Fellow's quick read · Infectious Diseases
Chronic hepatitis B — treatment
AASLD/IDSA Practice Guideline 2025 · Hepatology 2026;83:974–997 · reviewed 2026-06-16
Personal study digest for a new ID fellow. This 2025 guideline is a focused GRADE update of 6 PICO questions (pregnancy/MTCT, horizontal transmission, immune-tolerant phase, indeterminate phase, NA withdrawal, HCC surveillance); the 2018 AASLD guidance still governs everything else. The "What's changed since this guideline" section is reviewer synthesis of newer evidence, each claim cited. Not a substitute for the full guideline.
In one line
The 2025 update expands who gets treated — it now suggests therapy for the indeterminate ("grey-zone") phase and for immune-tolerant patients >40 yr — keeps TDF/TAF/entecavir as the three preferred drugs, says do NOT stop NA therapy until HBsAg loss in non-cirrhotics, and broadens HCC surveillance to coinfections and post-HBsAg-loss patients.◆Phases & treatment thresholds (the map you work from)
- ULN for ALT is 35 U/L (men) / 25 U/L (women) — use these low cutoffs, not the lab's 40s.
- Immune-active (= treat): HBeAg-positive → ALT ≥2× ULN and HBV DNA ≥20,000 IU/mL; HBeAg-negative → ALT ≥2× ULN and HBV DNA ≥2,000 IU/mL.
- Immune-tolerant: HBeAg-positive, HBV DNA ≥10,000,000 IU/mL, normal ALT. Inactive: HBeAg-negative, DNA <2,000, normal ALT.
- Indeterminate / "grey zone": anyone whose DNA/ALT falls outside the boxes above — up to 40% of adults with CHB.
- Always treat cirrhosis (any detectable DNA). Stage fibrosis with elastography (better than FIB-4) or biopsy if needed.
◆Drugs: the three preferred NAs
| Agent | Notes the fellow owns |
|---|---|
| Entecavir (ETV) | Avoid if prior lamivudine exposure (resistance) and in HIV coinfection unless HIV RNA suppressed on ART. Take on empty stomach. |
| Tenofovir disoproxil (TDF) | Renal & bone toxicity; dose-adjust / switch off TDF as CrCl falls. Most pregnancy safety data. Take with food. |
| Tenofovir alafenamide (TAF) | Better renal/bone profile; not recommended if CrCl <15 and not on dialysis. |
Peginterferon is now rarely used (efficacy modest, poorly tolerated). Goal of therapy = prevent cirrhosis, HCC, liver death; the aspirational endpoint is HBsAg loss (functional cure), which is uncommon with current NAs.
◆The 6 PICO answers (what's new)
| Question | 2025 recommendation | Strength / certainty |
|---|---|---|
| 1. Pregnancy / MTCT | If HBV DNA >200,000 IU/mL at any point: start TDF or TAF at week 28 (TDF has the longer safety record). Can stop at delivery if antivirals were for prophylaxis only. | Strong · Moderate |
| 2. Treat to reduce transmission | For viremic persons in high-risk transmission scenarios who don't otherwise meet treatment criteria: shared decision-making about antivirals. | Conditional · Very low |
| 3. Immune-tolerant phase | Suggest treating if age >40, or grade ≥2 inflammation / ≥F2 fibrosis. <40 & wants treatment → shared decision. Otherwise monitor (DNA/ALT ≥ q6 mo). | Conditional · Very low |
| 4. Indeterminate phase | NEW: suggest antiviral therapy via shared decision-making, re-evaluating each visit if not started. (2018 said monitor only.) | Conditional · Very low |
| 5. Stopping NA therapy | HBeAg-negative, non-cirrhotic, DNA undetectable ≥3 yr: do NOT withdraw NA until HBsAg loss. | Conditional · Very low |
| 6. HCC surveillance | Surveil after HBsAg loss if cirrhosis / FHx HCC / man >40 or woman >50 at loss; HDV coinfection → all adults regardless of cirrhosis; HIV coinfection → men ≥18, women ≥40; HCV coinfection → treat HCV, surveil per mono-infection rules. | Conditional · Very low |
◆Key decisions a fellow owns
- Screen with the triple panel (HBsAg + anti-HBs + total anti-HBc) — all adults once, every pregnancy, and risk groups. Positive HBsAg → reflex HBV DNA, HBeAg, ALT.
- Re-classify the "grey zone." Phase requires ≥2 ALT + DNA measurements over 6–12 mo before you commit to monitoring vs treating — and the bar to treat indeterminate patients is now lower.
- Don't reflexively stop a suppressed non-cirrhotic. The update reversed toward continuing NA until HBsAg loss.
- Pregnancy is a 200,000 IU/mL decision. Above that, TDF/TAF at week 28; infant still needs HBIG + birth-dose vaccine within ~12–24 h.
- Coinfection drives surveillance. HDV is the highest-risk modifier — surveil every adult. For triple/quadruple infection, follow the highest-risk member's rule.
◆Withdrawal & restart rules (if you do stop a NA)
- Eligible only if: no cirrhosis/decompensation/HCC, HBeAg-neg ≥1 yr, DNA undetectable ≥2 yr, HBsAg <100 IU/mL, no HIV/HDV, agrees to close monitoring.
- Monitor DNA/ALT q1–3 mo ×6 mo, then q3 mo, then q3–6 mo.
- Restart immediately if any one: DNA ≥10,000 IU/mL, ALT >5× ULN, bilirubin >2.5 mg/dL, or decompensation.
What's changed since this guideline (2025→2026)
Reviewer synthesis — not the guideline. Both items post-date the Sept-2025 lock.
- HDV now has an FDA-approved drug. The guideline states "there are no FDA-approved therapies for HDV" — that's outdated: the FDA granted accelerated approval to bulevirtide (Hepcludex), 8.5 mg SC daily, for chronic HDV (no/compensated cirrhosis) on May 22, 2026. Boxed warning: stopping can cause severe acute HDV/HBV exacerbations. (FDA / Gilead, May 2026)
- Functional cure is moving from aspiration toward reality. Phase 3 B-Well 1 & 2 of bepirovirsen (antisense oligonucleotide, 300 mg SC weekly ×24 wk added to NA) achieved HBsAg loss / functional cure in ~20% / ~19% vs 0% placebo — vs the ~1% the guideline cites for NAs. Best at baseline HBsAg ≤1000 IU/mL. Under Priority Review; not yet approved. (NEJM 2026, doi:10.1056/NEJMoa2515131; EASL 2026)
- Still current: TDF/TAF/ETV as preferred NAs, the expansion of treatment into the indeterminate phase, and "treat until HBsAg loss" all reflect the present standard.
◆Anki cards minted this run
- Indeterminate ("grey-zone") phase — 2025 now suggests treatment (was monitor-only).
- Immune-tolerant phase — treat if age >40 / ≥F2 / grade ≥2.
- NA withdrawal — don't stop until HBsAg loss in non-cirrhotics.
- HDV coinfection — HCC surveillance for all adults regardless of cirrhosis.
Sources: Ghany MG, Pan CQ, Lok AS, et al. AASLD/IDSA Practice Guideline on treatment of chronic hepatitis B. Hepatology 2026;83:974–997. doi:10.1097/HEP.0000000000001549. · Currency: FDA approval of bulevirtide (Hepcludex), May 2026; Bepirovirsen B-Well 1/2 Phase 3, NEJM 2026, doi:10.1056/NEJMoa2515131.