An ongoing dialogue on HIV/AIDS, infectious diseases,
June 27th, 2025
The Mystery of the Isolated Hepatitis B Core Antibody, Solved
(A post inspired by years of doing eConsults, an extremely common query about hepatitis B testing, and the latest BritBox series, “Core Antibody Confidential,” starring a grizzled detective with a faded suit and a haunted past.)
Your electronic medical record lists “deficiencies” in health care maintenance for one of your patients, so you order hepatitis B serologies. The next day, the results pop up on your screen (cue ominous base line):
HBsAg: negative
anti-HBs: negative
anti-HBc: positive
The start of the report was simple, but it’s the ending that pushes you to hit the “Next Episode” button.
Why? Because there’s no surface antigen to confirm an active villain. No reassuring surface antibody to declare the battle won. Just the mysterious core antibody, skulking around your labs like one of those brilliant character actors who also appeared in Broadchurch — or was it Shetland, or (changing British TV genres) Bleak House?
Let’s play the eccentric British detective, his career fading and forced to resign from a post in London due to a separate mystery on its own (and a very engaging subplot itself), and now arriving in a remote seaside town to solve this mystery.
- Resolved infection. Your patient cleared HBV long ago; anti-HBs has simply faded with time, like my memory of the names of the minor characters from Episode 1.
- Occult HBV infection. They have chronic hepatitis B, but the surface antigen is too low for detection — hiding in a witness protection program, likely somewhere in the right upper quadrant. Further inquiry with a hepatitis B DNA test (hepatitis B viral load) may snag this guy, but you’ll have to bring the patient back for more questioning … um, blood tests.
- The “window period” of acute infection. The crime just occurred, and the protective surface antibodies haven’t shown up yet, even though the surface antigen cleared. Even detectives on the downslope of their careers can chase down recent risk factors for HBV — and so should you.
- False-positive test. Tests aren’t perfect, and antibodies to hepatitis B core might cross react with other antigens — such as those triggered by eating marmite, haggis, or trifle. (Not a fan of any of these British food items, for the record. And yes, I made those up as the cause. In reality, we rarely know what triggers false positives, but low pre-test probability and imperfect assays are usually to blame.)
Practically, what to do next? And isn’t it time to stop this detective series metaphor?
(Yes. Apologies if I periodically lapse.)
Back to real life. Since by far the most likely explanation for anti-hepatitis B core antibody is resolved infection — item #1 above — the simplest thing to do is check for hepatitis B DNA. In the vast majority of cases, it will come back negative, and you can reassure your patient.
But are you done? Not quite — like any good mystery, a couple of loose threads remain, maybe even enough for Season 2. Importantly, people with isolated anti-HBc positivity may have occult hepatitis B infection (OBI), defined as HBV DNA in the liver with or without detectable HBV DNA in the blood. This becomes clinically relevant in immunosuppressed individuals, organ transplant recipients, and those with HIV or hepatitis C virus coinfection, as they are at increased risk for HBV reactivation and associated complications.
The population at greatest risk for this reactivation? People who receive B-cell depleting therapies such as rituximab, with the risk high enough to warrant antiviral therapy with either entecavir or tenofovir.
Note that this isolated core antibody pattern is particularly common in those with HIV and hepatitis C. Since most of those with HIV are already receiving anti-hepatitis B therapy with tenofovir and/or lamivudine/emtricitabine, reactivation is not a concern unless switching to a NRTI-free regimen — something increasingly done in the era of long-acting cabotegravir-rilpivirine. For those not on NRTIs who have isolated core antibodies to hepatitis B, periodic HBV DNA monitoring may be warranted, and I would certainly do this if the ALT and AST become abnormal.
Before wrapping up this mystery, let’s consider this important unresolved plot line:
Should people with isolated anti-HBc receive the hepatitis B vaccine?
The guidelines say yes, so clinicians who choose to do this certainly are taking a defensible position. There may be institutional or documentation-based reasons to vaccinate — fair enough. And you’d make the guidelines happy.
But in terms of virologic logic? Count me unconvinced. I’d argue that since the primary purpose of the hepatitis B vaccine is to prevent viral acquisition, what’s the point of vaccinating people who have already had hepatitis B?If there were convincing clinical studies demonstrating that those with isolated anti-HBc are at high risk for infection with de novo hepatitis B virus, then I’d be more enthusiastic. But I can’t find any.
Also, as far as I know, there aren’t even studies showing that giving the vaccine reduces the risk for reactivation of occult HBV — only studies that look at antibody responses after vaccination. Some respond, some don’t.
To quote one expert on viral hepatitis, University of Washington’s Dr. Nina Kim:
Bottom line: We don’t have but need longitudinal data showing that vaccination actually helps this subset of patients.
Agree 100%!
Take the poll, folks.
Now watch Nina’s great educational lecture on this mysterious serologic pattern, and come back for this classic.
17 Responses to “The Mystery of the Isolated Hepatitis B Core Antibody, Solved”
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Paul E. Sax, MD
Contributing Editor
NEJM Journal Watch
Infectious Diseases
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Em, then what do you make of Zoster vaccines? Vaccines can do other things 😉
I use one dose of the HBV vaccine as a diagnostic. “You say you’re cured? Well, show me the money.” If you bump up, then I’ll leave you alone. If you don’t, then I’ll start being suspicious.
I run a free clinic and see many undocumented immigrants and ex-convicts and are beginning to treat coinfection hepatitis B and C.
Thanks for raising this important and common issue.
In these cases I often give a single dose of vaccine to assess for an anamnestic response. If anti-HBs develops, I take that as evidence of immune memory. If not, especially in someone at risk for immunosuppression, I’m more cautious and monitor more closely — though I agree the best approach to follow-up isn’t well defined.
I’ve always worried about false positive hep B core antibodies and have vaccinated accordingly. Very interesting article though.
This comes up in our transplant/oncology ID clinic on occasion. My personal feeling is that vaccination is a low-risk/high-reward intervention in most of these patients. Assuming their HBV DNA is negative, you are providing protection to those people whose HBcAb is a false positive, and we hypothetically could reduce reactivation risk for the others – maybe not enough to prevent the need for secondary antiviral prophylaxis for patients getting rituximab, but maybe enough for those undergoing future kidney transplantation, for example.
Anyways, I don’t see a downside to vaccinating if it’s feasible. But as Dr. Kim said above, more data are needed.
Thanks for the comment. Your approach is similar to the rationale given to me by someone on the HIV opportunistic infections guidelines committee. However, vaccines are low risk, but not zero risk (there has been some controversy over Heplisav and CV risk, for example), and they certainly have a cost. I’d like to see at least some data that this “core alone” population benefits (the “reward” part!) from the vaccine before adopting it as a standard strategy.
-Paul
From my reading about reactivation Hep B in those with +hep B core, risk of reactivation increases as titer of HBsAb declines, so if vaccination can bump Ab, that is “probably” beneficial.
One of my HIV patients, had Hep B s Ab, core Ab “back in the day”–very poor adherence, eventually ESRD, so regular Hep B monitoring, eventually Hep B s Ag+ at low titer, with low or undetectable PCR, but even later (still untreated HIV), very high HBV PCR. So, once infected, always infected.
I saw a similar reactivation in a 70s yo West African man with a heme malignancy who was believed to be neg for all markers of HBV but after many rounds of tx of his heme malignancy, he had unexpected florid Hep B—and detective Jennyavita (me, to continue the metaphor) found ancient serologies with + Hep B s Ab in the EMR that were positive since in my experience older Africans have near universal HBV infection. So, once infected, always infected.
It is worth vaccinating to bump HBsAb probably, and certainly worth it, if isolated core is likely false positive.
But, once infected, always infected.
Thanks for this interesting post. I’ve always loved “pearls” since I was in training. Especially ID pearls.
Thanks for the noir movie melange, a nostalic reminder of when the outlaws were in the shadows, not running the Federal government.
Thanks for the excellent piece.
As raised by some of the other comments- one aspect to consider is whether vaccination of isolated c Ab (+) PWH will reduce the likelihood of reactivation when switching to HBV-sparing ART. We know the risk is higher if isolated cAb vs core Ab (+)/S ab (+) – the US VA VACS study (Denyer IDWeek 2024) and others have shown this. To my knowledge, no data on whether vaccinating isolated c ab (+) will reduce the risk of reactivation but data on this will be welcome as many HBV-sparing ART options are now available or in the pipeline. This would be a very welcome benefit of vaccination isolated core Ab(+).
Thanks SO much! I have wondered about this for decades!
Still dazed and confused by the lone HBcAB+, but an informative and clear-as-can-be piece, given what we know and don’t know. And worth re-reading until we know more.
Also some stimulating comments from the audience.
Thanks, again!
One additional and often missed false positive HBcAb can be seen in patients receiving IVIG infusions. These passive antibodies should clear on their own within 8 to 12 weeks post infusion.
If patient not vaccinated for Hep A, I vaccinate with combo vaccine for A and B with 3 doses
There is a 5th possibility in the setting of HBAg mutations where testing leads to false-negative HBsAg results. This occurs when monoclonal instead of polyclonal hepatitis B surface antibodies are used in enzyme immunoassays for capture and/or detection of HBsAg.
Source: Uptodate
Thank you for this interesting post on isolated anti-HBc! A common clinical conundrum. One other “suspect” I would add to your list is “a mutant HBsAg strain” – this would be diagnosed by sending an HBV DNA and the quantitative level would be high (rather than low-ish like in occult B infection). That is why I think checking an HBV DNA is important (despite not being recommended by the OI guidelines).
Hi Paul,
Thanks for tackling this maddening conundrum.
In your post you note that guidelines recommend vaccinating those with isolated anti-HBc+, but I have seen very different recommendations for those living with HIV vs those not living with HIV. Can you share the guidelines you cite?
In my previous searching I have found this from an old CDC page “Hepatitis B Questions and Answers for Health Professionals”:
“Is there any benefit or risk in vaccinating a person who has been infected with HBV?
Persons who have already been infected with HBV will receive no benefit from vaccination. However, there is no risk to a previously infected person who receives vaccination…Persons who are anti-HBc positive should be counseled about their prior exposure to HBV and potential risk for HBV reactivation.”
-https://stacks.cdc.gov/view/cdc/117930
People with isolated anti-HBc should be vaccinated with one standard dose of HepB vaccine (one dose of Heplisav-B, or Engerix-B, or Recombivax HB), and anti-HBs titers should be checked 1 to 2 months after vaccination (BII). If the anti-HBs titer is ≥100 mIU/mL, no further vaccination is needed, but if the titer is 18 months compared with only 23% of those who achieved a titer of 10 to 100 mIU/mL.61 If anti-HBs quantitative titers are not available, then the complete series of HepB vaccine should be completed followed by qualitative anti-HBs testing
– https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/hepatitis-b-virus
When working with a population with high risk for HBV exposure (people who inject drugs, people living with HCV and/or HIV), it seems very reasonable to assume prior infection is the explanation for this titer pattern. How, then, to reconcile these drastically different recommendations?
I had been educated by a hepatologist that the absence of circulating HBV virus in the blood does not eliminate the risk of HBV reactivation with HCV treatment, and so, since your clinical management would not change (no matter what you would educate the patient on the low but potentially serious risk and monitor for sxs of reactivation), and there is additional cost and delay to checking this lab, checking an HBV VL is not necessary.
In our HCV treatment program we are not routinely checking HBV VLs or vaccinating everyone we identify with an isolated anti-HBc+, except in cases of PLWH, though even that data feels shaky to me as it was following 54 patients to monitor for an anti-HBs titer response only, and did not evaluate reactivation at all. In hundreds of folks with HCV and isolated anti-HBc titers, we have had zero cases of reactivation.
Other cohorts have described very very low rates of reactivation in the isolated anti-HBc+ cohort undergoing HCV treatment. (https://journals.lww.com/hep/abstract/2017/07000/evaluation_of_hepatitis_b_reactivation_among.6.aspx; https://www.sciencedirect.com/science/article/abs/pii/S1386653217301610?via%3Dihub).
In terms of this risk among people with HIV undergoing an ART switch, case reports like this one (https://www.natap.org/2023/HIV/brief_report__hepatitis_b_infection_or.9.pdf) showed HBV reactivation among 4 individuals with a range of titer patterns, including an individual with anti-HBs+ only.
The risk of HBV reactivation with rituximab and other B-cell depleting meds seems much more concerning and better understood. I am not convinced that the data we have based our HCV and HIV assessment and management guidelines for anti-HBc+ patients are as sound.
We need recommendations grounded in large cohort data sets, focused on the concerning outcomes, not just titer levels or patterns, and with consideration of the practical and public health implications for the marginalized populations and health care settings most effected.
Thanks for listening and would love your thoughts!
maggie