Comparative biomarkers for HBsAg loss with antiviral therapy shows dominant influence of quantitative HBsAg (qHBsAg)

Abstract

SummaryBackgroundBiomarkers such as quantitative HBsAg (qHBsAg), quantitative hepatitis B virus (HBV) core‐related antigen (qHBcrAg) and HBV RNA may be useful in predicting HBsAg loss in patients with chronic hepatitis B (CHB) undergoing antiviral therapy.Aim(s)Our study evaluated qHBsAg, HBV RNA and qHBcrAg as a posthoc analysis of a randomized clinical trial of peginterferon±NA to determine their utility in predicting HBsAg loss.MethodsCHB patients who completed therapy with 48weeks peginterferon alpha2b ± nucleoside analogue therapy (clinicaltrial.gov NCT01928511) were evaluated at week 72 for HBsAg loss. The predictive ability of qHBsAg, qHBcrAg, HBV RNA and other variables were investigated by univariate and multivariate logistic models for HBeAg‐negative patients by odds ratios, area under the curve (AUC), sensitivity, specificity, and positive and negative likelihood ratios (LR).ResultsHBsAg loss occurred in 15/114(13%) HBeAg‐negative CHB patients who completed 48 weeks of peginterferon. At baseline, qHBsAg was superior to HBcrAg and HBV RNA with AUC 0.916, 0.649 and 0.542, respectively. Using multivariate analysis, the model comprising treatmentarm, age, gender, baseline qHBsAg, HBcrAg and HBV RNA, weeks 4 & 8 qHBsAg had the highest AUC(0.98), but the univariate model with week 8 qHBsAg <70 IU/mL had AUC 0.96. Hence, the contributions of variables other than qHBsAg were marginal. HBV RNA and qHBcrAg were weak predictors of HBsAg loss. Kinetics of the novel markers showed only qHBsAg had a good relationship with HBsAg loss while HBV RNA had a marginal relationship and HBcrAg did not change at all, and none had a good relationship with viral rebound.ConclusionsOn‐treatment biomarker predictors were better than baseline ones, and the best predictor of HBsAg loss at 72 weeks was week 8 qHBsAg <70 IU/mL.

Novel Biomarkers of Hepatitis B Virus and Their Use in Chronic Hepatitis B Patient Management

“…Low pre-treatment HBsAg levels and a strong decline of HBsAg during early treatment were found to be associated with higher rates of SVR to peg-IFN with or without NA treatment and HBsAg loss [ 89 , 113 , 115 , 116 , 117 , 118 , 119 ]. The likelihood of treatment-induced HBsAg clearance may be predicted using qHBsAg levels at baseline, such that HBeAg-negative CHB patients who achieved HBsAg seroclearance had significantly lower baseline serum qHBsAg (0.48–1.1 log 10 IU/mL) [ 110 , 120 ], and baseline levels below 50 IU/mL accurately predicted HBsAg loss [ 110 ]. HBsAg levels <70 IU/mL at week 8 of treatment were also found to distinguish patients who achieved HBsAg loss from those who did not [ 120 ].…”

“…The likelihood of treatment-induced HBsAg clearance may be predicted using qHBsAg levels at baseline, such that HBeAg-negative CHB patients who achieved HBsAg seroclearance had significantly lower baseline serum qHBsAg (0.48–1.1 log 10 IU/mL) [ 110 , 120 ], and baseline levels below 50 IU/mL accurately predicted HBsAg loss [ 110 ]. HBsAg levels <70 IU/mL at week 8 of treatment were also found to distinguish patients who achieved HBsAg loss from those who did not [ 120 ]. Interestingly, the composition of different surface antigen proteins in HBeAg-positive NA-treated patients could also predict HBsAg loss.…”

Reply

“…Other concerns raised included the use of different types of NAs Q2 in the SWAP RCT, and we have analyzed this in a multivariate analysis and found this to have no impact on the study outcomes. 3 The inclusion of both hepatitis B e antigen (HBeAg)-positive and -negative patients have been discussed extensively in our manuscript and these concerns may be superseded by the important finding of differential responses in HBeAgpositive and -negative patients and the baseline qHBsAg levels, pointing to the utility of having a mixed population of HBeAg-positive and -negative patients in RCT. Genotype status was not available in our patients at baseline, because they were on antiviral therapy.…”

“…There are insufficient data to determine the specifics of qHBsAg kinetics that can be used in clinical practice. We point the authors to our recent publication, 3 which describes the kinetics of qHBsAg, HBV RNA, and hepatitis B core-related antigen in responders from the SWAP RCT. One of the main objectives of the HBV SWAP RCT was to characterize and compare the HBV biomarkers in responders versus nonresponders, and we showed that qHBsAg was superior to HBV RNA and hepatitis B core-related antigen, and that qHBsAg <70 IU/mL at Week 8 was the strongest predictor of response.…”

“…Although the intention to treat showed that there was no difference in efficacy between switch and add-on arms, switch patients had higher risk of HBV flares and reactivation making this a suboptimal therapy. The study has provided insights into HBV biomarkers of response, 3 and also immunologic correlates of response. 4…”