Peg-interferon add-on clears HBsAg in 38% - if you pick by starting antigen level

Design

post-hoc individual participant data meta-analysis of 8 prospective trials

Population

581 patients with chronic hepatitis B on nucleos(t)ide analogues receiving peg-interferon add-on

Primary outcome

HBsAg loss 6-12 months after end of peg-interferon

Effect

8.6% overall; 37.7% if starting HBsAg under 100 IU/mL, 9.8% at 100-1000, 2.3% above 1000 (p<0.001)

PROSPER is a post-hoc individual participant data meta-analysis of eight trials in which patients with chronic hepatitis B already on nucleos(t)ide analogues received peg-interferon as an add-on, 581 patients in total. Forty-four per cent were HBeAg positive, mean HBsAg was 3.03 log10 IU/mL, and 85% were scheduled for 48 weeks of peg-IFN. The endpoint was HBsAg loss 6 to 12 months after peg-IFN stopped.

Overall, 50 of 581 patients (8.6%) lost HBsAg - a number that on its own would discourage anyone from offering the treatment. Split by the antigen level at the start of peg-IFN, it becomes a selection rule: 37.7% in those under 100 IU/mL, 9.8% between 100 and 1000, and 2.3% above 1000 (p<0.001). The gradient held across ethnicity, with Asian patients at 39.3%, 9.2% and 2.2% against Caucasian figures of 30.0%, 8.7% and 3.6%.

For patients starting above 1000 IU/mL there is still a use, but a different one. Forty-eight weeks of peg-IFN brought 47.5% of them below 1000 IU/mL and 16.3% below 100 - into the range where the newer agents in development are most likely to work. That reframes peg-IFN in this group as a lead-in rather than a cure attempt, and it is a claim about a surrogate, not about outcomes.

• Measure HBsAg quantitatively before offering peg-IFN add-on - the decision turns on it
• Quote 38% functional cure only to patients starting below 100 IU/mL; quote 2% above 1000
• Discuss the 48-week burden and interferon toxicity honestly against a 2% chance in high-antigen patients
• Where HBsAg is high and a trial of a novel agent is a realistic option, frame peg-IFN as a lead-in
• Continue the nucleos(t)ide analogue - this is add-on, not replacement

Why it matters

It converts peg-IFN add-on from a treatment offered on general grounds into one with an explicit selection criterion already measurable in clinic.

Don't overread it

HBsAg loss is a surrogate endpoint - nothing here shows a reduction in cirrhosis, liver cancer or mortality.

The statistics, in plain English

The 8.6% overall figure is an average across three groups whose results differ by more than tenfold, which makes it close to meaningless for any individual patient - this is the classic case where a pooled average hides the useful finding rather than summarising it. Note also that this is post-hoc: the stratification by baseline antigen was applied after the trials were done, so the thresholds should be read as descriptive of these data rather than as validated cut-offs. And HBsAg loss is a surrogate; the trials were not powered for cirrhosis, hepatocellular carcinoma or death.

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