Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B

Abstract

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG-IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg-positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99-01 study). Patients received 52 weeks PEG-IFN monotherapy (n = 136) or PEG-IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG-IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG-IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow-up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P = .01; week 24:3.7 vs 4.9 log c/mL, P < .001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG-IFN treatment. Early on-treatment HBV RNA level may be used to predict nonresponse.

Keywords: chronic hepatitis B infection; functional cure; peginterferon treatment; serum marker; treatment response.

Figure 1

HBV RNA dynamics and detectability in the total study population (N = 266). The line represents mean level of HBV RNA (log c/mL); bars represent the proportion of patients with either detectable or undetectable HBV RNA

Figure 2

Early on‐treatment HBV RNA dynamics according to therapy allocation and treatment response. Lines represent mean level of HBV RNA (log c/mL), according to therapy allocation (A), treatment response (B) or both (C,D). Grey lines in panels c and d represent individual HBV RNA dynamics in patients with HBsAg loss

Figure 3

A, Individual HBV RNA measurements according to HBeAg loss at the end of follow‐up. Dots represent individual HBV RNA measurements according to HBeAg loss at the end of follow‐up, with lines representing the mean level of HBV RNA (log c/mL). The red dotted line indicates a previously proposed HBV DNA cut‐off for the early identification of nonresponse (10). B, HBV RNA detectability according to HBeAg loss at the end of follow‐up. Bars represent the proportion of patients with detectable or undetectable HBV RNA levels according to HBeAg loss at the end of follow‐up. C, Univariable and multivariable diagnostic accuracy of early on‐treatment HBV RNA for the prediction of HBeAg loss at the end of follow‐up. Bars represent the area under the curve (AUC) for HBV RNA at baseline, week 12 and week 24 for the prediction of HBeAg loss at the end of follow‐up. Bars in dark grey represent univariable analysis; bars in light grey represent multivariable analysis adjusting for HBV genotype, ALT level, and presence of BCP or PC mutations. D, HBV RNA cut‐off for the prediction of HBeAg loss at the end of follow‐up. The dark line and grey line represent sensitivity and specificity of HBV RNA level for the prediction of HBeAg loss at the end of follow‐up

Figure 4

A, HBV RNA detectability according to HBsAg loss at the end of follow‐up. Bars represent the proportion of patients with detectable or undetectable HBV RNA levels according to HBsAg loss at the end of follow‐up. B, Univariable diagnostic accuracy of early on‐treatment HBV RNA for the prediction of HBeAg loss at the end of follow‐up. Bars represent the area under the curve (AUC) for HBV RNA at baseline, week 12 and week 24 for the prediction of HBeAg loss at the end of follow‐up. Because of the low number of patients with HBsAg loss, multivariable regression analysis could not be performed for this end point

Figure 5

A, HBV RNA, HBV DNA, qHBsAg and qHBeAg dynamics according to HBeAg loss and HBsAg loss. Boxes represent biomarker dynamics for HBV RNA (upper left panel), HBV DNA (upper right panel), qHBsAg (lower left panel) and qHBeAg (lower right panel). Dotted lines represent patients without HBeAg loss, black lines represent patients with HBeAg loss but without HBsAg loss, and grey lines represent patients with HBsAg loss. B, Univariable diagnostic accuracy of early on‐treatment levels of various serum markers for the prediction of HBeAg loss at the end of follow‐up. Bars represent the area under the curve (AUC) at baseline, week 12 and week 24 for the prediction of HBeAg loss at the end of follow‐up, for HBV RNA, HBV DNA, qHBsAg, qHBeAg and ALT