A randomized controlled trial of thymosin-alpha1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody-- and hepatitis B virus DNA--positive chronic hepatitis B
Andreone P, Cursaro C, Gramenzi A, Zavaglia C, Rezakovic I, Altomare E, Severini R, Franzone JS, +4 more
Hepatology (1996) · n=33
In a 33-patient head-to-head comparison, thymosin-α1 produced a similar response rate to interferon alfa in anti-HBe-positive chronic hepatitis B at end-of-treatment and a higher complete response rate at six-month follow-up — the comparator-grade evidence that anchored thymosin-α1's hepatitis B regulatory record.
This 1996 *Hepatology* paper is one of the foundational comparator trials that established thymosin-α1's place in the chronic hepatitis B treatment landscape and helped support its regulatory approval across 35+ countries. The investigators randomized 33 patients with anti-HBe-positive, HBV-DNA-positive chronic hepatitis B to receive either thymosin-α1 (n=17) or interferon alfa (n=16) for 26 weeks, with a six-month off-treatment follow-up. At end-of-treatment, complete response (defined as ALT normalization plus HBV-DNA loss) occurred in 5 of 17 (29.4%) on thymosin-α1 and 7 of 16 (43.8%) on interferon — a non-significant difference. At the six-month follow-up after treatment ended, the thymosin-α1 group's response rate had risen to 7 of 17 (41.2%) while the interferon group's had fallen to 4 of 16 (25%), suggesting that thymosin-α1's effect emerges more slowly but persists or strengthens after the active treatment period. Tolerability heavily favored thymosin-α1 — only localized injection-site discomfort was reported, contrasting with the well-known systemic side-effect profile of interferon alfa. The trial is small but informed the broader development arc that produced thymosin-α1 (Zadaxin / thymalfasin) as an alternative or adjunct in chronic hepatitis B treatment.
The sample size (33 patients total) is small even by 1996 hepatitis-B trial standards; the absolute differences in response rates are not statistically robust given the wide confidence intervals around such small cohorts. The "delayed response" framing — thymosin-α1 acts more slowly but more durably than interferon — is consistent with an immunomodulatory rather than directly antiviral mechanism, but the pattern is based on this and a small number of similarly-sized trials rather than on a definitive meta-analysis. The post-direct-acting-antiviral (DAA) era of hepatitis C treatment, plus the modern nucleoside/nucleotide analogue treatment of hepatitis B, has substantially superseded the thymosin-α1 vs interferon comparison the trial was designed to illuminate; readers interpreting this paper for current clinical context should weight that history. Industry sponsorship was disclosed; the methodology is appropriate for a 1996 Phase 2/3 design.