Chronic Hepatitis¶
Chapter 352 | Harrison's 22e · Part 10 – Gastrointestinal Disorders · Chapter 352
Key Clinical Points¶
- Chronic hepatitis is defined as hepatic inflammation and necrosis continuing for at least 6 months.
- Classification of chronic hepatitis is based on three pillars: (1) cause, (2) histologic grade (activity), and (3) stage (fibrosis).
- Hepatitis B risk of chronicity depends on age: birth infection → 90% chance; young adulthood → ~1% chance.
- Hepatitis C is treated with Direct-Acting Antivirals (DAAs) targeting NS3/4A, NS5A, and NS5B.
- Staging of fibrosis uses the HAI scale (0–6) or METAVIR scale (0–4).
- Noninvasive markers for staging include FIB-4, ELF score, and imaging of liver elasticity.
- HBeAg status and viral load are critical determinants in the management of Hepatitis B.
- Treatment for Hepatitis C is indicated for all patients with detectable HCV RNA regardless of fibrosis stage (except those with short life expectancies).
- Protease-inhibitor-containing regimens (glecaprevir, grazoprevir, voxilaprevir) are contraindicated in decompensated cirrhosis.
DEFINITION & CLASSIFICATION¶
• Definition: Chronic hepatitis represents a series of liver disorders of varying causes and severity in which hepatic inflammation and necrosis continue for at least 6 months. • Classification by Cause: ◦ Viral: Hepatitis B, Hepatitis C, and Hepatitis D. ◦ Non-viral: ◦ Drug- or toxin-induced chronic hepatitis. ◦ Alcohol-associated liver disease. ◦ Metabolic dysfunction-related chronic hepatitis. ◦ Autoimmune chronic hepatitis (including subcategories I and II). ◦ Cryptogenic (unknown cause) or 'idiopathic' cases (often presumed to be autoimmune). • Classification by Grade: ◦ Based on histologic assessment of necroinflammatory activity. ◦ Key features: Periportal necrosis (piecemeal or bridging), and the degree of hepatocyte degeneration/focal necrosis. • Classification by Stage: ◦ Based on the degree of hepatic fibrosis. ◦ Cirrhosis Definition: Fibrosis is so extensive that fibrous septa surround parenchymal nodules and alter the normal architecture of the liver lobule.
Staging Scales & Markers¶
• HAI (Histologic Activity Index): Scale 0–6 (common in the US). • METAVIR: Scale 0–4 (common in Europe). • Noninvasive Markers: ◦ FIB-4: Calculation based on age, AST, ALT, and platelet count. ◦ ELF Score: Proprietary score used primarily in steatotic liver disease. ◦ Imaging: Assessment of liver elasticity/stiffness.
ETIOLOGY & PATHOPHYSIOLOGY¶
• Viral Transmission Dynamics: ◦ Hepatitis A and E are self-limited and do not cause chronic hepatitis (except in immunocompromised hosts). ◦ Hepatitis B Chronicity Risk: ◦ Infection at birth → 90% chance of chronic infection. ◦ Infection in young adulthood → ~1% risk of chronicity. • Overlapping Conditions: ◦ Patients may present with multiple overlapping types (e.g., viral and steatotic liver injury; alcohol-related and nonalcohol-related steatotic liver injury).
DIAGNOSTIC APPROACH¶
- Identify Cause: Use serology and clinical markers to distinguish between categories.
- Hepatitis B: HBsAg, IgG anti-HBc, HBeAg, HBV DNA.
- Hepatitis C: Anti-HCV, HCV RNA.
- Hepatitis D: Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc.
- Autoimmune: ANA (homogeneous), anti-SMA, anti-SLA, anti-LKM1 (±), Hyperglobulinemia.
- Determine Grade: Assess necroinflammatory activity via biopsy or clinical markers.
- Periportal Necrosis: Includes piecemeal necrosis and/or bridging necrosis (BN).
- Determine Stage: Assess fibrosis progression.
- Use scoring systems: HAI (0–6) or METAVIR (0–4).
- Utilize noninvasive markers: FIB-4, ELF score, or imaging of liver elasticity.
MANAGEMENT & TREATMENT¶
- Chronic Hepatitis B Management:
- First-line Therapy: Entecavir (ETV) and Tenofovir (TDF/TAF) due to high potency and high barrier to resistance.
- Decision Pathway (Table 352-4):
- HBeAg-reactive:
- If HBV DNA ≤ 2 imes 10^4 AND ALT ≤ 2 imes ULN → No treatment; monitor.
- Exceptions for Treatment: Age > 40, family history of cirrhosis or HCC, extrahepatic manifestations, history of previous treatment, or biopsy/noninvasive evidence of moderate to severe inflammation or fibrosis.
- If HBV DNA > 2 imes 10^4 OR ALT > 2 imes ULN → Treat with oral agents (not PEG IFN).
- HBeAg-negative:
- If HBV DNA ≤ 2 imes 10^3 AND ALT ≤ 2 imes ULN → Inactive carrier; treatment not necessary.
- If HBV DNA > 2 imes 10^3 OR ALT > 2 imes ULN → Treatment suggested (oral agents).
- Drug Comparison Summary:
- PEG IFN: Poorly tolerated, high cost; limited use in HBeAg-negative patients.
- Lamivudine/Adefovir: No longer preferred due to high resistance rates (e.g., Lamivudine ≈ 70% at 5 years).
- Entecavir/Tenofovir: Preferred first-line; high potency and low resistance.
- Chronic Hepatitis C Management:
- Standard Indications: All patients with detectable HCV RNA, regardless of fibrosis stage (except those with short life expectancies due to comorbidities).
- Direct-Acting Antivirals (DAAs) by Target:
- NS3/4A protease inhibitors (-previr): Glecaprevir, voxilaprevir.
- NS5A inhibitors (-asvir): Velpatasvir, ledipasvir, nibrentasvir.
- NS5B inhibitors (-buvir): Sofosbuvir.
- Treatment Regimens (Table 352-6):
- Treatment-Naïve:
- All Genotypes → Sofosbuvir-velpatasvir (12 weeks) OR Glecaprevir-pibrentasvir (8 weeks).
- Cirrhosis - compensated → Glecaprevir-pibrentasvir (8 weeks) OR Sofosbuvir-velpatasvir (12 weeks).
- Previously Treated:
- All Genotypes → Sofosbuvir-velpatasvir-voxilaprevir (12 weeks) OR Glecaprevir-pibrentasvir (16 weeks).
- Cirrhosis - decompensated:
- Ribavirin-eligible (Genotypes 1, 4, 5, or 6) → Sofosbuvir-velpatasvir + ribavirin (12 weeks) OR Ledipasvi-sofosbuvir + ribavirin (12 weeks).
- Ribavirin-ineligible (Genotypes 1, 4, 5, or 6) → Sofosbuvir-velpatasvir (24 weeks) OR Ledipasvi-sofosbuvir (24 weeks).
- Multiple DAA Failures:
- All Genotypes → Sofosbuvir-velpatasvir-voxilaprevir + ribavirin (24 weeks).
- Contraindications:
- Any protease-inhibitor-containing regimen is CONTRAINDICATED in decompensated cirrhosis (glecaprevir, grazoprevir, voxilaprevir).
HCV Treatment Regimens (Table 352-6)¶
• Treatment-Naïve: ◦ All Genotypes: Sofosbuvir-velpatasvir (12 weeks) or Glecaprevir-pibrentasvir (8 weeks). ◦ Cirrhosis - compensated: Glecaprevir-pibrentasvir (8 weeks) or Sofosbuvir-velpatasvir (12 weeks). • Previously Treated: ◦ All Genotypes: Sofosbuvir-velpatasvir-voxilaprevir (12 weeks) or Glecaprevir-pibrentasvir (16 weeks). • Cirrhosis - decompensated: ◦ Ribavirin-eligible (Genotypes 1, 4, 5, 6): Sofosbuvir-velpatasvir + ribavirin (12 weeks) or Ledipasvi-sofosbuvir + ribavirin (12 weeks). ◦ Ribavirin-ineligible (Genotypes 1, 4, 5, 6): Sofosbuvir-velpatasvir (24 weeks) or Ledipasvi-sofosbuvir (24 weeks). • Multiple DAA failures: ◦ All Genotypes: Sofosbuvir-velpatasvir-voxilaprevir + ribavirin (24 weeks).
KEY PEARLS & HIGH-YIELD POINTS¶
• Hepatitis B Risk: Birth infection → 90% chance of chronicity; young adult infection → only ~1% risk. • HCV Treatment: All patients with detectable HCV RNA should be treated regardless of fibrosis stage (except those with short life expectancies). • Drug Selection (HBV): Entecavir and Tenofovir are first-line due to high potency and high barrier to resistance; Lamivudine is no longer preferred. • DAA Suffixes (HCV): -previr (NS3/4A), -asvir (NS5A), -buvir (NS5B). • Contraindication: Protease inhibitors (glecaprevir, grazoprevir, voxilaprevir) are contraindicated in decompensated cirrhosis.
Reference Tables¶
TABLE 352-1 Clinical and Laboratory Features of Chronic Hepatitis¶
Harrison's 22e, p.2673
| 352 | Chronic Hepatitis Esperance A. K. Schaefer, Raymond T. Chung, Jules L. Dienstag |
|---|---|
TABLE 352-1 Clinical and Laboratory Features of Chronic Hepatitis
| TYPE OF HEPATITIS | DIAGNOSTIC TEST(S) | THERAPY |
|---|---|---|
| Chronic hepatitis B | HBsAg, IgG anti-HBc, HBeAg, HBV DNA |
IFN-α, PEG IFN-α Oral agents: First-line: entecavir, tenofovir |
| Anti-HCV, HCV RNA | ||
| Chronic hepatitis D | Anti-HDV, HDV RNA, HBsAg, IgG anti-HBc |
IFN-α, PEG IFN-αc, bulevirtideb |
| ANA (homogeneous), anti-SMA, anti-SLA, anti-LKM1 (±) Hyperglobulinemia |
TABLE 352-2 Histologic Grading and Staging of Chronic Hepatitis¶
Harrison's 22e, p.2674
| HISTOLOGIC FEATURE | HISTOLOGIC ACTIVITY INDEX (HAI)a | METAVIRb | ||
|---|---|---|---|---|
| SEVERITY | SCORE | SEVERITY | SCORE | |
| Necroinflammatory Activity (grade) | ||||
| Periportal necrosis, including piecemeal necrosis and/or bridging necrosis (BN) |
None Mild Mild/moderate Moderate Severe |
0 1 2 3 4 |
None Mild Moderate Severe Bridging necrosis |
0 1 2 3 Yes No |
| —None —Focal —Zone 3 some —Zone 3 most —Zone 3 + BN few —Zone 3 + BN multiple —Panacinar/multiacinar |
0 1 2 3 4 5 6 |
None or mild Moderate Severe |
||
| Focal | —None —≤1 focus/10× field —2–4 foci/10× field —5–10 foci/10× field —>10 foci/10× field |
0 1 2 3 4 |
||
| None Mild Moderate Moderate/marked Marked Total |
0 1 2 3 4 0–18 |
A0–A3c | ||
| Fibrosis (stage) | ||||
| None Portal fibrosis—some Portal fibrosis—most Bridging fibrosis—few Bridging fibrosis—many Incomplete cirrhosis Cirrhosis |
Total | 0 1 2 3 4 5 6 6 |
F0 F1 F1 F2 F3 F4 F4 4 |
TABLE 352-3 Comparison of Pegylated Interferon¶
Harrison's 22e, p.2676
| FEATURE | PEG IFNb | LAMIVUDINE | ADEFOVIR | ENTECAVIR | TELBIVUDINE | TENOFOVIR (TDF) | TENOFOVIR (TAF) |
|---|---|---|---|---|---|---|---|
| Route of administration | Subcutaneous injection (180 μg/ week) |
Oral (100 mg/d) | Oral (10 mg/d) | Oral (0.5 mg/d) | Oral (600 mg/d) | Oral (300 mg/d) | Oral 25 mg/d) |
| First-line | No longer preferred |
No longer preferred |
First-line | No longer preferred, withdrawn |
First-line | ||
| Duration of therapyc | 48–52 weeks | ≥52 weeks | ≥48 weeks | ≥48 weeks | ≥52 weeks | ≥48 weeks | 48 weeks |
| Poorly tolerated | Well tolerated | Well tolerated; creatinine monitoring recommended |
Well tolerated | Well tolerated | Well tolerated; creatinine monitoring recommended |
||
| HBeAg seroconversion 1 yr Rx >1 yr Rx |
18–20% NA |
16–21% up to 50% at 5 yrs |
12% 43% at 3 yrsd |
21% 31% at 2 yrs 44% at 6 yrs |
22% 30% at 2 yrs |
21% 40% at 5 yrs |
10% (14% HBeAg loss) 18% at yr 2 (HBeAg loss 22%) |
| 4.5 4.1 |
5.5 4.4–4.7 |
Median 3.5–5 Median 3.5–3.9 |
6.9 5.0 |
6.4 5.2 |
6.2 4.6 |
||
| HBV DNA PCR negative (at then current PCR sensitivitya) at end of yr 1 HBeAg-reactive HBeAg-negative |
10–25% 63% |
36–44% 60–73% |
13–21% 48–77% |
67% (91% at 4 yrs) 90% |
60% 88% |
76% 93% |
64% 94% |
| 39% 34–38% |
41–75% 62–79% |
48–61% 48–77% |
68% 78% |
77% 74% |
68% 76% |
||
| HBsAg loss, yr 1 >yr 1 |
3–4% 12% 5 yr after 1 yr of Rx |
≤1% No data |
0% 5% at yr 5 |
2% 6% at yr 6 |
<1% No data |
3% 10% at yr 5 |
1% 1% |
| 38% 6 months after 48% 6 months after |
49–62% 61–66% |
53–68% 64% |
72% 70% |
65% 67% |
74% 72% |
||
| Viral resistance | None | 15–30% at 1 yr 70% at 5 yrs |
None at 1 yr 29% at 5 yrs |
≤1% at 1 yre 1.2% at 6 yrse |
Up to 5% at yr 1 Up to 22% at yr 2 |
0% at yr 1 0% through yr 8 |
0% at yr 1 0% through yr 2 |
| C | Cf | C | C | B | B |
TABLE 352-4 Recommendations for Treatment of Chronic Hepatitis B a HBeAg STATUS HBeAg-reactive¶
Harrison's 22e, p.2681
| HBeAg STATUS | CLINICAL | HBV DNA (IU/mL) | ALT | RECOMMENDATION |
|---|---|---|---|---|
| HBeAg-reactive | b Chronic hepatitis Cirrhosis: Cirrhosis compensated Cirrhosis decompensated |
>2 × 104 >2 × 104d >2 × 103 <2 × 103 Detectable Undetectable |
≤2 × ULNc >2 × ULNd < or > ULN >ULN < or > ULN < or > ULN |
No treatment; monitor, except in patients >40, with family history of cirrhosis or hepatocellular carcinoma, with extrahepatic manifestations, with a history of previous treatment, and/or with liver biopsy (or noninvasive fibrosis determination) evidence for moderate to severe inflammation or fibrosis Treatd Treatd with oral agents, not PEG IFN Treatd with oral agents, not PEG IFN; refer for liver transplantation Observe; refer for liver transplantation |
| HBeAg-negative | b Chronic hepatitis Chronic hepatitis Cirrhosis: Cirrhosis compensated Cirrhosis decompensated |
≤2 × 103 >2 × 103 >2 × 103 >2 × 103 <2 × 103 Detectable Undetectable |
≤ULN 1 to >2 × ULNd >2 × ULNd < or > ULN >ULN < or > ULN < or > ULN |
Inactive carrier; treatment not necessary No treatment; monitor, except in patients >40, with family history of cirrhosis or hepatocellular carcinoma, with extrahepatic manifestations, with a history of previous treatment, and/or with liver biopsy (or noninvasive fibrosis determination) evidence for moderate to severe inflammation or fibrosis Treate,f Treatd with oral agents, not PEG IFN Treatment suggestedf Treatd with oral agentsg, not PEG IFN; refer for liver transplantation Observe; refer for liver transplantation |
TABLE 352-5 Pegylated Interferon Versus Oral Nucleoside Analogues for the Treatment of Chronic Hepatitis B…¶
Harrison's 22e, p.2682
| PEG IFN | NUCLEOSIDE ANALOGUES | |
|---|---|---|
| Administration | Weekly injection | Daily, orally |
| Poorly tolerated, intensive monitoring |
||
| Duration of therapy | Finite, 48 weeks | ≥1 year, indefinite in most patients |
| 4.5 log 10 |
||
| Effective in high-level HBV DNA (≥109 IU/mL) |
No | Yes |
| ~30% Not applicable |
||
| HBeAg-negative posttreatment HBV DNA suppression |
17% at 5 years | 7% at 4 years (lamivudine) |
| 3–4% Not applicable 12% at 5 years |
||
| Antiviral resistance | None | Lamivudine: ~30% year 1, ~70% year 5 Adefovir: 0% year 1, ~30% year 5 Telbivudine: up to 4% year 1, 22% year 2 Entecavir: ≤1.2% through year 6 Tenofovir: 0% through year 8 |
| No | ||
| Cost, 1 year of therapy | ++++ | + to ++ |
TABLE 352-6 Indications and Recommendations for Antiviral Therapy of Chronic Hepatitis C a Standard Indications for…¶
Harrison's 22e, p.2688
| Standard Indications for Therapy All patients with chronic HCV infection (detectable HCV RNA, with or without elevated ALT) except for those with short life expectancies owing to comorbid conditions. Any stage of fibrosis; pretreatment biopsy is no longer embraced and has been supplanted by noninvasive measures of fibrosis, e.g., imaging to determine liver elasticity. Retreatment Recommended Relapsers, partial responders, or nonresponders after a previous course of interferon-based therapy or prior direct-acting antiviral therapy Antiviral Therapy Not Recommended Pregnancy: No sizable clinical studies of direct- acting antivirals during pregnancy are available. Ribavirin is contraindicated during pregnancy; therefore, any regimen including ribavirin should not be used. Sofosbuvir and sofosbuvir plus ledipasvir are classified as pregnancy category B, but the other direct-acting antivirals do not have a pregnancy classification. Therefore, these therapies are not indicated routinely in pregnancy and should be used, with caution, only if the benefit of treatment outweighs the potential for fetal risk. Therapeutic Regimens (based on AASLD-IDSA recommendations, www.hcvguidelines.org)b |
Treatment-Naïve | Previously Treated with DAA |
|---|---|---|
| Simplified treatment regimenb All genotypes Sofosbuvir-velpatasvir × 12 weeks Glecaprevir-pibrentasvir × 8 weeks |
Sofosbuvir failure All genotypes Sofosbuvir-velpatasvir-voxilaprevir × 12 weeks Genotypes 1, 2, 4, 5, or 6 (alternative) Glecaprevir-pibrentasvir × 16 weekse |
|
| Cirrhosis – compensatedc Genotypes 1–6 Glecaprevir-pibrentasvir × 8 weeks Genotypes 1, 2, 4, 5, or 6 Sofosbuvir-velpatasvir × 12 weeks |
Glecaprevir-pibrentasvir failure All genotypes Glecaprevir-pibrentasvir plus sofosbuvir and weight- based ribavirin × 16 weeks Sofosbuvir-velpatasvir-voxilaprevir × 12 weeksf |
|
| Cirrhosis – decompensated Ribavirin-eligible Genotypes 1–6 Sofosbuvir-velpatasvir with weight-based ribavirind × 12 weeks Genotypes 1,4, 5, or 6 Ledipasvir-sofosbuvir with ribavirine × 12 weeks Ribavirin-ineligible Genotypes 1–6 Sofosbuvir-velpatasvir × 24 weeks Genotypes 1, 4, 5, or 6 Ledipasvir-sofosbuvir × 24 weeks |
Multiple direct-acting antiviral failures All genotypes Glecaprevir-pibrentasvir plus sofosbuvir and weight- based ribavirin × 16 weeksg Sofosbuvir-velpatasvir-voxilaprevir plus weight-based ribavirin × 24 weeks Cirrhosis – decompensated All genotypes Sofosbuvir-velpatasvir plus weight-based ribavirin × 24 weeks Genotypes 1, 4, 5, or 6 Ledipasvir-sofosbuvir plus ribavirine × 24 weeks |
|
| FEATURES ASSOCIATED WITH REDUCED RESPONSIVENESS TO DIRECT-ACTING ANTIVIRAL COMBINATION THERAPY Genotype and subtype (genotype 1a less responsive than genotype 1b for several drugs) Treatment experience Advanced fibrosis (bridging fibrosis, cirrhosis) Reduced adherence |
DECOMPENSATED CIRRHOSIS Any protease-inhibitor-containing regimen is CONTRAINDICATED in decompensated cirrhosis (glecaprevir, grazoprevir, voxilaprevir). |