Immune tolerant hepatitis B: most patients become immune active, and high-normal ALT flags who

Design

International multicentre retrospective cohort (RADICAL consortium), median follow-up 13 years

Population

951 patients with strictly defined immune tolerant chronic hepatitis B, median age 33

Primary outcome

Transition to immune active disease (ALT 50 U/L or more), significant fibrosis and hepatocellular carcinoma

Effect

Transition 51% at 5 years, 67% at 10, 72% at 15; ALT above 30 U/L sHR 3.130; fibrosis 6.3% and HCC 1.1% at 15 years

The RADICAL consortium analysed 951 patients with chronic hepatitis B in the strictly defined immune tolerant phase: HBeAg positive, ALT 40 U/L or less, HBV DNA above 7 log10 IU/mL and minimal fibrosis (F0 to F1) during the first year. Median age was 33, 40% were men and median follow-up was 13 years.

The probability of transition to immune active disease (ALT 50 U/L or more) was 51% by 5 years, 67% by 10 years and 72% by 15 years. A high-normal ALT predicted it: subdistribution hazard ratio 1.744 for 20 to 30 U/L and 3.130 above 30 U/L, compared with lower values. Progression to significant fibrosis (6.3% at 15 years) and hepatocellular carcinoma (1.1%) was uncommon.

The data argue against treating this phase as inert and support closer follow-up, especially for patients with ALT above 20 U/L. They do not show that earlier antiviral therapy improves outcomes, and the authors say only that such patients 'may benefit' from closer monitoring or pre-emptive therapy. Local guideline thresholds for treatment have not changed because of this study.

• Check ALT and HBV DNA at least as often as your guideline advises, and more often when ALT is high-normal
• Do not describe immune tolerant hepatitis B as permanently benign to patients
• Assess fibrosis non-invasively at baseline and periodically
• Discuss treatment thresholds with a hepatologist when ALT is persistently above 30 U/L
• Existing guidelines for starting antiviral therapy have not changed on this evidence

Why it matters

Whether to treat the immune tolerant phase is a long-running debate, and this clarifies how often it ends within a few years.

Don't overread it

A natural-history cohort does not show that earlier treatment improves outcomes, and low rates of fibrosis and cancer argue for caution about treating everyone.

The statistics, in plain English

The probabilities of 51%, 67% and 72% come from time-to-event analysis that allows for patients who were lost or developed other outcomes. A subdistribution hazard ratio of 3.13 for ALT above 30 U/L means those patients moved to immune active disease at about three times the rate of the lowest ALT group at any time, and ALT thresholds also define the outcome, which makes the link partly built in.

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