Hepatitis B Virus Mutations and Chronic Hepatitis B Clinical Outcomes During Pregnancy and Post-Partum Follow-up

Abstract

Chronic hepatitis B (CHB) is a dynamic disease, that may be affected by host immunological changes in pregnancy. Certain HBV genotypes (i.e., C vs B) and HBV core (C), basal core promoter (BCP) and surface (S) variants are associated with increased liver disease risk, and rarely linked to vaccine failure due to mother-to-child transmission (MTCT) of vaccine escape mutants (VEM). In highly viremic mothers guidelines recommend consideration of nucleos/tide analogs (NA) therapy targeting the HBV polymerase (P) to reduce MTCT risk. AIM: To follow untreated and NA-treated CHB carriers during pregnancy until ~ 6 months postpartum to assess HBV viral load, liver enzymes and HBV eAg (HBeAg) status, and to evaluate for changes in the HBV genome. METHODS: In this prospective study, demographic and clinical data were collected from 21 women recruited in the 2^nd trimester (one with 2 pregnancies), and during post-partum follow-up. In plasma collected during pregnancy (20/21), and post-partum (11/21), the HBV pre-S/S overlapping P region in all, and the HBV pre-C/C gene (9/21 to date) were PCR amplified, amplicons cloned and ~15 clones/plasma sample sequenced and analyzed with MEGA V5.0. Maternal clinical outcomes assessed included changes in HBV DNA, quantitative HBV surface antigen (qHBsAg) titres, ALT and HBeAg serconversion. RESULTS: In 21 patients (median age 31 y, 62% Asian with genotype B or C, 41% HBeAg+, 23% (5/21) were treated with TDF to reduce maternal viremia (median baseline HBV DNA 8.5 log IU/ml). In 16 untreated patients, the median baseline vs postpartum ALT increased (19.5 [range 6-43] vs 24.5 [range 7- 64], P<0.01) albeit with no significant change in HBV DNA (2.7 vs 2.4 log10 IU/ml). All had normal post-partum liver stiffness measurement (LSM) by transient elastography (median LSM 4.7 kpa, range 2.8-6.1) and none had HBeAg loss. Clonal sequencing analysis of the HBV preS/S/overlapping P region showed that patients often carried minor variants associated with immune escape (N=12) and liver disease (N=8), as well as NA resistance (N=4). Clonal sequencing analysis of the HBV pre C/C region in 9 patients to date showed that patients often carried pre C variants (N=7), only a few had carried BCP variants (N=1). SUMMARY: CHB carriers followed during pregnancy and post-partum often experience mild ALT elevations from baseline and carry minor HBV variants at residues associated with vaccine escape, liver disease and NA resistance. Analysis of the pre C/C region to date showed variants associated with HBeAg(-) CHB and increased risk of liver disease.