Viral Hepatitis
Hepatitis B and C are now screen-everyone diseases: every adult gets tested at least once. HCV is curable in 8 to 12 weeks of pills, HBV is controllable and its reactivation is preventable, and the serology panel that residents fear is a logic puzzle with six standard answers. The two rules that prevent disasters: check HBV before immunosuppression, and check HBV before treating HCV.
🔍 Overview
The Five Viruses in One Paragraph Each
- Hepatitis A: fecal-oral, acute only, never chronic. Supportive care; fulminant failure is rare (higher with underlying chronic liver disease, which is why chronic HBV/HCV patients get the HAV vaccine). Vaccine or immunoglobulin for close contacts within 2 weeks of exposure.
- Hepatitis B: blood and sexual transmission. Chronicity is inversely proportional to age at infection: ~90% chronic when acquired at birth, < 5% as an adult, because the adult immune system clears the virus and the infant's tolerates it. Chronic HBV drives cirrhosis and hepatocellular carcinoma, and HBV causes HCC even without cirrhosis (the viral DNA integrates into the host genome).
- Hepatitis C: blood-borne (injection drug use is the dominant US route). 50-85% of infections become chronic. Curable in > 95% with 8-12 weeks of oral therapy, which is why finding it is the whole battle.
- Hepatitis D: a defective virus that requires HBsAg to replicate -only exists with HBV. Check anti-HDV in any HBsAg-positive patient with severe or rapidly progressive disease, or risk factors. Superinfection of a chronic HBV carrier is the classic cause of sudden decompensation.
- Hepatitis E: fecal-oral, usually self-limited, but up to 20-25% mortality in pregnancy (third trimester) and can become chronic in the immunosuppressed (transplant patients). Think of it in the returned traveler with hepatitis and negative A-C workup.
Who Gets Screened (both are now universal)
- HCV: every adult 18 and older at least once, and every pregnancy (CDC 2020, USPSTF Grade B). Risk-based screening missed half of infections because half of patients had no identified risk factor -that is why the policy changed.
- HBV: every adult 18 and older at least once with the triple panel (HBsAg, anti-HBs, total anti-HBc; CDC 2023). The triple panel is deliberate: one test tells you infected, immune, or exposed-and-at-risk-of-reactivation, which a lone HBsAg cannot.
- Rescreen with ongoing risk: injection drug use, HIV, dialysis, incarceration, HBsAg-positive household or sexual contacts.
- Vaccinate: HBV vaccine is now universal for adults 19-59 (ACIP 2022) and risk-based at 60+. HAV vaccine for chronic liver disease of any cause.
Why the internist owns this: most chronic HBV and HCV is asymptomatic until cirrhosis, both are found by screening rather than symptoms, and the two highest-stakes moments (starting immunosuppression in unrecognized HBV, and missing a curable HCV) happen in clinics and on wards, not in hepatology offices.
🧪 Serologies & Workup
The HBV Serology Puzzle (six standard answers)
| Pattern | HBsAg | Anti-HBs | Anti-HBc | Interpretation & Why |
|---|---|---|---|---|
| Acute infection | + | - | + (IgM) | Surface antigen means virus present; IgM core says the infection is new (first 6 months). |
| Chronic infection | + (> 6 mo) | - | + (IgG) | HBsAg persisting past 6 months defines chronicity. Next steps: HBeAg, HBV DNA, ALT to stage the phase. |
| Immune from vaccination | - | + | - | Vaccine contains only surface antigen, so it raises anti-HBs and nothing else. Core antibody negative is the giveaway. |
| Immune from resolved infection | - | + | + (IgG) | Real infection exposed the immune system to core protein too. Virus is controlled, not eradicated -cccDNA persists in hepatocytes, which is why reactivation is possible. |
| Window period | - | - | + (IgM) | HBsAg has cleared but anti-HBs has not yet appeared: IgM anti-HBc is the only positive marker. Miss this and an acute infection reads as "negative." |
| Isolated anti-HBc | - | - | + (IgG) | Four possibilities: resolved infection with waned anti-HBs (most common), occult infection (check DNA), window period, or false positive. Treat as prior infection when immunosuppression is planned -this pattern still reactivates. |
Once a Diagnosis Is Made (either virus)
- Stage the liver: ALT/AST, platelets (thrombocytopenia is the earliest cirrhosis clue), FIB-4 then elastography -biopsy is now the exception. Why: fibrosis stage sets surveillance and urgency, and F3-F4 changes management forever even after cure.
- Check the companions: HIV (shared routes; coinfection changes therapy), HAV immunity (vaccinate if absent), HDV if HBsAg-positive with severe disease or risk factors, and for HCV patients an HBV triple panel before DAAs (reactivation risk, below).
- HCC surveillance: ultrasound ± AFP every 6 months for all cirrhosis, and for HBV without cirrhosis in higher-risk groups (family history of HCC, and patients from high-prevalence regions by age thresholds). NEW 2026 Also HDV coinfection at any fibrosis stage, HIV coinfection (men from 18, women from 40), and after HBsAg loss if there is cirrhosis, a family history of HCC, or the loss came after age 40 in men or 50 in women; HCV coinfection is surveyed as for HBV alone once the HCV is treated. Why: HBV integrates and causes HCC without cirrhosis.
- Extrahepatic clues that should trigger testing: cryoglobulinemia, membranoproliferative GN, porphyria cutanea tarda, lichen planus point to HCV; polyarteritis nodosa and membranous nephropathy point to HBV.
🦠 Hepatitis B
Who Gets Treated (AASLD/IDSA 2026, building on AASLD 2018)
What changed in 2026 (AASLD/IDSA guideline, Hepatology, April 2026): the immune-active thresholds are unchanged. New: treatment is suggested for immune-tolerant patients over 40 or with F2+ fibrosis, there is a shared-decision path for the indeterminate "gray zone", tenofovir from week 28 in pregnancy is now a strong recommendation, therapy is not stopped in HBeAg-negative patients before HBsAg loss, and more groups qualify for HCC surveillance. Everything else in AASLD 2018 still applies.
- Immune-active disease: UNCHANGED ALT ≥ 2x upper limit of normal PLUS HBV DNA ≥ 20,000 IU/mL (HBeAg-positive) or ≥ 2,000 IU/mL (HBeAg-negative). Why the thresholds: treatment benefits patients whose immune system is actively fighting (and damaging) the liver. Use an ALT upper limit of normal of 35 U/L in men and 25 U/L in women, the guideline's own cutoffs, rather than the lab's printed range.
- Immune-tolerant (HBeAg-positive, DNA > 10,000,000 IU/mL, persistently normal ALT): usually monitored, with HBV DNA and ALT at least every 6 months to catch the switch to immune-active disease. CHANGED 2026 AASLD/IDSA now suggests treating if the patient is over 40 or has grade 2+ inflammation or F2+ fibrosis on biopsy or noninvasive testing, because that is where liver damage and HCC risk accumulate while the ALT still looks normal; under 40, decide together (conditional, very low certainty).
- Indeterminate ("gray zone"): NEW 2026 up to 40% of adults fit no defined phase. For HBeAg-negative patients without cirrhosis, the guideline suggests offering treatment by shared decision and revisiting it at every visit if it is not started. If the ALT is above normal but DNA is under 2,000, look for another cause of the enzyme rise first.
- Cirrhosis with any detectable DNA: treat regardless of ALT -the liver has no reserve left to spend on flares.
- Acute HBV: supportive care for most (adults clear it > 95% of the time); antivirals only for fulminant or severe disease (rising INR, bilirubin, encephalopathy) and always alongside a transplant-center conversation.
- Special indications regardless of the numbers: reactivation prophylaxis (below), pregnancy with DNA > 200,000 IU/mL at any point, regardless of HBeAg: start TDF or TAF at week 28 STRENGTHENED 2026 (now a strong recommendation; TDF has the longer pregnancy safety record, and a patient on entecavir is switched to one of them), because 8-10% of infants are still infected at that viral load despite birth-dose vaccine + HBIG; and HDV coinfection. Viremic patients below the thresholds who are in high-risk settings for transmitting HBV can also be offered treatment by shared decision (conditional, 2026).
The Drugs
- First-line: entecavir, tenofovir disoproxil (TDF), or tenofovir alafenamide (TAF) -high-barrier nucleos(t)ide analogs taken once daily, usually indefinitely. Choice is by comorbidity: TDF stresses kidneys and bone (avoid in CKD/osteoporosis, prefer TAF or entecavir); entecavir needs renal dosing and loses potency in lamivudine-experienced patients.
- Why "control, not cure": nucleos(t)ide analogs suppress replication but cannot remove cccDNA from hepatocyte nuclei, so stopping invites relapse and treatment is long-term. HBsAg loss ("functional cure") happens in only a few percent. NEW 2026 In HBeAg-negative patients without cirrhosis whose DNA is suppressed, the guideline suggests not stopping until HBsAg loss. Anyone determined to stop needs strict criteria (no cirrhosis, decompensation or HCC, DNA undetectable for at least 2 years, HBsAg under 100 IU/mL, no HIV or HDV) and HBV DNA plus ALT every 1-3 months for the first 6 months, because relapse after stopping is common and a flare can be severe.
- Do not use lamivudine as a primary agent -resistance develops in most patients within a few years, and it burns the entecavir option too.
Reactivation prophylaxis is the highest-stakes HBV decision an internist makes. Before rituximab or any anti-CD20 therapy, stem cell transplant, or high-dose steroids (≥ 20 mg prednisone for ≥ 4 weeks), check HBsAg AND anti-HBc. HBsAg-positive OR anti-HBc-positive patients starting anti-CD20 therapy or transplant get prophylactic entecavir or tenofovir, continued 12-18 months after the last dose, because reactivation in that setting can be fulminant and fatal, and it is entirely preventable. This is why the site's lymphoma content repeats "screen before rituximab" -this page is the why.
💊 Hepatitis C
Diagnosis to Cure in Four Steps
- 1. Antibody, then RNA: a positive anti-HCV means exposure ever; HCV RNA confirms current infection (20-25% clear spontaneously and stay antibody-positive for life). Never label someone "hepatitis C" on antibody alone.
- 2. Stage fibrosis (FIB-4, elastography) -not to decide whether to treat (everyone with viremia gets treated) but because cirrhosis changes the regimen details and mandates lifelong HCC surveillance even after cure.
- 3. Treat with a pan-genotypic DAA: glecaprevir/pibrentasvir (Mavyret) 3 tabs daily x 8 weeks, or sofosbuvir/velpatasvir (Epclusa) 1 tab daily x 12 weeks. The AASLD/IDSA simplified pathway lets non-specialists treat treatment-naive patients without decompensation -genotyping is no longer required for these regimens. Cure (SVR12: undetectable RNA 12 weeks after finishing) exceeds 95%.
- 4. Confirm SVR12 and close the loop: cured patients with F3-F4 fibrosis keep 6-monthly HCC surveillance (risk falls but never returns to baseline); reinfection is possible, so ongoing risk means periodic RNA rechecks -and reinfection is treated again, not moralized about.
Traps and Truths
- Treat acute HCV immediately -the old "wait 6 months for spontaneous clearance" is gone; early DAA therapy is recommended, cures at the same rate, and prevents transmission in the meantime.
- Watch the interactions: DAAs tangle with statins (dose limits), amiodarone (bradycardia with sofosbuvir -avoid), PPIs (velpatasvir needs acid to absorb -a hidden cause of "treatment failure"), and anticonvulsants/rifampin (induce DAAs to subtherapeutic levels).
- Protease-inhibitor regimens (glecaprevir/pibrentasvir) are contraindicated in decompensated (Child-Pugh B/C) cirrhosis -use sofosbuvir-based therapy and involve hepatology.
- Active injection drug use is NOT a contraindication to treatment -cure rates are comparable, treatment is prevention, and guidelines are explicit about it.
- No post-cure immunity: unlike hepatitis B, cured HCV leaves no protective antibody. Counsel on reinfection; the anti-HCV stays positive for life, so rechecking requires RNA, not serology.
Check the HBV triple panel before starting any DAA. HCV suppresses HBV replication; cure the HCV and an unrecognized HBV coinfection can reactivate, occasionally fulminantly -this is an FDA boxed warning on DAAs. HBsAg-positive coinfected patients need HBV therapy or close monitoring during and after DAA treatment.
🏥 Rounds
Pimp Questions
❓ The panel shows anti-HBc positive but HBsAg and anti-HBs negative. What are the four explanations, and what is the practical implication?
Isolated anti-HBc = (1) resolved infection with waned anti-HBs (most common), (2) occult HBV (check DNA), (3) the window period of acute infection (IgM distinguishes it), or (4) false positive. The implication: treat it as prior infection whenever immunosuppression is planned -cccDNA persists in hepatocytes, so this pattern can still reactivate under rituximab or transplant, and it earns the same prophylaxis as anti-HBc-positive patients with anti-HBs.
❓ Why must the HBV panel be checked before starting hepatitis C DAA therapy?
HCV actively suppresses HBV replication in coinfected patients. Cure the HCV in 8-12 weeks and that suppression vanishes -unrecognized HBV can reactivate, occasionally as fulminant hepatitis. It is an FDA boxed warning on all DAAs. HBsAg-positive patients need concurrent HBV therapy or tight monitoring; anti-HBc-only patients need surveillance for reactivation during and after treatment.
❓ During the "window period" of acute hepatitis B, what is the ONLY positive marker, and why does the window exist?
IgM anti-HBc. The window is the gap after HBsAg falls below detection but before anti-HBs rises into it -antigen and antibody are binding each other into immune complexes, so neither is measurable free in serum. A patient tested only with HBsAg and anti-HBs reads falsely "negative" in exactly the window when they are acutely infected, which is why the core antibody belongs in every acute hepatitis workup.
❓ Why does chronic hepatitis B cause hepatocellular carcinoma without cirrhosis, when hepatitis C essentially requires it?
HBV is a DNA virus that integrates into the host genome, directly mutagenizing hepatocytes -oncogenesis without needing decades of cirrhotic regeneration. HCV is an RNA virus that never integrates; its HCC risk is carried almost entirely by cirrhosis-driven regeneration. Practical consequence: HBV patients can warrant HCC surveillance without cirrhosis (family history of HCC, high-prevalence-region patients past age thresholds), while HCV surveillance is tied to F3-F4 fibrosis, continuing even after cure.
❓ A cured HCV patient with prior F4 fibrosis asks if they are "done." What two things continue forever?
HCC surveillance (ultrasound ± AFP every 6 months) continues indefinitely -SVR drops HCC risk substantially but never to baseline in established cirrhosis. And reinfection surveillance with RNA if risk continues, because cure confers no immunity and the anti-HCV antibody stays positive for life (making serology useless for rechecking). Portal hypertension follow-up also continues if varices were present.
Sample Presentation
Mr. Reyes is a 58-year-old man flagged on universal screening with a positive HCV antibody, confirmed RNA of 2.1 million IU/mL, genotype not sent. History of remote injection drug use in the 1990s, no alcohol for a decade. Labs: ALT 62, AST 55, platelets 148, FIB-4 2.9; elastography shows F3 fibrosis, no decompensation. HBV triple panel: HBsAg negative, anti-HBc positive, anti-HBs positive. HIV negative, HAV immune.
Key Points: (1) He qualifies for the simplified pathway: treatment-naive, compensated -glecaprevir/pibrentasvir for 8 weeks without genotyping, after a med-rec for statin and PPI interactions. (2) The resolved HBV (anti-HBc+/anti-HBs+) is exactly the boxed-warning scenario in miniature: no HBV therapy needed, but monitor ALT during treatment and know that reactivation is the explanation if it spikes. (3) F3 fibrosis means HCC surveillance every 6 months continues after cure, and SVR12 at week 24 from start is the finish line that must actually get ordered -the commonest failure in HCV care is the loop that never closes.
Clinic & Ward Checklist
- Every admission med-rec with rituximab, chemotherapy, or transplant plans: HBsAg and anti-HBc documented? Prophylaxis arranged if either is positive?
- Every positive anti-HCV: RNA sent? (Antibody alone is exposure, not infection.)
- Before any DAA: HBV triple panel, fibrosis stage, interaction check (statins, PPIs, amiodarone, anticonvulsants).
- SVR12 ordered and tracked -a cure that is never confirmed is a loop that never closed.
- Cirrhosis or F3: HCC ultrasound q6 months on the problem list, cure or no cure.
- Vaccinations: HAV for all chronic liver disease; HBV vaccine for the unvaccinated under 60 (universal) and at-risk 60+.
- HBsAg-positive patients: HDV checked if severe, progressive, or risk factors; household contacts screened and vaccinated.
📋 Summary
Summary
Screen Everyone, Once
HCV: all adults 18+ and every pregnancy (CDC 2020). HBV: all adults 18+ with the triple panel, HBsAg + anti-HBs + anti-HBc (CDC 2023). Risk-based screening missed half of infections because half of patients reported no risk factor. The triple panel earns its three tests: infected, immune, or exposed-and-reactivatable are three different futures.
Read the Panel Like a Logic Puzzle
HBsAg = virus present; anti-HBs = protection; anti-HBc = ever truly infected (vaccine never raises it). IgM core = new. The two patterns that fool people: the window period, where IgM anti-HBc is the only positive, and isolated anti-HBc, which still reactivates under immunosuppression and gets treated as prior infection.
HBV: Treat the Immune-Active, Watch the Tolerant
ALT ≥ 2x normal plus DNA > 20,000 (HBeAg+) or > 2,000 (HBeAg-) IU/mL = treat; cirrhosis with any detectable DNA = treat regardless. Entecavir or tenofovir long-term: they suppress but cannot excise cccDNA, so this is control, not cure. Choose by comorbidity (TDF spares neither kidney nor bone; TAF and entecavir do).
The Reactivation Rule Saves Lives
Before rituximab, transplant, or prolonged high-dose steroids: HBsAg AND anti-HBc. Either positive before anti-CD20 therapy or transplant means prophylactic entecavir or tenofovir, continued 12-18 months past the last dose. Reactivation in this setting can be fulminant and fatal, and it is the most preventable disaster in hepatology.
HCV: Antibody Finds It, RNA Confirms It, Pills Cure It
Positive antibody needs RNA confirmation (a quarter clear spontaneously and stay seropositive forever). Then glecaprevir/pibrentasvir 8 weeks or sofosbuvir/velpatasvir 12 weeks cures > 95%, no genotyping needed on the simplified pathway, no waiting in acute infection, and active drug use is not a contraindication -treatment is prevention.
DAA Traps Are Pharmacologic, Not Virologic
Check HBV first (boxed warning), then the med list: amiodarone + sofosbuvir (bradycardia), PPIs starving velpatasvir of the acid it needs to absorb, statin dose caps, and enzyme inducers gutting drug levels. Protease-inhibitor regimens are barred in decompensated cirrhosis -sofosbuvir-based therapy with hepatology instead.
Cure Is Not Closure in F3-F4
SVR12 is the finish line and must actually be ordered. After it: cirrhosis and F3 keep 6-monthly HCC surveillance indefinitely (risk falls, never to baseline), reinfection checks use RNA because the antibody stays positive for life, and no immunity is conferred. HBV differs: it integrates, so HBV can cause HCC without cirrhosis and surveillance rules reflect it.
The Small Print That Recurs on Rounds
HDV only exists with HBV -check it when an HBsAg-positive patient decompensates abruptly. HEV kills in pregnancy (up to 20-25% in the third trimester) and turns chronic in transplant patients. HAV vaccine for every chronic liver disease patient, because acute-on-chronic hepatitis A is the preventable fulminant failure. Tenofovir (TDF or TAF) from week 28 when maternal DNA > 200,000 blocks vertical HBV transmission on top of birth-dose vaccine + HBIG.
