Viral Hepatitis: Hepatitis B and D

0:00Welcome to Board Pearls. This is episode two of three of the Viral Hepatitis chapter, in the Liver Disease module. This episode is hepatitis B and D: the serology that tells the phase, the nucleoside-analog treatment by phase, the bundle that prevents vertical transmission, the screen-and-prophylax rule for reactivation, and hepatitis D with its new entry inhibitor.

0:20The prior episode treated acute hepatitis as a serologic pattern read off a panel. This episode steps inside hepatitis B, where the panel is not just diagnostic, it's a phase grid, and the phase determines the treatment, the pregnancy strategy, the reactivation rule, and the hepatitis D testing decision. Get the grid and the management falls out. Start with the markers, because they're the language. The surface antigen is the envelope protein made in vast excess during active infection, so it's the marker that says the patient is currently infected. The surface antibody is the neutralizing antibody, marking immunity from natural recovery or the vaccine. The core antibody only appears after natural infection, and since the vaccine contains surface antigen alone, the core antibody is what distinguishes the recovered patient from the vaccinated one, which matters under immunosuppression. The core antibody has two flavors: the IgM marks acute infection in most patients, and the total marks remote exposure, with the trap that the IgM can repositivate during a chronic flare, so an isolated positive IgM in a known chronic carrier isn't necessarily new acute infection. The e-antigen is a secreted protein co-expressed during high-replication infection, a marker of replication and infectivity, and the e-antibody appears with seroconversion signaling lower replication, with the caveat that precore mutant strains replicate without producing the e-antigen, which is the whole reason the e-antigen-negative active phase exists. And the viral DNA is the direct quantitative measure of viremia, the truth-teller when serology gets ambiguous.

1:57Now the grid the boards exploit, reading surface antigen, core antibody, and surface antibody together. Negative across the board is uninfected and unvaccinated, so vaccinate. Surface antibody positive with core antibody negative is vaccine-induced immunity. Surface antibody positive with core antibody positive is resolved natural infection, immune in the everyday sense but still carrying the covalently closed circular DNA reservoir in hepatocyte nuclei, which is the management hinge for reactivation. Surface antigen positive with core antibody positive and surface antibody negative is active infection, acute if the IgM is positive and chronic if the IgM is negative with the total positive. The pattern that gets the most board space is isolated core antibody positive with surface antigen and surface antibody negative, under which sit four explanations, a window-period acute infection, a remote resolved infection with waned surface antibody, an occult chronic infection detectable only on DNA, or a false positive, so the workup is viral DNA and a repeat panel with vaccination considered if it stays isolated and the DNA undetectable.

3:07The second grid is the phase of chronic infection, where mechanism predicts therapy, defined by three things against histology: e-antigen status, viral DNA, and ALT, and the reason it earns memorization is that it maps directly onto whether you treat. The immune-tolerant phase is e-antigen positive, DNA above a million, and a normal ALT with minimal histology, the young patient infected at birth whose immune system isn't yet attacking, replication without inflammation, and you don't treat. The e-antigen-positive immune-active phase keeps the e-antigen positive and DNA above twenty thousand but now with an elevated ALT, using the tighter staging upper limits of thirty-five in men and twenty-five in women, with moderate-to-severe inflammation, so the immune system has engaged and this phase is treated. The inactive carrier phase is e-antigen negative with e-antibody positive, DNA below two thousand, and a normal ALT with benign histology, monitored every three to six months and not treated, with the trap that DNA up to twenty thousand can occur in inactive carriers, so the inactive label is the combination of low DNA plus normal ALT plus benign histology, not DNA alone, and a single normal ALT doesn't lock it in because some patients oscillate. The e-antigen-negative immune-active phase is the precore-mutant story, e-antigen negative because the mutant can't make it, but DNA above two thousand and ALT elevated or fluctuating with moderate-to-severe inflammation, the escape phase from inactivity, and it's treated. Both immune-active phases earn treatment because the natural history is progressive in both, somewhat faster in the e-antigen-positive one. And resolved hepatitis B is surface antigen negative, core antibody positive, and DNA undetectable, but the reservoir persists in the nuclei, which is the molecular reason these patients reactivate under immunosuppression. A few pitfalls travel with the grid: e-antigen seroconversion isn't cure, because disease can persist as e-antigen-negative active disease from precore mutants; the functional cure endpoint is surface antigen loss with undetectable DNA, rarely achieved on current oral drugs; and eradicating the nuclear reservoir isn't achievable with current agents, which is why treatment is generally indefinite.

5:30Now treatment, where the principle beats the threshold list: you treat patients with active disease in the immune-active phases, you treat cirrhotic patients regardless of DNA and ALT, you treat in high-transmission or high-reactivation contexts like immunosuppression and pregnancy, and you treat the small minority of acute cases that turn fulminant. The numerical thresholds inside the principle are DNA above twenty thousand with elevated ALT for e-antigen-positive active disease and DNA above two thousand with elevated ALT for e-antigen-negative active disease, with treatment also indicated when histology or elastography shows significant inflammation or fibrosis regardless of DNA and ALT, compensated cirrhosis treated for any detectable DNA, and decompensated cirrhosis with surface antigen positivity treated regardless of anything, because an unsuppressed flare there is a decompensation the liver can't tolerate. The drug menu has narrowed to three agents, entecavir and the two tenofovir prodrugs, with interferon a niche option now because of side effects, a fixed duration, and its potential to precipitate decompensation in cirrhotics. Entecavir is given at half a milligram daily naive, with the one-milligram dose reserved for prior lamivudine exposure because of cross-resistance. Both tenofovir prodrugs deliver the active drug intracellularly, but alafenamide achieves higher intracellular concentrations with lower serum exposure, giving equivalent virologic suppression with smaller declines in kidney function and bone density, so the practical choice is mechanism-driven: alafenamide is preferred in patients at risk for renal impairment or osteoporosis, while the disoproxil form is the preferred tenofovir in pregnancy because its safety and efficacy data are more robust, which is the pregnancy carve-out. Duration is essentially indefinite, with the acceptable stopping points being confirmed surface-antigen seroconversion, which is functional cure and rare, or sustained e-antigen seroconversion with prolonged DNA suppression in carefully selected non-cirrhotic patients, while cirrhotic and post-transplant patients continue indefinitely.

7:30Now the highest-yield pearl in the chapter, reactivation under immunosuppression, whose mechanism predicts the entire prophylaxis rule. The nuclear reservoir persists even in apparently recovered patients, surface antigen negative and core antibody positive, so when immune control is lost, the DNA rises abruptly, the ALT rises, and clinical hepatitis follows once the immune system reconstitutes, running from subclinical to fulminant failure with high mortality in severe cases despite rescue therapy, which is exactly why the standard of care is preemptive prophylaxis rather than rescue. Risk stratification combines serology with the intensity of immunosuppression, splitting patients into surface-antigen-positive, the higher risk, and surface-antigen-negative core-antibody-positive, a lower but real risk. The drugs that define the high-risk group are anti-CD20 antibodies like rituximab and stem-cell-transplant conditioning, because B-cell depletion produces reactivation rates in the resolved-infection group approaching those of the surface-antigen-positive group, with other high-risk settings being moderate-to-high-dose steroids, meaning above ten milligrams of prednisone daily for more than four weeks, anthracycline chemotherapy, and JAK inhibitors in surface-antigen-positive patients, while TNF inhibitors and other biologics carry moderate risk. The prophylaxis rule follows the risk: all surface-antigen-positive patients on any meaningful immunosuppression get entecavir or tenofovir, ideally started a week before or with the immunosuppression, continued for six months after standard therapy and for a year to eighteen months after B-cell-depleting therapy or transplant; surface-antigen-negative core-antibody-positive patients on anti-CD20 therapy or transplant also get prophylaxis because their risk approaches the surface-antigen-positive group; and those on lower-risk immunosuppression may be managed with monthly ALT and quarterly DNA surveillance with on-demand therapy, though the practical answer when monitoring is uncertain or the consequences severe is to give prophylaxis. The data behind this come from lymphoma cohorts, where preemptive antiviral therapy sharply reduced reactivation, jaundice, severe flares, and death versus on-demand treatment, and the canonical stem is a lymphoma patient about to start rituximab who is surface-antigen negative, core-antibody positive, surface-antibody positive, with undetectable DNA, where the answer is start prophylaxis, not monitor.

9:41Now pregnancy, where the mechanism explains the management. Perinatal infection produces the highest chronicity of any age window, with about ninety percent of neonates infected at birth becoming chronic carriers versus a small fraction of infected adults, through direct exposure to maternal blood at delivery with a smaller transplacental fraction, and the transmission risk tracks maternal DNA, so below two hundred thousand, passive plus active immunoprophylaxis of the newborn is highly effective, while above two hundred thousand, immunoprophylaxis alone fails in a meaningful fraction, which is the rationale for adding maternal antiviral therapy in the third trimester. The standard of care has three pillars. First, every pregnant woman is screened for surface antigen at the first visit, and positive women have DNA quantified, ALT measured, and a baseline fibrosis and cancer-risk assessment. Second, every infant of a surface-antigen-positive mother gets immunoglobulin plus the first vaccine dose within twelve hours of birth regardless of maternal viral load, with the series completed over months and post-vaccination antibody testing confirming the response, and this combination reduces transmission from over ninety percent without prophylaxis to a low level, with residual transmission concentrated in high-viral-load mothers, which the third pillar addresses. Third, mothers with DNA above two hundred thousand get tenofovir disoproxil started at twenty-eight to thirty-two weeks, earlier in very-high-baseline mothers to let the DNA fall by delivery, with lamivudine and telbivudine no longer used for resistance and alafenamide not yet recommended in pregnancy, and a mother on a non-disoproxil antiviral who becomes pregnant is switched to disoproxil if continuing. Past delivery, the antiviral can be stopped at delivery or a few weeks postpartum in mothers who otherwise lack a treatment indication, but a postpartum flare occurs in a notable fraction within the first few months, so mothers get ALT and DNA monitoring for six months after stopping, and mothers with advanced fibrosis shouldn't stop, because the decompensation risk is too high. And a few practical items: cesarean delivery hasn't been shown to reduce transmission and isn't indicated for hepatitis B alone, amniocentesis is avoided when possible, and breastfeeding isn't contraindicated when the infant has received immunoglobulin and vaccine, even with cracked nipples, because the immunoprophylaxis is the dominant protection.

11:58Now hepatitis D, the defective virus that depends on hepatitis B for its envelope, a negative-stranded RNA virus that requires the hepatitis B surface antigen to package itself, so there's no hepatitis D without hepatitis B, and the scenarios split by whether the infections arrive together or sequentially. Coinfection is simultaneous exposure, with a biphasic illness, an initial transaminase peak from hepatitis B and a second peak as hepatitis D replicates, a high acute failure risk during the second peak, and serology showing the D antibody, D RNA, and the hepatitis B core IgM together, meaning acute B alongside acute D, with most coinfected patients clearing both if they survive the acute illness. Superinfection is hepatitis D infecting a patient who already has chronic hepatitis B, looking like an acute flare in a known carrier, where chronicity is the rule, over ninety percent, and progression to cirrhosis is faster, with serology showing the D antibody and D RNA but the core antibody total positive without IgM, because the underlying B is chronic, and that distinction is how the boards make you tell coinfection from superinfection. The biology explains the recognition cue: hepatitis D uses surface antigen already in circulation, so it doesn't need active hepatitis B replication, and DNA can be low or suppressed while hepatitis D still drives a major ALT flare, which is why an ALT flare with low DNA in a known chronic hepatitis B patient is the trigger to test for hepatitis D. It's the most aggressive of the chronic hepatitis viruses, with more cirrhosis, sooner decompensation, and higher cancer risk, which is why cancer surveillance in D-positive patients begins regardless of fibrosis stage. The screening recommendation depends on the guideline body, one recommending universal testing of all surface-antigen-positive patients at least once and another risk-based testing, with the algorithm being the D antibody first, then D RNA to confirm active infection, and antibody-positive RNA-negative patients not actively infected and not needing treatment.

14:00Treatment has been historically poor, with interferon the historic option achieving sustained suppression in a minority and relapse the rule after stopping, so many centers extend it long-term. The new agent that changed the equation is bulevirtide, and the mechanism is the high-yield point: it's a synthetic lipopeptide mimicking the part of the surface antigen that binds the sodium taurocholate cotransporting polypeptide, the entry receptor both hepatitis B and D use to get into hepatocytes, so bulevirtide occupies that receptor and blocks entry, the first entry inhibitor for this disease. It's given subcutaneously, with monotherapy helping about half of patients, a higher dose more, and combination with interferon achieving the best response the disease has seen, though sustained response after stopping is uncommon so treatment is generally continued indefinitely, and it's approved in Europe and parts of Asia but not yet in the US, so the exam reaches for the mechanism, which is why owning the entry-inhibitor concept is the move.

15:04So pull it together. Hepatitis B is read off two grids: the serologic grid of surface antigen, core antibody, and surface antibody tells you whether the patient is uninfected, vaccinated, recovered, actively infected, or sitting on an isolated core antibody needing DNA to sort out, and the phase grid of e-antigen, DNA, and ALT tells you whether to treat. Treatment is entecavir or a tenofovir prodrug, indefinitely in almost all cases, with alafenamide preferred for renal and bone protection and disoproxil in pregnancy. Pregnancy is a three-pillar bundle: universal surface-antigen screening, infant immunoglobulin plus vaccine within twelve hours regardless of viral load, and maternal tenofovir disoproxil from twenty-eight to thirty-two weeks when DNA is above two hundred thousand. Reactivation under immunosuppression is the rule of preemptive prophylaxis over rescue, with the canonical stem being the surface-antigen-negative core-antibody-positive patient starting rituximab. And hepatitis D always rides on hepatitis B, is the most aggressive of the chronic hepatitis viruses, is triggered as a test when a chronic hepatitis B patient has an ALT flare with low DNA, and is now addressed by the entry inhibitor bulevirtide.

16:24The next episode is hepatitis C, where the disease has become curable and the boards test the workflow of cure: the reflex antibody-then-RNA diagnostic algorithm, the pangenotypic direct-acting antiviral regimens and the salvage regimen, special populations including decompensated cirrhosis where protease inhibitors are forbidden, and the post-cure cancer surveillance question where cure reduces but doesn't eliminate the risk.

16:51For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode two of three of chapter eighteen, and I'll see you in the next one.