Table 2. Recommendations for treatment initiation.
| Parameter | Recommendation of guidelines | ||||
| HBeAg | HBV-DNA (IU/mL) | ALT | AASLD (2015) (ULN: ALT = 30 (men) and 19 (women) IU/mL)& | APASL (2015) (ULN: ALT = 40 IU/mL) | EASL (2012) (ULN: ALT = 40 IU/mL, DNA = 2000 IU/mL) |
| Positive | <2000 | < or >ULN | Treat if cirrhotic | Assess* | NA |
| Positive | >2000 | <ULN | No treatment with 6-month interval monitoring of ALT if in the immune-tolerant phase. Treat if age >40 years, DNA >106 and significant necroinflammation or fibrosis on liver biopsy. | If DNA >20000 and ALT persistently normal (age < 30) (immune-tolerant phase) → Assess* | Monitor at 3- to 6-month intervals. Liver biopsy and therapy if age >30 years or family history of HCC. Treat if moderate or greater inflammation. |
| Positive | >2000 | 1–2 ULN | Exclude other causes of elevated ALT# | Assess* | Monitor at 3- to 6-month intervals. Liver biopsy recommended. Treat if moderate to severe necroinflammation and/or at least moderate fibrosis |
| Positive | >20000 | >2 ULN | Treat. Exclude other causes of elevated ALT. | If no threat of decompensation, wait for 3 months to check spontaneous e antigen loss or else treat. Assess histology non-invasively. | Start treatment without biopsy |
| Negative | <2000 | <ULN | No treatment if in the inactive phase (persistently normal ALT). Monitor ALT, HBeAg and DNA at 3- to 6-month intervals for e seroreversion, reactivation of hepatitis. Treat# | Monitor ALT every 3–6 months and/or DNA every 6–12 months. Assess* | No treatment. Monitor. |
| Negative | 2000–20000 | <ULN | Treat# | Assess* | No treatment. Monitor ALT at 3-month interval and DNA at 6- to 12-month intervals for 3 years. Fibroscan might be useful. |
| Negative | 1–2 ULN | Exclude other causes of elevated ALT# | Assess* | Treat if liver disease is evident on Fibroscan or biopsy | |
| Negative | >2 ULN | Exclude other causes of elevated ALT# | DNA > 2000 →If no threat of decompensation, observe for 3 months or else treat. Assess histology non-invasively. | Treat if liver disease is evident on Fibroscan or biopsy | |
| Negative | >20000 | >2 ULN | Treat. Exclude other causes of elevated ALT | Start treatment without biopsy. Fibroscan may be done. | |
| Compensated cirrhosis (any e antigen status) | >2000 <2000 |
<ULN >ULN |
Treat for any ALT and DNA level | Treat Treat (assess histology by biopsy or non-invasive method) |
Treat for any ALT and DNA level |
| Decompensated cirrhosis | Any | Any | Treat | Treat ± LT. No biopsy. | Treat |
| 1st line drugs (any e antigen status) | PegIFN alpha 2a 180 mcg for 48 weeks (except cirrhosis and contraindications), TDF 300 mg, ETV 0.5 or 1 mg. Monotherapy recommended.$ | PegIFN alpha 2a 180 mcg or pegIFN alpha 2b 1.5 mcg/kg for 48 weeks (except cirrhosis and contraindications), TDF 300 mg, ETV 0.5 or 1 mg. Monotherapy recommended. | PegIFN alpha 2a 180 mcg (except cirrhosis and contraindications), TDF 300 mg, ETV 0.5 or 1 mg. Monotherapy recommended. | ||
| Drug response | PegIFN: DNA <2000–40000 (e+ve), <20000 (e−ve) and NA: <60 for both response and relapse | PegIFN: DNA <2000 for both e+ve and e−ve). NA: undetectable DNA (response), >2000 (relapse). | |||
APASL recommends monitoring every 3 months and exclusion of other causes in cases of elevated ALT. Assess fibrosis noninvasively. Biopsy if ALT becomes elevated (in cases of normal ALT) or remains persistently elevated (in cases of increased ALT), non-invasive tests suggest significant fibrosis, age >35 years, family history of HCC or cirrhosis. Treat if there is moderate to severe inflammation or significant fibrosis. Moderate to severe inflammation on liver biopsy means either hepatic activity index by Ishak activity score of >3/18 or METAVIR activity score of A2 or A3.
Significant fibrosis on liver biopsy means F ≥2 by METAVIR fibrosis score or Ishak fibrosis stage of ≥3.
Liver stiffness of ≥8 kPa (by Fibroscan) or aspartate aminotransferase to platelet ratio index (APRI) of ≥1.5 indicates significant fibrosis; Liver stiffness ≥11 kPa (by Fibroscan) or APRI ≥2.0 indicates cirrhosis.
AASLD recommends treatment if significant liver disease or cirrhosis on biopsy or non-invasive testing in such cases.
Therapy decisions should also be based on the following (especially in cases of DNA below threshold or ALT <2 ULN): Age >40 years (significant histological disease), family history of HCC, previous treatment history with pegIFN (delayed HBeAg and HBsAg loss) or NA (risk for drug resistance), presence of extrahepatic manifestations (indication for treatment independent of liver disease severity).
Level of HBV DNA should be compatible with immune-active disease and the cut-offs recommended should be viewed as a sufficient, but not absolute, requirement for treatment.
There is no superiority of one drug over other, recommendation based on lack of resistance on long-term use. Choice of drugs based on: desire for finite therapy (pegIFN), tolerability of treatment side effects, comorbidities (peg-IFN is contraindicated in persons with autoimmune disease, uncontrolled psychiatric disease, cytopenias, severe cardiac disease, uncontrolled seizures, anddecompensated cirrhosis), previous history of LAM resistance (ETV not preferred here), family planning (finite therapy with pegIFN pre-pregnancy or use of NA that is safe in pregnancy is best), HBV genotype (A and B genotypes are more likely to achieve HBeAg and HBsAg loss with pegIFN than non-A/B genotypes), medication costs.
Abbreviations: ALT, alanine aminotransferase; DNA, HBV DNA in IU/mL; LT, liver transplantation; PegIFN, pegylated interferon; ULN, upper limit of normal.