Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment

Abstract

Antiviral drug resistance hepatitis B virus (HBV) variants (HBV-DR) occur spontaneously in chronic hepatitis B (CHB) patients and after exposure to nucleos(t)ide analogues (NUCs). We determined the prevalence of HBV-DR variants among participants of the Hepatitis B Research Network (HBRN) Cohort Study conducted at 21 sites in the United States (US) and Canada. Samples obtained from 1342 CHB participants aged ≥18 years, and who were currently not receiving NUCs, were tested for HBV-DR variants by Sanger sequencing. In addition, next generation sequencing (NGS) was used to characterize HBV-DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg positive. Primary HBV-DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV-DR variants in a higher proportion of participants: primary variants in 18 (13.6%) (8 [12.1%] with, and 10 [15.2%] without prior NUC therapy) and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV-DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV-DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon.

Keywords: Sanger sequencing; antiviral treatment; hepatitis B virus; next generation sequencing; nucleos(t)ide analogues.

Figure 1

Flow diagram of participant selection. Among 1993 participants enrolled, 11 were excluded because they were found to be HBsAg negative at enrollment based on testing at the central laboratory and 419 were excluded because they had acute HBV or HDV infection or belong to special groups enrolled after the protocol was switched from ‘consecutive’ to ‘target’ enrollment. Of the 1563 potentially eligible participants, 198 were excluded because samples within the first 24 weeks of enrollment were not available or HBV-DR resistance data were not available (mostly due to low viremia precluding sequencing). An additional 23 participants were excluded because research samples were collected after the participants started treatment or within 90 days of stopping treatment or dates of HBV treatment were unknown. Thus, 1342 participants were included in the analysis.

Figure 2

Prevalence of primary and secondary HBV-DR variants in relation to prior NUC therapy