What to do in case of isolated anti-hepatitis B core antibodies in HIV?

A new diagnosis of HIV requires measurement of Hepatitis B virus (HBV) serology. This heuristic is straightforward, the result of the serology not always. Especially in the case of isolated anti-hepatitis B core antibodies (anti-HBc antibodies), the following questions arise:

1. What does the presence of isolated anti-HBc antibodies mean?

2. What to do in case of isolated anti-HBc antibodies?

3. How to manage HIV infection with isolated anti-HBc antibodies?

1) What does the presence of isolated anti-HBc antibodies mean?

Hepatitis B core antigen is part of a precursor molecule that also produces hepatitis E antigen (1). It ends up as a component of the viral nucleocapsid (2) and is often considered as the most immunogenic part of the hepatitis B virus (1). Consequently, Hepatitis B core antigens induce a longtime cellular and humoral immune response. For instance, anti-HBc antibodies are the only antibodies present in all stages of a HBV infection and outlast any other anti-hepatitis B antibody (1).

In case of isolated anti-HBc antibodies, hepatitis B surface antigens and antibodies are absent while anti-HBc antibodies are present (1). This can be seen in the following clinical scenarios:

a. False positive reactivity of anti-HBc

This is a common finding, especially with the earlier generations of anti-HBc tests and in populations in which hepatitis B is uncommon. Old studies demonstrated that an important fraction of isolated anti-HBc antibodies is false positive, varying from less than 10% to more than 50%(1).

b. Seroconversion of an acute HBV infection

After an acute HBV infection, there is a transient state, in which anti-hepatitis B surface antibodies still have to appear and therefore anti-HBc antibodies are solely present (3).

c. Decades after the resolution of an HBV infection

The most common scenario of isolated anti-HBc antibodies is waning immunity (6) as these antibodies persist longer than any other hepatitis B antibodies (3).

d. Occult hepatitis B virus infection

An occult HBV infection is defined as the presence of replication-competent viral DNA in the liver while Hepatitis B surface antigens are negative (1). In 90% of cases, anti-HBc antibodies are still present (2). This might be the only abnormality in these patients as HBV DNA in blood is often below the limit of detection of the current assays (less than 20 IU/ml copies in 80 to 90% of cases) and thus reported negative (4).

e. Mutated hepatitis B surface antigen

Mutations in the hepatitis B surface antigen can render it undetectable by the standard serological assays (1)

2) What to do in case of isolated anti-HBc antibodies?

Step 1:  Exclude false positivity of the anti-HBc test.

Especially in low-prevalent regions, it is recommended to repeat the test with another assay (preferably with a newer generation assay as they have lower false positive ratios) (1,3).

Step 2:  Exclude resolving hepatitis B infection.

This can be done by repeating the serology after a few weeks. At that time, Hepatitis B surface antibodies are expected to emerge in case of a previous hepatitis B infection (3).

Step 3: Differentiating waning immunity from occult hepatitis B infection.

This is unexpectedly hard. Besides an invasive liver biopsy, there is, after all, no good way to distinguish both scenarios (2). Other tests that might be helpful:

I) HBV DNA in blood

As mentioned before, the level of HBV DNA is mostly very low in occult HBV infection (4).

II) Quantification of anti-HBc antibodies

The level of anti-Hbc antibodies can be used to distinguish between an occult and resolved hepatitis B infection although there is an important overlap between both pathologies (4). For instance, one study defined an optimal cut-off of more than 6.6 IU/ml to differentiate both pathologies. However, this cutoff only had a sensitivity of 60.7% and a specificity of 75.3% (5).

3) How to manage a HIV infection with isolated anti-HBc antibodies?

Hepatitis B serology should be part of the workup in case of a new HIV diagnosis. In case of isolated anti-HBc antibodies, the following two treatments come to mind:

a. Vaccination

Vaccination against hepatitis B should be considered in people living with HIV (PLWH), especially in case of isolated anti-HBc antibodies. In contrast to HIV-negative people, there is often no immune protection after loss of anti-HBs (6). American guidelines for opportunistic infections recommend vaccinating PLWH and isolated anti-HBc antibodies with a standard dose of hepatitis B vaccine (7). 1 to 2 months afterwards, anti-HBs antibodies should be measured and if they exceed 100mIU/mL, a sustained amnestic response is likely (8). In all other cases, a complete vaccination scheme should be administered, followed by anti-HBs testing. Re-vaccination might be postponed till CD4 rise above 200 as otherwise the response rate is quite poor (6). The following options are suggested:

I. Double dose of standard hepatitis B vaccines at week 0, 4, 24 (e.g. Engerix-B).

Double dose is preferred as a meta-analysis showed a superior serological response rate of this dose, compared to standard dosing.

II. Adjuvanted recombinant HBV vaccine at week 0, 4, 24 (e.g. Heplisav-B).

In one recombinant trial, this dosing regimen was superior in terms of response and durability of immunity compared to three-dose Engerix-B single strength and two-dose Hepislav (10).

b. Anti-hepatitis B treatment

Some nucleoside reverse transcriptase inhibitors (NRTI) such as tenofovir, lamivudine and emtricitabine are active against both hepatitis B and HIV, although monotherapy with lamivudine is contra-indicated because of the high risk of hepatitis B acquiring resistance during therapy. Guidelines therefore recommend that all persons with HBV/HIV co-infection should be treated with at least tenofovir or if tenofovir is strictly contraindicated entecavir (11).

In case of isolated anti-HBc antibodies, however, the answer is more complicated. In general, taking an HBV-active NRTI reduces the risk of HBV-acquisition or reactivation (12). Nevertheless, this risk is low in PLWH in Europe/USA. Therefore, the European and American Guidelines don’t recommend a specific regimen in case of isolated anti-HBc antibodies (3,11).

One special scenario is when an HBV-active NRTI is withdrawn in people with isolated anti-HBc antibodies as this entails a small risk of HBV reactivation (11). Therefore, regular monitoring of the liver tests in the following months is recommended and if deranged, blood HBV DNA level should be determined (11).

References:

 1. Moretto F, Catherine FX, Esteve C, et al. Isolated Anti-HBc: Significance and Management. J Clin Med. 2020 Jan 11;9(1):202.

 2. Lazarevic I, Banko A, Miljanovic D, et al. Clinical Utility of Quantitative HBV Core Antibodies for Solving Diagnostic Dilemmas. Viruses. 2023 Jan 28;15(2):373.

 3. Rydén H, Nicolini LA, Andersson MI, et al. Isolated anti-HBc: reflections from clinical microbiology and infectious diseases. Germs. 2022 Jun 30;12(2):155-157.

 4. Wang C, Xue R, Wang X, et al. High-sensitivity HBV DNA test for the diagnosis of occult HBV infection: commonly used but not reliable. Front Cell Infect Microbiol. 2023 May 16;13:1186877.

5. Song LW, Liu PG, Liu CJ, et al. Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection. Clin Microbiol Infect. 2015 Feb;21(2):197-203.

 6. Corcorran MA, Kim HN. Strategies for Hepatitis B Virus Prevention in People Living with HIV. Curr HIV/AIDS Rep. 2023 Dec;20(6):451-457.

 7. National Institutes of Health; Centers for Disease Control and Prevention; HIV Medicine Association of the Infectious Diseases Society of America Panel on Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV— A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. [Updated 2025 Apr 23]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK586304/

 8. Piroth L, Launay O, Michel ML, et al. Vaccination Against Hepatitis B Virus (HBV) in HIV-1-Infected Patients With Isolated Anti-HBV Core Antibody: The ANRS HB EP03 CISOVAC Prospective Study. J Infect Dis. 2016 Jun 1;213(11):1735-42.

9. Lee JH, Hong S, Im JH, et al. Systematic review and meta-analysis of immune response of double dose of hepatitis B vaccination in HIV-infected patients. Vaccine. 2020 May 19;38(24):3995-4000.

 10. Marks KM, Kang M, Umbleja T, et al. HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial. JAMA. 2025 Jan 28;333(4):295-306.

11. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Year. Available at https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv. Accessed 16th May 2025.

 12. Abdullahi A, Fopoussi OM, Torimiro J, et al. Hepatitis B Virus (HBV) Infection and Re-activation During Nucleos(t)ide Reverse Transcriptase Inhibitor-Sparing Antiretroviral Therapy in a High-HBV Endemicity Setting. Open Forum Infect Dis. 2018 Oct 5;5(10):ofy251.