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We thank Dr Tseng and colleagues for their interest1 in our recent study that identified a negative association between the presence of hepatitis B virus (HBV) basal core promoter (BCP)/precore (PC) and precore (PC) variants mutants at baseline and lower likelihood of hepatitis B surface antigen (HBsAg) loss among 157 subjects with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) treated for 4 years with tenofovir therapy. 2–4 The likelihood of HBsAg loss was 41% in subjects with wild-type (WT) sequence at the BCP/PC loci versus 3% in subjects with detectable BCP/PC variants (next generation sequencing (NGS), Illumina MiSeq—threshold for detection >1%). The cohort included subjects with a broad range of HBV genotypes (genotype A, n=36 (23%); genotype B, n=24 (15%); genotype C, n=51 (32%) and genotype D, n=46 (29%)). HBsAg loss was more common in subjects with genotype A/D (24%) versus genotype B/C HBV (1%), and although genotype A was associated with HBsAg loss following univariate analysis, HBV genotype was not associated with HBsAg loss in multivariate analysis after adjustment for the presence of BCP/PC variants. We acknowledge that an effect of HBV genotype cannot be excluded in a cohort of this size. Further, BCP/PC variants were detected almost universally in subjects with genotype B (24/24 (100%)) or genotype C (46/51 (90%)), whereas HBsAg loss was very rare (genotype B 1/24 (4%) and genotype C 0/51 (0%)). The analysis was, therefore, underpowered to detect an association between WT versus BCP/PC variants and HBsAg loss in subjects with genotype B/C infection.
Similarly, it is difficult to compare findings from the correspondent's cited work,5 which focused on HBsAg loss over decades in the natural history of subjects enrolled in the ERADICATE-B study with HBeAg-negative CHB, in the absence of antiviral therapy. Although no association was observed between BCP/PC variants and HBsAg loss, a TaqMan-based qualitative PCR was assay was used to determine the frequency of the dominant sequences. This population-sequencing approach was less sensitive than the NGS method used in our study, and it is likely that NGS would have identified BCP/PC variants in the vast majority of this HBeAg-negative cohort, meaning that power to detect an effect was small. We are also familiar with the study in which immunotolerant subjects were treated with tenofovir±emtricitabine for 4 years.6 Although subjects enrolled in this study had high rates of genotype B/C HBV and were likely to be WT at the BCP/PC loci, no HBsAg loss was observed. HBsAg loss is likely to involve a host–viral interaction that requires immune pressure absent among individuals in the immunotolerant phase of CHB. Indeed, we hypothesise that the BCP/PC variants represent an immune evasion mechanism that aborts serological control among HBeAg-positive individuals who have entered the immune control phase of disease.
In conclusion, the observed association between the presence of BCP/PC variants and lower likelihood of HBsAg loss in individuals with HBeAg-positive CHB treated with long-term tenofovir therapy was robust, particularly in genotype A/D HBV. We agree that future studies should evaluate the association between BCP/PC sequence and HBsAg loss during nucleos(t)ide analogue therapy for HBeAg-positive CHB in people infected with genotype B/C HBV. These studies will need to be adequately powered to account for the high prevalence of BCP/PC variants in HBeAg-positive genotype B/C HBV observed using NGS.
Contributors All authors contributed equally to this letter.
Funding Gilead Sciences.
Competing interests PR and SL have received grant/research support from Gilead Sciences; SL is an advisor for Gilead Sciences and Bristol-Myers Squibb (BMS); AT is an advisor for and has received grant/research support from Merck, Janssen/Tibotec, Gilead Sciences and Roche and speaker's fees from Merck, Roche and BMS. PR is currently in receipt of a Royal Melbourne Hospital Keir Research Fellowship.
Patient consent Obtained.
Ethics approval Gilead Sciences.
Provenance and peer review Not commissioned; internally peer reviewed.
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