Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B
Peginterferon (PEG-IFN) treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) results in HBeAg loss in 30% of patients, but clearance of hepatitis B virus (HBV) DNA and hepatitis B surface antigen (HBsAg) from serum is less often achieved. We investigated whether the presence of precore (PC) and basal core promoter (BCP) mutants before PEG-IFN treatment affects serological and virological response. A total of 214 HBeAg-positive CHB patients treated with PEG-IFN±lamivudine for 52 weeks in a global randomized trial were classified at baseline as wildtype (WT) or non-WT (detectable mutants at PC/BCP) by line-probe assay. Response was assessed at 6 months posttreatment and through long-term follow-up (LTFU). Mutants were detected in 64% of patients, in varying frequencies across HBV genotypes A through D. Patients with WT had higher baseline HBV DNA, HBeAg, and HBsAg levels than patients with non-WT. Patients with WT were more likely to achieve HBeAg loss with HBV DNA <10,000 copies/mL (response, 34 versus 11%, P < 0.001) and HBsAg clearance (18 versus 2%, P < 0.001) at week 78 than non-WT patients. Among WT patients who achieved HBeAg clearance at week 78, 78% had undetectable HBV DNA and 61% achieved HBsAg clearance at LTFU (versus 26% and 15% in non-WT patients, P < 0.001 for both). The presence of WT virus at baseline was an independent predictor of response (odds ratio [OR] 2.90, 95% confidence interval [CI]: 1.15-7.31, P = 0.023) and HBsAg clearance (OR 5.58, 95% CI: 1.26-24.63, P = 0.013) and patients with non-A genotypes with detectable mutants had a low probability of response. Conclusion: The presence of only WT virus at baseline is a strong predictor of response (HBeAg loss with HBV DNA <10,000 copies/mL) to PEG-IFN for HBeAg-positive CHB. Patients with detectable PC and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.
|Keywords||Hepatitis B virus, adult, antiviral therapy, article, controlled study, drug dose reduction, female, follow up, gene dosage, gene frequency, genotype, hepatitis B, human, major clinical study, male, monotherapy, nonhuman, predictor variable, priority journal, treatment response, virus core, virus detection, virus mutant|
|Persistent URL||dx.doi.org/10.1002/hep.25636, hdl.handle.net/1765/39057|
Sonneveld, M.J, Rijckborst, V, Zeuzem, S, Heathcote, E.J, Simon, K, Senturk, H, … Janssen, H.L.A. (2012). Presence of precore and core promoter mutants limits the probability of response to peginterferon in hepatitis B e antigen-positive chronic hepatitis B. Hepatology, 56(1), 67–75. doi:10.1002/hep.25636