1. Viral minority variants in the core promoter and precore region identified by deep sequencing are associated with response to peginterferon and adefovir in HBeAg negative chronic hepatitis B patients.
- Author
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Jansen L, Welkers MRA, van Dort KA, Takkenberg RB, Lopatin U, Zaaijer HL, de Jong MD, Reesink HW, and Kootstra NA
- Subjects
- Adenine administration & dosage, Adenine therapeutic use, Adult, Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, DNA, Viral blood, DNA, Viral genetics, Drug Therapy, Combination, Female, Genotype, Hepatitis B Surface Antigens genetics, Hepatitis B, Chronic blood, Hepatitis B, Chronic drug therapy, High-Throughput Nucleotide Sequencing, Humans, Interferon-alpha administration & dosage, Male, Middle Aged, Mutation, Organophosphonates administration & dosage, Polyethylene Glycols administration & dosage, Prospective Studies, Recombinant Proteins administration & dosage, Recombinant Proteins therapeutic use, Viral Load, Adenine analogs & derivatives, Genetic Variation, Hepatitis B, Chronic virology, Interferon-alpha therapeutic use, Organophosphonates therapeutic use, Polyethylene Glycols therapeutic use, Promoter Regions, Genetic
- Abstract
Background and Aim: Precore (PC) and basal core promoter (BCP) mutations are associated with responses to interferon-based treatment in HBeAg-positive chronic hepatitis B (CHB) patients. Here, we identify viral minority variants in these regions and assess association with response to peginterferon-alfa (Peg-IFN) and adefovir combination therapy., Patients and Methods: Ultra-deep pyrosequencing analysis of the BCP and PC region was performed for 89 CHB patients (42 HBeAg-positive; 47 HBeAg-negative), at baseline and during treatment. Specifically, associations of individual positions with the HBeAg-negative phenotype were studied, as well as the association of the most prevalent mutations with combined response in HBeAg-positive and -negative patients at week 72 (HBeAg negativity, HBV-DNA <2000 IU/mL and ALT normalization at 24 weeks of treatment-free follow-up)., Results: The mutations most strongly correlated with the HBeAg-negative phenotype were at positions 1762/1764 and 1896/1899 in the BCP and PC region, respectively. No major changes in nucleotide composition of these positions were observed during treatment. In HBeAg-negative patients, a combined presence of 1764A and 1896A was correlated with lower ALT levels (p = 0.004), whereas the presence of 1899A was correlated with higher age (p = 0.030), lower HBV-DNA level (p = 0.036), and previous IFN therapy (p = 0.032). The presence of 1764A/1896A or the absence of 1899A at baseline, was associated with lower response rates, after adjustment for HBV genotype (p = 0.031 and p = 0.017) and HBsAg level (p = 0.035 and p = 0.022)., Conclusion: We identified novel correlations between common BCP and PC variants with response to Peg-IFN and adefovir in HBeAg-negative patients. Ultimately, this may guide the selection of those patients most likely to benefit from Peg-IFN-based treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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