Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg‐positive chronic hepatitis B treated with nucleos(t)ide analogues

Abstract

Summary Background Serum hepatitis B virus (HBV) RNA is a novel biomarker for evaluating treatment response. Detailed information regarding serum HBV RNA kinetics during treatment with nucleos(t)ide analogues (NAs) is limited. Aims To ascertain serum HBV RNA kinetics during long‐term NA treatment and identify associated factors. Methods We enrolled 76 HBeAg‐positive chronic hepatitis B patients receiving NA from randomised controlled trials. Laboratory assays were undertaken every 3 months. Factors associated with serum HBV RNA kinetics were identified by generalised estimating equations. Results Baseline serum HBV RNA was 8.5 ± 1.0 log10 copies/mL. Decline in serum HBV RNA during NA therapy was biphasic: the first phase (HBV DNA detectable) had a fast decrease (median slope, −0.207 log10 copies/mL/month) and was followed by a second phase (HBV DNA undetectable) with slow decrease (median slope, −0.071 log10 copies/mL/month). In the first phase, factors independently associated with lower initial serum HBV RNA were male sex (OR, 0.685, P = 0.044), low baseline HBsAg (OR, 0.525, P = 0.001) and rapid virological response (RVR) (OR, 0.624, P = 0.031). In the second phase, only RVR was independently associated with serum HBV RNA kinetics, including its lower initial level (OR, 0.694, P = 0.043) and greater decline (OR, 0.966, P = 0.002). Based on viral dynamics, time needed to achieve undetectable serum HBV RNA from baseline was 43.56 (IQR: 29.49‐66.40) months. Conclusion RVR was a significant determinant for biphasic decline in serum HBV RNA during NA treatment, which significantly influenced the treatment duration required to achieve undetectable serum HBV RNA.

What drives the dynamics of HBV RNA during treatment?

“…This finding, consistent with the observed measurements in vitro and in transgenic mice, 5 enhances the current knowledge of HBV RNA kinetics under NA therapy. In particular, we show that HBV RNA may transiently increase in the first days of treatment reflecting the accumulation of pgRNA in infected cells before decreasing in the long run as shown by Liu et al 33 Our model also predicted that NA treatment leads to an increase in the ratio of HBV RNA/HBV DNA, from 0.01 at baseline to up to 100 after a couple of weeks (Figure 5). 5,7 Interestingly, we predicted that this increase was also likely to occur during treatment combination of CpAM + NA.…”

“…After this initial decline, both HBV RNA and HBV DNA declined at a slower rate, reflecting the progressive loss of productively infected cells, with a half-life of 5.3 days. 33 Our model also predicted that NA treatment leads to an increase in the ratio of HBV RNA/HBV DNA, from 0.01 at baseline to up to 100 after a couple of weeks ( Figure 5). 5,7 Interestingly, we predicted that this increase was also likely to occur during treatment combination of CpAM + NA.…”

Letter to the Editor: Can the Ratio of Serum HBV RNA to DNA Reflect the Reverse‐Transcription Efficiency of Viral pgRNA?

“…Different from this study, we have recently quantified serum HBV RNA and DNA in 304 patients with treatment‐naïve chronic hepatitis B using our in‐house assays targeting the S region and calibrated with our in‐house HBV‐DNA standard. ( 4 ) Our results showed that the median level of serum HBV RNA was higher than that of HBV DNA by 0.49 log 10 copies/mL ( P < 0.001), inconsistent with the finding of higher median level of serum HBV DNA than HBV RNA in the study by Mak et al…”

Early HBV RNA kinetics under NA treatment may reveal new insights into HBV RNA dynamics and NA mode of action‐more detailed kinetic studies are needed

“…Interestingly, in Liu et al5 some NA-treated patients had sRNA and sDNA declines of a similar magnitude as early as 12 weeks of therapy which cannot be predicted by Goncalves et al model. Larger and more detailed kinetic studies are needed to characterize early sRNA kinetics under NA in humans, which may provide an opportunity to examine the HBV-host dynamics and NA mode of actions proposed by Goncalves and colleagues that drives sRNA dynamics.…”