Hepatitis B virus RNA decline without concomitant viral antigen decrease is associated with a low probability of sustained response and hepatitis B surface antigen loss

Abstract

SummaryBackgroundSerum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti‐viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen (HBsAg) decrease. How this relates to off‐treatment response is yet unclear.AimTo study the degree of on‐treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off‐treatment sustained response and HBsAg loss.MethodsHBV RNA, HBsAg and hepatitis B core‐related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon‐based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on‐treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on‐treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5‐1/>1 log).ResultsWe enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)‐positive, and 103 were HBeAg‐negative. Sustained response was achieved in 20.4% of patients. At on‐treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non‐responders, P = 0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss.ConclusionsIn this cohort, many patients with HBV RNA response during peginterferon‐based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti‐viral efficacy.Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705.

Incidence of Hepatic Decompensation After Nucleos(t)ide Analog Withdrawal: Results From a Large, International, Multiethnic Cohort of Patients With Chronic Hepatitis B (RETRACT-B Study)

“…Although existing studies have shown the ability of HBsAg levels at EOT to reasonably predict HBsAg loss after cessation (4,(28)(29)(30), it is unable to estimate the probability that a patient will not experience exacerbation and decompensation of hepatitis B. Other studies have shown that detectable levels of hepatitis B core-related antigen (HBcrAg) and HBV RNA at EOT can predict an unfavorable outcome such as relapses; however, the assays lack sensitivity, and the undetectability of these markers is not a strong predictor of HBsAg loss (31)(32)(33)(34)(35). Nevertheless, a recent study by Sonneveld et al (28) showed that quantification of HBcrAg at EOT may be useful in predicting off-therapy HBsAg loss.…”

Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine

“…Thus, their use in combination with on-treatment predictors, such as HBsAg, HBcrAg or HBV-RNA, is under investigation to develop more personalized treatment scores. According to recent reports, an early serum HBV-RNA decline appears to correlate with response to Peg-IFN-α treatment, however only the combined kinetics of viral nucleic acids (HBV-DNA and HBV-RNA) and antigens (HBsAg and HBcrAg) identifies with higher accuracy the patients who achieve a functional cure [43,44].…”