Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg‐negative chronic hepatitis B

Abstract

Funding information Bristol-Myers Squibb; EASL SummaryThe optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg-negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off-treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off-treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed 'inactive carriers') served as controls. Results were validated using qRT-PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long-term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off-treatment remission segregated as a distinct out-group. Twenty-one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off-treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78-0.92. IFNγ, IL-8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long-term NA therapy had expression levels of all these four genes below cut-off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg-negative CHB who remain in off-treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL-8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy.

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

“…In ten studies suppling such data [17,22,24,29,[31][32][33]35,37,40], retreatment was started in 447 (84%) of 534 patients with BR or 447 (52%) of 859 patients with VR.…”

“…Sixteen studies included Asian patients[17,[20][21][22][23][24][25][26]28,31,33,[36][37][38][39]42], six studies involved Caucasian patients[18,19,27,30,34,40], and four studies included mixed patients population[29,32,35,41].Lamivudine were used in one[30], entecavir in three[21,22,26], tenofovir in two[18,32], several NAs in fifteen[17,19,20,24,28,29, 31,[33][34][35][36][37][38][39]42], and NAs was not reported in the remaining five studies[23,25,27,40,41] (Table 1).Only HBeAg-positive patients were involved in three studies [23,24,41], only HBeAg-negative patients in ten[18,27,29,30,[32][33][34][35][36]40], and both HBeAg-positive and HBeAg-negative patients in thirteen[17,19,21,22,[24][25][26]28,31,[37][38][39]42]. In total, 747 (29.0%) HBeAg-positive and 1826 (71.0%) HBeAg-…”

Cessation of nucleos(t)ide analogues therapy in chronic hepatitis B: a systematic review and meta-analysis

“…At baseline, 337 (13.9%) of the 2433 patients with cirrhosis (information of cirrhosis was not reported in two studies [24,27], including 140 off-NAs patients), which was diagnosed by histology ndings and/or imaging studies. [32], entecavir in three [23,24,28], tenofovir in two [20,34], several NAs in fteen [19,21,22,26,30,31,33,[35][36][37][38][39][40][41]44], and NAs was not reported in the remaining ve studies [25,27,29,42,43] ( Table 1).…”

“…Only HBeAg-positive patients were involved in three studies [25,26,43], only HBeAg-negative patients in ten [20,29,31,32,[34][35][36][37][38]42], and both HBeAg-positive and HBeAg-negative patients in thirteen [19,21,23 Table 2). The shortest duration of follow up after NAs cessation was 12 months, and the longest was 62 months.…”

“…One study speci ed ve de nitions of BR which were based on ALT >ULN, > 2 ULN, > 3 ULN, > 5 ULN and > 10 ULN [37]. While it was not speci ed in ve studies [21,22,30,40,42]. As to the two studies [36,37] provided more than one de nition of BR, when calculating the overall pooled rates of BR, we adopted the de nition of BR based on ALT level >2×ULN.…”