HIV and ID Observations

(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.

The suspects:

1. 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.
2. 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.
3. 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.
4. 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.