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Viral Hepatitis: Serologic Interpretation & HBV/HCV Management

Name: Viral Hepatitis: Serologic Interpretation & HBV/HCV Management
Creator: Veli Bakalov, MD

Decode the markers, then decide who needs antivirals

Gastroenterology·Hepatitis & Liver Injury·6 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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HBsAg = current infection (over 6 months = chronic); anti-HBs alone = vaccinated; anti-HBs + anti-HBc = resolved infection; IgM anti-HBc = acute infection and the only marker in the window period.
HBV chronicity depends on age at infection: ~90% of perinatal infections, 25–50% at ages 1–5, and under 5% of immunocompetent adults.
Treat chronic HBV for ALT over 2× ULN with HBV DNA over 20,000 IU/mL (HBeAg+) or ≥2,000 IU/mL (HBeAg−), cirrhosis with detectable DNA, acute liver failure, or extrahepatic disease; use tenofovir or entecavir after testing for HIV.
HCC surveillance (ultrasound ± AFP every 6 months) in HBV even without cirrhosis: Asian men ≥40, Asian women ≥50, African origin, family history of HCC, or HDV coinfection.
Check HBsAg and anti-HBc before rituximab, chemotherapy, anti-TNF drugs, high-dose steroids, transplant, or HCV DAAs; give entecavir/tenofovir prophylaxis, even for HBsAg−/anti-HBc+ patients on rituximab.
Infant of an HBsAg-positive mother: HBIG + vaccine within 12 hours, then HBsAg/anti-HBs at 9–12 months; mother starts tenofovir at 28 to 32 weeks and continues it through delivery if HBV DNA is over 200,000 IU/mL; breastfeeding is allowed.
HAV is fecal-oral and never chronic (PEP within 14 days: vaccine if ≥12 months, immune globulin for infants); HEV is fulminant in third-trimester pregnancy and chronic in transplant recipients.
HDV needs HBsAg: coinfection usually clears, superinfection of a chronic carrier causes severe chronic hepatitis and rapid cirrhosis.
HCV: screen all adults once and every pregnancy, anti-HCV → HCV RNA; glecaprevir-pibrentasvir 8 weeks or sofosbuvir-velpatasvir 12 weeks (plus ribavirin if decompensated); SVR12 = cure; never sofosbuvir with amiodarone.

Enteric hepatitis: HAV and HEV

Hepatitis A. A picornavirus (RNA) spread fecal-orally through contaminated food and water. Risk groups are travelers, men who have sex with men, people experiencing homelessness, and people who use drugs. After an incubation of about 4 weeks, infection is silent in young children but icteric in most adults, with ALT often in the thousands. IgM anti-HAV means acute infection; IgG means past infection or vaccination. Care is supportive, and there is no carrier state.

Fulminant HAV is rare, but it is more likely with older age or underlying chronic liver disease. This is one reason patients with chronic liver disease are vaccinated.

HAV postexposure prophylaxis. Give it within 14 days of exposure:

Healthy people ≥12 months: hepatitis A vaccine
Infants <12 months, or when the vaccine is contraindicated: immune globulin
Immunocompromised patients or those with chronic liver disease: immune globulin plus vaccine

HAV vs HEV

Feature	Hepatitis A	Hepatitis E
Virus and spread	Picornavirus; fecal-oral via food and water	RNA virus; waterborne epidemics (genotypes 1–2, South Asia and Africa) or undercooked pork and game (genotype 3)
Diagnosis	IgM anti-HAV	IgM anti-HEV; HEV RNA PCR in immunosuppressed hosts, who may not make antibody
High-risk host	Older age, chronic liver disease (fulminant course)	Third-trimester pregnancy: fulminant failure with mortality up to ~20%
Chronicity	Never chronic	Chronic hepatitis in transplant recipients: reduce immunosuppression, give ribavirin

Hepatitis B: virology and serology

The virus. HBV is a partially double-stranded DNA hepadnavirus that replicates through a reverse transcriptase. It spreads perinatally, sexually, and by blood. HBsAg that persists for >6 months defines chronic infection. How often infection becomes chronic depends on age at infection:

~90%of perinatal infections

25–50%of infections at ages 1–5

<5%of immunocompetent adult infections

Reading the HBV panel

Pattern	Meaning
HBsAg +	Current infection, acute or chronic; >6 months = chronic
Anti-HBs + alone	Vaccine immunity: the vaccine contains only surface antigen
Anti-HBs + and anti-HBc +	Resolved natural infection
IgM anti-HBc +	Acute infection. It is the only positive marker in the window period, after HBsAg clears but before anti-HBs appears
HBsAg + with IgG anti-HBc, anti-HBs −	Chronic infection
HBeAg +	High replication and infectivity

Anti-HBc comes only from natural infection, because core antigen is not in the vaccine. IgG anti-HBc lasts for life in both resolved and chronic infection.

Course of acute, self-limited infection.

HBsAg and HBV DNAAppear 1–10 weeks after exposure, before symptoms.
IgM anti-HBcArrives with symptoms and the ALT peak.
HBeAg → anti-HBeAs replication falls.
Window periodHBsAg gone; anti-HBs not yet detectable.
Anti-HBs plus IgG anti-HBcRecovery with lasting immunity.

HBeAg vs HBV DNA. HBeAg-positive mothers infect most unprotected newborns. Anti-HBe usually means lower replication. However, precore and core-promoter mutants cause HBeAg-negative chronic hepatitis with high DNA levels, so quantitative HBV DNA is the true measure of replication.

An HBeAg-negative patient with HBV DNA ≥2,000 IU/mL and a raised ALT has HBeAg-negative chronic hepatitis and needs treatment. This patient is not an inactive carrier.

Chronic hepatitis B: who and how to treat

Treat immune-active disease. This means ALT >2× the upper limit of normal (or significant fibrosis) together with HBV DNA above a cutoff: >20,000 IU/mL if HBeAg-positive, or ≥2,000 IU/mL if HBeAg-negative. Also treat:

Cirrhosis with any detectable DNA
Acute liver failure
Extrahepatic disease: polyarteritis nodosa, membranous nephropathy, MPGN

Patients in the immune-tolerant phase and inactive carriers, both with normal ALT, are monitored.

The immune-tolerant phase is HBeAg-positive with very high DNA, normal ALT, and minimal inflammation. It is typical of young adults infected at birth.

Drugs. The first-line agents are nucleos(t)ide analogs that block HBV reverse transcriptase and have a high barrier to resistance:

Tenofovir. TDF can cause proximal tubular injury and bone loss; TAF is gentler. TDF is the agent used in pregnancy.
Entecavir.

Both are usually continued long term because HBsAg loss is rare. Lamivudine is obsolete because it selects YMDD resistance mutants. Finite-course peginterferon is an option, but it is contraindicated in decompensated cirrhosis.

Test for HIV before starting HBV therapy. Tenofovir or entecavir given alone to a patient with unrecognized HIV selects resistant HIV.

HCC surveillance. Integrated HBV DNA is oncogenic, so HCC can develop without cirrhosis. Ultrasound with or without AFP every 6 months is advised for:

All carriers with cirrhosis
Asian men ≥40 and Asian women ≥50
People of African origin
A first-degree family history of HCC
HDV coinfection

Reactivation, pregnancy, and hepatitis D

Universal screening. CDC 2023: test all adults 18 or older at least once with the triple panel (HBsAg, anti-HBs, and total anti-HBc), and test people with ongoing risk periodically.

Screen before immunosuppression. Check HBsAg and anti-HBc before chemotherapy, anti-CD20 agents (rituximab), anti-TNF drugs, high-dose steroids, transplant, or HCV DAAs. Give entecavir or tenofovir prophylaxis during therapy and for ≥6–12 months afterward to:

All HBsAg-positive patients
HBsAg-negative, anti-HBc-positive patients receiving rituximab

Reactivation can be fulminant.

Anti-CD20 therapy carries the highest risk. Even resolved infection (HBsAg-negative, anti-HBc-positive) can reactivate, and a positive anti-HBs does not prevent it.

Perinatal prevention.

Screen HBsAg in every pregnancy.
If the mother is positive, give the newborn HBIG plus the first vaccine dose within 12 hours of birth and complete the series.
Check the infant's HBsAg and anti-HBs at 9–12 months.
If maternal HBV DNA is >200,000 IU/mL, the mother starts tenofovir at 28 to 32 weeks and continues it through delivery.
Breastfeeding is fine, and cesarean delivery is not required.

Hepatitis D (HDV). A defective RNA virus that borrows HBsAg for its envelope. It infects only HBsAg-positive people, so HBV vaccination prevents it. Coinfection (HBV and HDV acquired together, with IgM anti-HBc positive) usually clears along with the acute HBV. Superinfection of a chronic carrier (IgM anti-HBc negative) causes a severe, usually chronic hepatitis with rapid progression to cirrhosis. HBV DNA is often suppressed during a superinfection flare. Test anti-HDV, then HDV RNA. Peginterferon is the main therapy.

Hepatitis C

Screening. Test all adults ≥18 at least once, every pregnant woman in each pregnancy, and people with ongoing risk (such as injection drug use) periodically. A reactive anti-HCV reflexes to HCV RNA. RNA-positive means current infection; RNA-negative means cleared infection or a false-positive antibody. About 75–85% of infections become chronic. Antibody does not protect against reinfection.

Before treatment.

Quantitative HCV RNA
Fibrosis staging with FIB-4 or elastography. Cirrhosis changes the regimen and requires HCC surveillance.
HBsAg and anti-HBc. DAAs can reactivate HBV (boxed warning).
HIV test and pregnancy test
Drug-interaction review

Genotyping is optional with pangenotypic regimens.

Key interactions: sofosbuvir plus amiodarone causes severe, even fatal, bradycardia. PPIs lower velpatasvir absorption. Rifampin, carbamazepine, and St John's wort lower DAA levels.

Pangenotypic DAA regimens (cure >95%)

Feature	Glecaprevir-pibrentasvir	Sofosbuvir-velpatasvir
Targets	NS3/4A protease + NS5A	NS5B polymerase + NS5A
Duration (treatment-naive, with or without compensated cirrhosis)	8 weeks	12 weeks
Decompensated cirrhosis	Avoid: protease inhibitor hepatotoxicity	12 weeks plus ribavirin

Cure. SVR12, undetectable RNA 12 weeks after therapy, is a cure. Antibody persists, reinfection is possible, and patients with cirrhosis continue HCC surveillance every 6 months.

Extrahepatic HCV. Many of these regress after cure:

Mixed (type II) cryoglobulinemia: palpable purpura, arthralgia, neuropathy, low C4, positive RF, with membranoproliferative GN
Porphyria cutanea tarda: blistering, fragile sun-exposed skin
B-cell non-Hodgkin lymphoma, especially splenic marginal zone
Lichen planus
Insulin resistance