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Serological Diagnosis and Management of Hepatitis B Virus (HBV) Infection

(β‰ˆ 1800 words)

Answer 1

1. Introduction

Hepatitis B virus (HBV), a 3.2-kb partially double-stranded DNA hepadnavirus, chronically infects an estimated 260 million people and caused approximately 820,000 deaths in 2019β€”primarily from cirrhosis and hepatocellular carcinoma (HCC).

HBV replicates via an RNA intermediate and cccDNA minichromosome, allowing lifelong persistence. The cornerstones of clinical practice include:

  • Accurate interpretation of serologic markers
  • Evidence-based antiviral therapy to prevent progression and transmission

2. Serological Markers – Biology and Assays

Marker Description Method First detectable
HBsAg Surface envelope protein Qualitative & quantitative ELISA/CLIA 4–10 weeks post-exposure
Anti-HBs Neutralising antibody to β€˜a’ determinant ELISA Appears after clearance of HBsAg or vaccination
Anti-HBc IgM Antibody to nucleocapsid core ELISA Hallmark of acute infection
Anti-HBc IgG Total anti-HBc Persists lifelong after infection
HBeAg Secreted precore protein, parallels high DNA CLIA Early in acute phase
Anti-HBe Seroconversion marker
HBV DNA Viral load Quantitative PCR Best infectivity/disease activity marker
Emerging – qHBsAg, HBcrAg, HBV RNA Phase definition & treatment stop rules

3. Interpreting Common Serologic Patterns

Pattern HBsAg Anti-HBs Anti-HBc IgM Anti-HBc IgG HBeAg Anti-HBe
Acute infection + – + Β± + –
β€˜Window’ period – – + + – –
Chronic infection + (>6 mo) – – + Β± Β±
Resolved infection – + – + – Β±
Vaccinated – + – – – –
Occult HBV – –/low – + – Β± (DNA low)

4. Natural History and Phases – Serially Defined

  1. Immune-tolerant (HBeAg-positive chronic infection):

    • Very high DNA (β‰₯10⁷ IU/mL), normal ALT, minimal fibrosis
    • Common in perinatally-infected young adults

  2. Immune-active (HBeAg-positive chronic hepatitis):

    • DNA β‰₯20,000 IU/mL, ALT ↑, necro-inflammation Β± fibrosis

  3. Inactive carrier (HBeAg-negative chronic infection):

    • anti-HBe+, DNA <2000 IU/mL, normal ALT

  4. HBeAg-negative chronic hepatitis:

    • Fluctuating DNA >2000 IU/mL and ALT, progressive fibrosis

  5. HBsAg-negative phase (occult HBV):

    • anti-HBc Β±, DNA <200 IU/mL; reactivation risk in immunosuppression

Adapted from AASLD 2018 / EASL 2017; see HPIM 21e, Ch. 364

5. Initial Evaluation of an HBsAg-Positive Patient

  • Confirm chronicity (HBsAg β‰₯6 mo or repeated HBV DNA+)
  • Determine phase: HBeAg, HBV DNA, ALT, qHBsAg
  • Stage liver disease: FIB-4, APRI, elastography, or biopsy
  • Screen for co-factors: HCV, HDV, HIV, alcohol, metabolic syndrome
  • Baseline labs: CBC, INR, LFTs, renal profile, pregnancy status, HCC risk

6. Indications for Treatment (Adults, Non-Cirrhotic)

HBeAg-Positive

  • Definite: DNA > 20,000 IU/mL + ALT β‰₯2Γ— ULN
  • Relative: DNA > 20,000 IU/mL + age >30 y even if ALT normal

HBeAg-Negative

  • DNA > 2,000 IU/mL + ALT β‰₯2Γ— ULN
  • Any DNA level + fibrosis (β‰₯F2)

Cirrhosis (Any stage)

  • Treat regardless of DNA/ALT

Special Situations

  • Acute severe hepatitis (INR > 1.5, bilirubin > 3 mg/dL)
  • MTCT prevention (DNA >200,000 IU/mL)
  • HBV/HIV co-infection: TDF + FTC/3TC
  • Immunosuppressed patients: prophylaxis
  • Liver transplantation: pre/post-op therapy

7. Antiviral Options

7.1 First-line Nucleos(t)ide Analogues (High Barrier to Resistance)

Drug Dose Toxicities Notes
TDF 300 mg od Renal tubular, bone loss Safe in pregnancy, monitor eGFR
TAF 25 mg od Less renal/bone toxicity Not for eGFR <15 mL/min
ETV 0.5 mg od (1 mg if LAM-resistant) Minimal Adjust for CrCl <50 mL/min; take on empty stomach

7.2 Pegylated Interferon-Ξ±-2a (PEG-IFN)

  • 180 Β΅g SC weekly Γ— 48–96 weeks
  • Pros: Finite course, HBsAg loss (~10%)
  • Cons: Flu-like symptoms, cytopenias, pregnancy and autoimmune contraindications

7.3 Obsolete or Secondary Agents

  • Lamivudine, telbivudine, adefovir: high resistance rates

8. Treatment Monitoring and Endpoints

Parameter Frequency Goal
ALT, AST q3–6 mo Normalize
HBV DNA q3–6 mo (NA); weeks 24–72 (PEG) >1 log↓ by 3 mo, PCR undetectable by 12–24 mo
HBeAg/anti-HBe q6 mo Seroconversion β‰₯12 mo
qHBsAg Yearly Predict functional cure
Renal function Yearly eGFR decline <10 mL/min/year
USG Β± AFP q6 mo HCC surveillance

Treatment Endpoints

  • Functional cure: HBsAg loss Β± anti-HBs (rare, 1–3%/year)
  • Partial response: DNA < 2000 IU/mL, normal ALT
  • Relapse: Biochemical + virologic after stopping β†’ restart

Stopping Rules

  • HBeAg+: β‰₯12 mo post-seroconversion + DNA undetectable x2
  • HBeAg–: Indefinite; may stop after β‰₯3 years undetectable (Asia-Pacific)
  • Cirrhosis: Lifelong treatment

9. Special Populations

9.1 Pregnancy and MTCT

  • Screen all; if DNA > 200,000 IU/mL β†’ TDF from week 28–32
  • Infant: HBIG + vaccine within 12 hrs, complete 3 doses, test at 9–12 months
  • Failure rate: <2%

9.2 Immunosuppression / Chemotherapy

  • HBsAg+ or anti-HBc+: prophylaxis with ETV/TDF
  • Start 1–2 weeks before and continue β‰₯6–12 mo post-therapy
  • Rituximab/HSCT: extend to β‰₯12 mo

9.3 Acute HBV

  • Supportive
  • If ALF or severe/prolonged: start TDF/ETV

9.4 Coinfections

  • HBV/HIV: TDF/TAF + 3TC/FTC in ART
  • HBV/HDV: PEG-IFN; emerging drugs: bulevirtide, lonafarnib
  • HBV/HCV: Treat HCV with DAAs, monitor HBV

10. Prevention

10.1 Universal Vaccination

  • 3 doses (0, 1, 6 mo), β‰₯95% efficacy (anti-HBs β‰₯10 mIU/mL)
  • Birth dose within 24 hrs is critical in endemic areas

10.2 Post-Exposure Prophylaxis

  • Percutaneous/mucosal: HBIG + vaccine
  • Non-responder: HBIG Γ—2 (0 and 1 mo)

10.3 Other Measures

  • Blood/organ donor screening
  • Safe injection practices
  • Harm reduction in PWID
  • Condom use

11. Future and Emerging Therapies

  • Capsid inhibitors (e.g. vebicorvir)
  • siRNA agents, entry inhibitors (bulevirtide)
  • PD-1 blockade, therapeutic vaccines
  • Aim: Increase HBsAg loss, finite curative combinations in trials

12. Conclusion

Correct serological interpretation:

  • Identifies infection phase
  • Guides antiviral therapy
  • Informs patient counselling

Long-term NUC or PEG-IFN therapy reduces cirrhosis, HCC, and transmission. Prevention through vaccination, MTCT strategies, and high-risk group monitoring are vital to reach WHO 2030 HBV elimination goals.

Suggested Core Reading

Harrison’s Principles of Internal Medicine, 21st Ed.

  • Chapter 364 – Viral Hepatitis B
  • Chapter 361 – Approach to the Patient with Liver Disease
  • Chapter 362 – Evaluation of Abnormal Liver Tests

Major Guidelines:

  • AASLD Hepatitis B Guidance 2018 (Updated 2022)
  • EASL HBV Guidelines 2017
  • WHO Guidelines for Chronic HBV Infection 2015

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Answer 2

Here is the same content reformatted into Obsidian callouts using collapsible sections for optimal use inside your Obsidian vault:

[!info]+ 1. Introduction Hepatitis B virus (HBV), a 3.2-kb partially double-stranded DNA hepadnavirus, infects an estimated 260 million people chronically and caused ~820,000 deaths in 2019, mainly due to cirrhosis and hepatocellular carcinoma (HCC). Replicates via RNA intermediate & cccDNA β†’ lifelong persistence Management depends on: 1. Accurate serologic interpretation 2. Evidence-based antiviral therapy

[!example]+ 2. Serological Markers – Biology and Assays Marker / Method / First detectable HBsAg – Envelope protein | ELISA/CLIA | 4–10 wks post-exposure Anti-HBs – Neutralising antibody | ELISA | Appears post-vaccine/clearance Anti-HBc IgM – Core antibody | ELISA | Acute infection hallmark Anti-HBc IgG – Persists lifelong post-infection HBeAg – Precore protein, parallels high DNA | CLIA Anti-HBe – Indicates seroconversion HBV DNA – Quant PCR | Best for infectivity & activity Emerging: qHBsAg, HBcrAg, HBV RNA

[!table]+ 3. Interpreting Serologic Patterns

Pattern HBsAg Anti-HBs Anti-HBc IgM Anti-HBc IgG HBeAg Anti-HBe
Acute infection + – + Β± + –
β€˜Window’ period – – + + – –
Chronic infection + (>6 mo) – – + Β± Β±
Resolved infection – + – + – Β±
Vaccinated – + – – – –
Occult HBV – –/low – + – Β± (DNA low)
--
[!abstract]+ 4. Natural History – Defined Phases
Immune-tolerant: HBeAg+, DNA β‰₯10⁷ IU/mL, normal ALT, minimal fibrosis
Immune-active: HBeAg+, DNA β‰₯20,000 IU/mL, ↑ALT, necro-inflammation
Inactive carrier: HBeAg–, anti-HBe+, DNA <2000 IU/mL, normal ALT
HBeAg– chronic hepatitis: DNA >2000 IU/mL, ALT↑, fibrosis progression
Occult HBV: HBsAg–, anti-HBc Β±, DNA <200 IU/mL β†’ reactivation risk
> Adapted from AASLD 2018 / EASL 2017; HPIM 21e, Ch. 364
-

[!check]+ 5. Initial Evaluation of HBsAg+ Patient Confirm chronicity (HBsAg β‰₯6 mo or persistent DNA+) Assess phase (HBeAg, DNA, ALT, qHBsAg) Stage liver disease: FIB-4, APRI, elastography, biopsy Screen co-factors: HCV, HDV, HIV, alcohol, metabolic Baseline labs: CBC, INR, LFTs, renal, pregnancy, HCC risk

[!tip]+ 6. Treatment Indications HBeAg-Positive DNA >20,000 IU/mL & ALT β‰₯2Γ— ULN (definite) DNA >20,000 IU/mL & age >30 even if ALT normal (relative)

HBeAg-Negative DNA >2,000 IU/mL & ALT β‰₯2Γ— ULN Any DNA level + β‰₯F2 fibrosis

Cirrhosis – Treat all

Special Situations Severe acute hepatitis MTCT prevention (DNA >200k IU/mL) HBV/HIV (use TDF+FTC/3TC) Immunosuppression, transplant

[!note]+ 7. Antiviral Options First-line NA therapy TDF 300 mg od – Renal/bone toxicity | Safe in pregnancy TAF 25 mg od – Less renal/bone issues | Not <15 mL/min eGFR ETV 0.5–1 mg od – Minimal toxicity | Adjust in renal failure

PEG-IFN 180 Β΅g SC weekly x 48–96 wks Finite, higher HBsAg loss (~10%) Flu-like, cytopenia, CI in pregnancy/autoimmunity

Obsolete drugs: Lamivudine, adefovir, telbivudine

[!question]+ 8. Monitoring & Treatment Endpoints Frequency & Targets ALT/AST: q3–6 mo β†’ Normalize HBV DNA: ↓1 log₁₀ by 3 mo; PCR– by 12–24 mo HBeAg/anti-HBe: q6 mo β†’ Seroconversion β‰₯12 mo qHBsAg: yearly β†’ Decline predicts cure Renal/BMD: yearly if TDF/TAF USG Β± AFP: q6 mo (HCC surveillance)

Stopping Rules HBeAg+: After β‰₯12 mo consolidation + undetectable DNA (Γ—2) HBeAg–: Consider after β‰₯3 y undetectable DNA + tight f/u Cirrhosis: lifelong therapy

[!quote]+ 9. Special Populations Pregnancy & MTCT Screen early; TDF if DNA >200,000 IU/mL at 28–32 wks Infant: Vaccine + HBIG <12 h; test @ 9–12 mo

Immunosuppression/Chemo Prophylaxis with ETV/TDF in HBsAg+ or anti-HBc+ Start 1–2 wks before, continue β‰₯6–12 mo post

Acute HBV Supportive Start NA if INR >1.5, encephalopathy

Coinfections HBV/HIV: TDF/TAF + 3TC/FTC HBV/HDV: PEG-IFN, bulevirtide (trials) HBV/HCV: DAA for HCV, monitor HBV

[!caution]+ 10. Prevention Vaccination 3 doses (0, 1, 6 mo), β‰₯95% protection Birth dose <24h critical

Post-Exposure HBIG (0.06 mL/kg) + vaccine series Non-responders: HBIG Γ— 2 (0 & 1 mo)

Other: Blood/organs screened, safe injections, PWID harm reduction

[!future]+ 11. Future & Emerging Therapies Capsid modulators: vebicorvir siRNA agents, entry inhibitors: bulevirtide PD-1 blockers, therapeutic vaccines Aim: finite β€˜curative’ therapy β†’ HBsAg loss Multiple agents in Phase II/III trials

[!summary]+ 12. Conclusion Correct HBV serology interpretation is critical NA/PEG-IFN therapy ↓ cirrhosis, HCC, transmission Prevention via vaccination, MTCT prophylaxis, high-risk screening essential WHO 2030 HBV elimination goal achievable with persistent strategy

[!book]+ Suggested Reading Harrison’s Internal Medicine, 21e Ch. 364 – Viral Hepatitis B Ch. 361 – Liver Disease Approach Ch. 362 – Abnormal Liver Tests

Guidelines AASLD 2018/2022 EASL 2017 WHO 2015 Chronic HBV