Viruses | Free Full-Text | Kinetics and Value of Hepatitis B Core-Related Antigen in Patients with Chronic Hepatitis B Virus Infection during Antiviral Treatment

During antiviral treatment of patients with chronic HBV infection, the repeated measurement of HBV DNA levels is the standard of care recommended by the current guidelines [1,2] and HBV DNA suppression is the immediate goal to evaluate treatment response. It has been shown that the suppression of HBV DNA by NA treatment is associated with an improved long-term outcome, lower risk of development of liver cirrhosis and hepatocellular carcinoma (HCC), and the regression of liver fibrosis [12,13,14,15]. During NA treatment the correlation of HBV DNA and HBV cccDNA transcriptional activity is lost, since NA block the reverse transcriptase but do not have any effect on HBV cccDNA. It has been shown that HBcrAg correlates well not only with the amount of intrahepatic HBV cccDNA [6,16,17] but also with its transcriptional activity [17,18], irrespective of NA treatment. Therefore, HBcrAg has been proposed as a novel marker for the identification of treatment indication, treatment monitoring, and risk stratification [19,20,21,22]. In comparison to quantitative HBV DNA measurement, the assay for the detection and quantification of HBcrAg is cheaper and simpler [19] and a rapid diagnostic assay is available [23], which makes HBcrAg an attractive marker for regions with limited healthcare-related resources. Both HBcrAg assays have already been evaluated in studies from LMIC and showed good performances for the determination of treatment eligibility [19,23]. In our study, we were able to demonstrate that median HBcrAg levels decreased significantly during NA treatment. However, compared to the decrease in HBV DNA, median HBcrAg levels decreased less rapidly and over a longer period of time. This may be due to different effects of NA treatment. NA treatment directly affects HBV DNA by inhibiting replication, resulting in reduced HBV DNA levels. However, an additional, indirect effect of NA treatment is a reduction in the hepatic HBV cccDNA reservoir as a result of reduced HBV cccDNA replenishment, which may be reflected in HBcrAg levels. Still, some individual courses of HBcrAg and HBV DNA showed divergent patterns with increasing HBcrAg and decreasing HBV DNA. Comparable results were shown for HBcrAg kinetics after the termination of NA treatment. Overall, similar kinetics of mean HBcrAg and HBV DNA levels were observed. However, at the individual level, HBcrAg levels did not always follow the same pattern as HBV DNA. In three patients, a virological relapse would have been missed if only HBcrAg had been determined. Based on these data, HBcrAg is not completely equivalent to HBV DNA for the management of patients during and off NA therapy. Our findings are in line with a recently published meta-analysis focusing on the clinical utility of HBcrAg in chronic HBV infection [24]. In their analyses, Adraneda et al. calculated a false positive and negative rate for the assay of 9% and 12–35%, respectively. These rates might partially explain the divergent HBcrAg and HBV DNA patterns in some individuals of our study. Currently, a more sensitive assay is being developed, which will lead to a reduction of the false negative rate [25]. However, false positive rates would need to be determined and might still have an effect on the clinical utility of HBcrAg.

Apart from on- and off-treatment monitoring, we also addressed the predictive value of HBcrAg on HBeAg seroconversion and HBsAg loss. In line with previous publications from large studies, in our study lower levels of HBcrAg were associated with these treatment endpoints [10,26]. Markers to identify patients with chances of HBeAg seroconversion and HBsAg loss or decline have been studied as part of large HBV cohort studies. Patient demographics, liver enzymes, HBV DNA, and quantitative HBsAg levels, as well as HBcrAg and HBV RNA levels, have been proposed as markers to predict these endpoints [1,27,28]. Recently, the addition of HBcrAg and HBV RNA to the readily available patient demographics, clinical and virological data has been questioned. By analyzing data from a large, prospective HBV registry, Ghany and colleagues showed that lower levels of HBcrAg were associated with HBsAg loss and HBeAg seroconversion. The addition of HBcrAg levels to models with already existing host, clinical, and virological factors achieved minor improvements of predictive capability [29]. Unfortunately, our study is too small to evaluate and compare models including different virological endpoints and multiple predictive markers. Also, the calculated cut-offs need to be interpreted with caution due to the small sample size of our cohort.

The limitations of measuring HBcrAg have been discussed previously [24], and we have shown that quantification of HBcrAg during treatment is limited for the evaluation of treatment efficacy as well as for the detection of virologic relapse after NA discontinuation. Nevertheless, the clinical utility for determining treatment indication in the absence of quantitative HBV DNA has been demonstrated [19], which is a particularly important role in countries with limited access to healthcare resources.