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. 2021 Jan;53(2):314-320.
doi: 10.1111/apt.16172. Epub 2020 Nov 21.

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

Sylvia M Brakenhoff  1 , Robert A de Man  1 , André Boonstra  1 , Margo J H van Campenhout  1 , Robert J de Knegt  1 , Florian van Bömmel  2 , Annemiek A van der Eijk  3 , Thomas Berg  2 , Bettina E Hansen  4   5 , Harry L A Janssen  4 , Milan J Sonneveld  1
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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

Sylvia M Brakenhoff et al. Aliment Pharmacol Ther. 2021 Jan.

Abstract

Background: Serum 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.

Aim: To 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.

Methods: HBV 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).

Results: We 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.

Conclusions: In 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.

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Figures

FIGURE 1
FIGURE 1
(A) Rates of sustained response (HBV DNA <2000 IU/mL) and hepatitis B surface antigen (HBsAg) loss in patients with and without hepatitis B virus (HBV) RNA response at on‐treatment week 24 (n = 258). (B) Rates of sustained response and HBsAg loss in subgroup of patients with HBV RNA response at on‐treatment week 24 (n = 133), stratified by HBsAg decline (<0.5, 0.5‐1 or >1 log). HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus
FIGURE 2
FIGURE 2
(A) Hepatitis B surface antigen (HBsAg) decline during treatment and follow‐up in patients with an hepatitis B virus (HBV) RNA response at on‐treatment week 24, stratified by patients with and without sustained response (HBV DNA <2000 IU/mL; SR). (B) Hepatitis B core‐related antigen (HBcrAg) decline during treatment and follow‐up in patients with an HBV RNA response at on‐treatment week 24, stratified by patients with and without SR. Assessed in patients with positive hepatitis B e antigen (HBeAg) at baseline. P‐value for comparison at week 24. BL, baseline; EOF, end of follow‐up; EOT, end of treatment; HBcrAg, hepatitis B core‐related antigen; HBsAg, hepatitis B surface antigen; SR, sustained response; wk, week
FIGURE 3
FIGURE 3
(A) Rates of sustained response (HBV DNA <2000 IU/mL) and hepatitis B surface antigen (HBsAg) loss in patients with and without hepatitis B virus (HBV) RNA response at on‐treatment week 24. Assessed in patients with positive hepatitis B e antigen (HBeAg) at baseline (n = 157). (B) Rates of sustained response and HBsAg loss in subgroup of patients with HBV RNA response at on‐treatment week 24 (n = 79), stratified by hepatitis B core‐related antigen (HBcrAg) decline (<1, 1‐3 or >3 log). Assessed in patients with positive HBeAg at baseline. HBcrAg, hepatitis B core‐related antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus
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