Serum IL-21 levels predict HBeAg decline during rescue therapy in patients with partial response to nucleos(t)ide analogues

Abstract

To investigate whether IL-21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL-21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)-positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL-21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)-DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL-21 levels at treatment week 12 in patients who achieved an HBeAg-level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10-90th percentile) levels of HBeAg, HBV-DNA and ALT at baseline were 2.7 (0.2-3.1) log10 S/CO, 5.2 (3.5-7.5) log10 IU/ml and 0.9 (0.5-3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL-21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL-21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL-21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R2=0.23; P=0.047). In conclusion, the serum IL-21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

Keywords: IL-21; antiviral therapy; hepatitis B virus; outcome predictors; suboptimal response.

Copyright: © Li et al.

Figures

Figure 1

Changes in HBV virological markers and IL-21 concentration. (A) Comparison of the changes in HBV-DNA, HBeAg and ALT levels over 104 weeks of salvage therapy in 24 HBeAg-positive CHB patients with suboptimal response to nucleos(t)ide analogues. *P<0.001 and **P=0.01. (B) Serum IL-21 concentration (median, 25-75th percentile, range) over 104 weeks of salvage therapy. The dot indicates an outlier; HBV, hepatitis B virus; ALT, alanine aminotransferase; ULN, upper limit of normal; HBeAg, hepatitis B e antigen.

Figure 2

Association between treatment response and IL-21 concentration. (A) Comparison of the serum IL-21 concentration (median, 25-75th percentile, range) during 104 weeks of salvage therapy in the CR and NCR groups. (B) Comparison of the HBV-DNA levels during 104 weeks of salvage therapy in the CR and NCR groups. *P<0.05 vs. CR. Groups; CR, patients with HBeAg loss and HBV-DNA undetectable at week 104; The dots indicate outliers; NCR, patients with HBeAg-positive status at week 104. NCR, no complete response; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen.

Figure 3

Prediction of serum HBeAg level decline. (A) Comparison of the serum HBeAg levels (median, 25-75th percentile, range) during 104 weeks of salvage therapy in the ED and NED groups. (B) Comparison of the serum IL-21 concentrations (median, 25-75th percentile, range) during 104 weeks of salvage therapy in the ED and NED groups. (C) Comparison of the serum HBV-DNA and ALT levels during 104 weeks of salvage therapy in the ED and NED groups. (D) ROC curve indicating the influence of the elevated levels of IL-21 over the initial 12 weeks of treatment on the probability of HBeAg decline during 104 weeks of salvage therapy. An AUC of 1.0 is indicative of a maximum diagnostic value, whereas an AUC10S/CO) from baseline to week 104 by ≥50%; NED, patients with a decline in the serum level of HBeAg (log10S/CO) from baseline to week 104 by <50%. NED, no HBeAg level decline. The dots indicate outlier; ROC, receiver operating characteristic; AUC, area under the curve; HBV, hepatitis B virus; ALT, alanine aminotransferase; ULN, upper limit of normal; HBeAg, hepatitis B e antigen.