Characterization of hepatitis B virus surface antigen variability and impact on HBs antigen clearance under nucleos(t)ide analogue therapy

Abstract

For hepatitis B virus (HBV)-related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV-vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non-resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs 'a' determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence.

Effect of hepatitis B virus (HBV) surface‐gene variability on markers of replication during treated human immunodeficiency virus‐HBV infection in Western Africa

“…Whether it contributed to the increased rate of this therapeutic end‐point is questionable. In NA‐treated HBV mono‐infected patients harbouring genotype D, network analysis showed a variety of mutations of the S ‐gene, particularly in the transmembrane domain‐3/4, common to patients with persistent HBsAg‐positive serology . Most were linked to mutations at positions sT125M and sP127T, which were not observed in our study.…”

“…Most were linked to mutations at positions sT125M and sP127T, which were not observed in our study. Furthermore, higher genomic variability of the S ‐gene, as determined by ultra‐deep sequencing, is actually more conducive to HBsAg persistence during treatment . As MUPIQHs covaried with several other S ‐gene mutations, suggesting higher overall variation on the S ‐gene, their importance in HBsAg seroclearance is likely restrained.…”

Molecular epidemiology of hepatitis B virus mutants associated with vaccine escape, drug resistance and diagnosis failure

“…There is growing evidence that HBV genotypes may play a role in causing different disease profiles in chronic hepatitis B infection . Furthermore, there is evolving evidence that HBsAg variants may influence HBV vaccine and treatment response . Several studies have addressed the association between HBV genotype and VEMs .…”

The use of Phyllanthus niruri L. as an immunomodulator for the treatment of infectious diseases in clinical settings

“…Further, IFN use is limited due to its highly expensive cost and intolerable adverse effects. Long-term use of the current antivirals is also hindered due to the emergence of drug resistance [34,37]. The overall limitations of those currently available therapies for chronic HBV infection underline the need for more cost-effective and safer alternative therapies.…”

“…To date, IFN-α or pegylated IFN-α, and long-term therapy with nucleos(t)ide analogues are the primary treatment strategies for chronic hepatitis B. IFNs exert antiviral, antiproliferative, and immunomodulatory activities. Nucleos(t)ide analogues, such as lamivudine, adefovir, entecavir and tenofovir directly inhibit HBV DNA polymerase, thus suppressing viral replication [36,37]. To date, pegylated IFN treatment given concomitantly with a nucleos(t)ide analogue antiviral is disappointing due to its short-term efficacy.…”