Big Advance for Hepatitis B, Plus One

A recent open-label randomized controlled study (M Bazinet et al. Gastroenterol 2020; 158: 2180-94https://doi.org/10.1053/j.gastro.2020.02.058) showed that the addition of nucleic acid polymers (NAPs) which inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles significantly improved outcomes in a phase 2 HBV trial (n=40).

Full text: Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

NAP therapy was administered intravenously once a week.

Key findings:

  • During the first 24 weeks of tenofovir (TDF) and peg-Interferon (pegIFN) administration, significantly higher proportions of patients in NAP groups had decreases in HBsAg to below 1 IU/mL (P < .001 vs control) and HBsAg seroconversion (P = .046 vs control).
  • At the time patients completed the TDF + pegIFN + NAP regimen, HBsAg levels were 0.05 IU/mL or lower in 24/40 participants
  • During 48 weeks of treatment-free follow-up, virologic control persisted in 13 of 40 participants (2 lost to follow-up after 24 weeks), whereas functional cure persisted in 14 of 40 participants (all completing 48 weeks of follow-up) with persistent HBsAg seroconversion

The associated editorial (pg 2051-4 by D Durantel, T Asselah) makes the following points:

  • The authors call for larger multicenter studies with longer followup.  They note that more evaluation is needed to determine if seroconversion is sustained.
  • It remains unclear whether PEG-IFN is needed. TDF/NAP therapy without PEG-IFN was not studied.
  • They state that more information about flares during treatment are needed.  In this study, flares were safe and associated with beneficial outcomes.  It is not clear if therapy flares would be detrimental in those with advanced fibrosis.
  • Optimistically, they state that there are multiple competing therapies being studied (eg. small interfering RNA, and small molecule HBs-RNA destabilizer) which could be more easily administered.

My take (borrowed from authors): In a phase 2 randomized trial, “we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy.”

A related commentary (Gastroenterol 2020; 158: 2028-32) calls for investment/study of treatment for immune-tolerant patients along with curative therapy when it becomes available.  The authors also argue for a study of long-term viral suppression with either entecavir or tenofovir alafenamide.

Plus one: N Rodriguez-Baez et al. JPGN 2020; 71: 99-105.  This study examined liver histology from 134 liver biopsies from treatment-naive children with chronic hepatitis B infection. 60% acquired infection vertically, 69% were HBeAg-positive.   Interface hepatitis was mild in 31%, moderate in 61% and severe in 6%; lobular inflammation was mild in 54%, moderate in 29% and severe in 7%. Fibrosis: 18% had no fibrosis, 59% had portal fibrosis without bridging, 19% had bridging fibrosis and 4% had cirrhosis. Alanine amnotransferase was a fairly good indicator of the severity of hepatic inflammation and extent of fibrosis.

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