened for HBV?

The CDC guidelines changed in 2023, and now recommend that all adults should be screened for Hepatitis B at least once in their lifetime (Conners et al, 2023).  Prior to this change, guidelines recommended selective screening based on risk factors. The goal of this update was both to enhance our ability to identify individuals who are infected and may benefit from treatment, as well as to better recognize individuals who lack immunity and should be vaccinated. The move towards universal screening avoids providers having to memorize a long list of risk factors, and also accounts for the fact that patients may not report certain risk factors due to associated stigma or other reasons. According to Dr. Kim, HBV is an ideal candidate for screening as it has a long asymptomatic period before consequences, is a transmissible infection, can have significant health consequences (e.g. is a major cause of cirrhosis and liver cancer), and is treatable with effective antivirals if identified (Conners et al, 2023). Dr. Kim notes that HBV screening should generally be performed regardless of a patient’s history of vaccination (it is possible, for instance, that a patient was infected before they were vaccinated, and thus screening would be important to identify this).

There are several situations in which HBV testing may need to be repeated after initial screening.  These include: a) patients without adequate immunity who have ongoing risk factors (for instance, individuals with multiple sexual partners or active injection drug use) (Conners et al, 2023), and b) patients with a greater than average risk for reactivation, for instance prior to immunosuppressive agents (including cancer chemotherapy, rituximab, JAK/STAT inhibitors, and others) (Myint et al, 2020; Hwang et al, 2020).

What screening tests should be sent, and how should the results be interpreted?

HBV screening consists of “triple testing” for HBV surface antigen (HBsAg; indicative of chronic active infection or acute infection), HBV surface antibody (indicative of immunity from either natural infection or vaccination; mutually exclusive with HBV surface antigen), and HBV core antibody (develops first and is indicative of exposure; does not provide information about whether disease is active or not).

There are several possible scenarios for various permutations of HBV test results (Terrault et al, 2018; Conners et al, 2023).

• HBsAg negative / anti-HBc negative / anti-HBs negative: Patient lacks immunity to HBV, and should be vaccinated.
•  HBsAg negative / anti-HBc negative / anti-HBs positive: Patient is immune to HBV due to prior vaccination.
• HBsAg negative / anti-HBc positive / anti-HBs positive: Patient is immune to HBV due to prior exposure.
• HBsAg positive / anti-HBc positive / anti-HBs negative: Patient has current HBV infection (most likely chronic disease, less likely acute).
• HBsAg negative / anti-HBc positive  / anti-HBs negative: Can represent either a) window period of acute HBV, b) chronic HBV with loss of detectable HBsAg, c) recovery from acute HBV with loss of detectable anti-HBs, or d) false positive anti-HBc

Dr. Kim notes that there are several situations to be aware of that may yield false positives:

• HBV core antibody can be falsely positive in individuals receiving IVIG (Ramsay et al, 2016).
• HBV surface antigen can be falsely positive if the patient was screened and vaccinated on the same day, and vaccination was performed before screening (Dow et al, 2002). HBV vaccines contain some HBV surface antigen, which can leak into the bloodstream and be detected by the screening test for up to days afterwards. Dr. Kim emphasizes that if patients are being screened and vaccinated on the same day, testing should always be done before vaccination!

Hepatitis B Vaccination

When should we be vaccinating adult patients for HBV?

As of 2022, the ACIP now recommends that all adults <60 without risk factors for HBV should be vaccinated, as well as all adults at high risk of HBV regardless of age (Weng et al, 2022).

Dr. Kim notes that providers can generally wait until HBV screening results are available prior to vaccinating. Exceptions include if there is concern that the patient may be at risk for acquiring HBV between this visit and the next, or if there is concern that they may not return for a follow-up visit, in which case screening and vaccination on the same day may be warranted (in the correct order – see above).

Dr. Kim emphasizes that providers do not need to hold off on initiating the HBV vaccine series for concern that the patient may not be able to return to the office at the exact timing interval indicated in the series; it is better to start out the vaccine series and go from there.

What HBV vaccine formulations are available?

There are several HBV vaccine formulations available (Jeng et al, 2023):

• The traditional three vaccine series
• HBV and HAV combination vaccine
• PreHevbrio: recently approved vaccine that includes three different antigens related to HBV surface antigen; may achieve higher antibody titers that may last longer (Vesikari et al, 2021). This vaccine is newer and generally pricier.
• CpG-adjuvanted vaccine: available since 2017 and approved for adults. Can be given in a two or three dose series. Contains a TLR9 stimulant as an adjuvant, which improves responses compared to the traditional vaccine (Halperin et al, 2012; Heyward et al, 2013). The CpG-adjuvanted vaccine appears to be a particularly promising option in patients who have traditionally not responded well to the standard vaccine (Jackson et al, 2018, Amjad et al, 2021). This includes persons with HIV based on recent trials (Marks et al, CID, 2023; Marks et al, CROI 2024), as well as individuals with end-stage renal disease who are awaiting transplant.

In terms of safety, there is a higher risk of local injection site reactions with the CpG-adjuvanted vaccine. However, in general these vaccines are very safe.

What should you do for patients who do not respond to the HBV vaccine?

For patients with a prior history of vaccination but no evidence of immunity, they may have lost detectable HBV surface antibody titers over years to decades in the absence of continued antigen stimulation. In these situations, Dr. Kim notes that you can attempt to revive HBV surface antibody positivity by administering one dose of the vaccine and re-checking; if HBV surface antibody remains negative, you can  proceed with repeating the full vaccine series. While in the past, this repeat vaccination series has typically been accomplished using traditional vaccines, Dr. Kim notes that many practices have moved towards using two-dose CpG-adjuvanted vaccines for this purpose in recent years (this strategy is of interest for healthcare workers, for example).

Management of Chronic Hepatitis B

Phases of Chronic Hepatitis B

The natural history of chronic Hepatitis B involves multiple phases (Jeng et al, 2023). The initial phase of chronic HBV is the immune tolerant phase, in which the body is tolerating the infection and the immune system is not sending in lymphocytes to trigger inflammation; during this stage, ALT levels are flat. This phase usually lasts decades for individuals who were infected perinatally. The second phase is the Hepatitis E antigen positive immune active phase, which begins during the second or third decade of life for those infected perinatally; during this phase, inflammation occurs and ALT rises. Hopefully, eventually HBV E antigen disappears and HBV E antibody appears, at which time HBV DNA should drop and the patient should be less infectious. Some patients can remain in this inactive carrier stage with very low HBV DNA and low ALT. However, some patients can revert back to a Hepatitis E antigen negative immune active phase, which can occur with immunosuppression or aging.

Initial work-up in patient with newly diagnosed chronic Hepatitis B

The initial work-up for a patient newly diagnosed with chronic Hepatitis B includes the following (UWashington manual on HBV management for the primary care provider):

• Comprehensive metabolic panel, including liver function tests and kidney function
• CBC with differential
• Calculation of APRI or FIB4 score based on liver function tests and platelet count; can provide an idea of the patient’s risk for advanced liver disease.
• PT/INR (especially in patients with concern for advanced liver disease)
• HBV virological parameters: HBV DNA, HBV E antigen / anti-HBe
• Co-infection status: HIV, HCV, HDV
• Abdominal ultrasound

Counseling patients with Chronic Hepatitis B

Preventing transmission to others

Dr. Kim covers the following topics when counseling patients about preventing transmission to others (UWashington manual, Terrault et al, 2018):

• Casual contact is fine (unless an open wound is present). This includes food sharing. Dr. Kim emphasizes that he does not want to convey to patients that they should isolate themselves or withdraw from activities.
• Regarding household transmission, patients should be counseled to not share razors or toothbrushes, and to clean up any visible blood spills with bleach.

• The patient’s sexual partner should be screened for HBV and vaccinated against HBV if they are non-immune. Use of barrier protection can prevent transmission of HBV.
• Harm reduction is crucial for patients who inject drugs, including avoidance of sharing injection equipment.
• Breastfeeding is not contraindicated (Terrault et al, 2018; Society for Maternal-Fetal Medicine, 2016)

Protecting liver health

Patients with HBV should be counseled on protecting their liver health (UWashington manual, Terrault et al, 2018). This includes the following topics:

• Limiting alcohol use
• Eating a heart-healthy diet and optimizing body weight to prevent concurrent steatotic liver disease
• A detailed herbal history should be taken. No conclusive evidence for the benefit of herbal formulations for the liver.
• Caffeine is okay!
• Patients should receive vaccination for Hepatitis A
• If advanced fibrosis or cirrhosis is present, patients should receive early pneumococcal vaccination

Stigma and psychosocial factors

Dr. Kim notes that the diagnosis of HBV can be associated with stigma, and many patients with chronic HBV feel a sense of shame or guilt. He emphasizes that it is important to explore these feelings and to provide counseling, as well as reassurance that any risks they are worried about can be mitigated (for instance, through vaccinating partners). For severe cases, cognitive behavioral therapy can be helpful.

Treatment of Chronic Hepatitis B

Referral to a specialist for management of patients with chronic HBV is generally appropriate (other than in some select primary care practices that are very familiar with HBV treatment). However, primary care physicians can help share visits for on-treatment laboratory monitoring.

Indications for treatment

For patients with cirrhosis, treatment with antiviral therapy is indicated. For patients without cirrhosis, antiviral therapy is generally recommended in the setting of active disease (Terrault et al, 2018). The AASLD recommends an algorithm combining HBV DNA and ALT levels to determine whether treatment is indicated in these cases (Terrault et al, 2018). There is currently debate regarding whether treatment criteria should be broadened.

Treatment options and monitoring on treatment

The current preferred treatment regimens are either a) entecavir or b) tenofovir in the form of either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) (Jeng et al, 2023, UWashington manual, Terrault et al, 2018).

These regimens are generally safe. There is a rare risk of lactic acidosis for all agents, which is usually more of a concern in sicker patients. TDF can impact the kidneys and bones, which is less of an issue with TAF (Chan et al, 2016) (though TAF is more expensive); generally, Dr. Kim will try to get TAF for patients who are older or are post-menopausal women in which kidney and/or bone health are more of a concern.

While both tenofovir and entecavir have a generally high barrier to resistance, Dr. Kim notes that tenofovir-based agents have a higher barrier to resistance than entecavir. Additionally, unlike entecavir, tenofovir can be used without concern in patients with prior resistance to lamivudine (Terrault et al, 2018).

According to Dr. Kim, patients should receive laboratory monitoring every 6 months with HBV DNA and ALT, as well as potentially safety labs for renal dosing.

How long should treatment be continued?

Most patients will be on antiviral therapy for an extended period of time. Patients with cirrhosis should be continued on antiviral treatment indefinitely (Terrault et al, 2018). For patients without cirrhosis, there are options to consider stopping therapy if patients achieve seroconversion. For patients who are HBV E antigen positive at treatment initiation, Dr. Kim notes that therapy can potentially be stopped if they seroconvert to anti-HBe positive (following at least a 12-month consolidation period after seroconversion), though he emphasizes that close monitoring should be continued (Terrault et al, 2018; Sarin et al, 2015). For patients who are HBV E antigen negative at treatment initiation, Dr. Kim notes that therapy cessation may be considered if they seroconvert to HBV surface antigen negative (following 12-month consolidation period after HBV surface antigen seroconversion) (Terrault et al, 2018; Sarin et al, 2015). However, the vast majority of patients will remain HBV surface antigen positive.

Dr. Kim notes that there are several novel medications in the pipeline that may enable individuals with HBV to not need lifelong therapy in the future.

Hepatocellular Carcinoma Screening

Hepatocellular carcinoma (HCC) screening should be conducted every 6 months with abdominal ultrasound +/- alpha-fetoprotein in patients with chronic HBV who meet the following criteria, according to the AASLD guidelines: a) all patients with cirrhosis, b) patients with hepatitis D positivity, c) patients with a family history of HCC,  d) Asian females older than 50 years or e) African American or Asian males older than 40 years (Terrault et al, 2018).

See also Linking To And Embedding “CT Scan Liver Normal Vs Hepatocellular Carcinoma (HCC) Images | Liver Cancer Imaging Diagnoses” From Dr. Sam’s Imaging Library
Posted on October 18, 2024 by Tom Wade MD

Links

University of Washington manual, “Hepatitis B Management: Guidance for the Primary Care Provider”