DARING-B: Discontinuation of Effective Entecavir or Tenofovir Disoproxil Fumarate Long-Term Therapy before HBsAg Loss in Non-Cirrhotic HBeAg-Negative Chronic Hepatitis B

Papatheodoridis, George V.; Rigopoulou, Eirini I.; Papatheodoridi, Μargarita; Zachou, Kalliopi; Xourafas, Vassilios; Gatselis, Nikolaos; Hadziyannis, Emilia; Vlachogiannakos, John; Manolakopoulos, Spilios; Dalekos, George Ν.

doi:10.3851/imp3256

Cited by 77 publications

(139 citation statements)

References 23 publications

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“…This study echoed the findings of a systematic review of predominantly Asian studies, which showed that the weighted probability of HBsAg seroclearance was only 2% . Several studies have now indicated that the relapse occurs later with entecavir than with TDF; whether this is related to the differences in NAs or ethnic groups warrants further investigation by prospective studies of different ethnicities …”

Section: Discussionsupporting

confidence: 76%

“…whether this is related to the differences in NAs or ethnic groups warrants further investigation by prospective studies of different ethnicities. 28,29 Functional cure further improves the prognosis of CHB patients who have achieved complete viral suppression as shown in our recent territory-wide cohort study of 20 263 NA-treated patients, as…”

Section: Safety Of Stopping Namentioning

confidence: 78%

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The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

Wong

Chan

Yuen

et al. 2019

Liver International

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Background The rates of hepatitis B surface antigen (HBsAg) seroclearance after stopping nucleos(t)ide analogues (NA) in European (19% in 2 years) and Asian (13% in 6 years) patients with chronic hepatitis B (CHB) vary dramatically. We evaluated the incidence of hepatitis flare and HBsAg seroclearance in hepatitis B e antigen (HBeAg)‐negative Chinese CHB patients who had stopped NA. Methods This was a territory‐wide retrospective study in Hong Kong. We identified HBeAg‐negative CHB patients from January 2000 to December 2017 who had stopped NA treatment for more than 3 months. Hepatitis flare was defined as ALT >2×ULN. Results The 1076 patients were predominantly middle‐aged men (mean age 52 years, male 74.8%) when starting NA; they stopped NA after 82 ± 35 months of treatment. At 44.3 ± 24.6 months after stopping NA, 147 (13.6%) patients had hepatitis flare, which led to resumption of NA; whereas 77 (7.2%) patients had flare but did not resume NA. Decompensation occurred in 7/914 (0.8%) patients. A total of 695 (64.6%) patients remained on NA treatment at the last visit. Eleven patients had achieved HBsAg seroclearance (6 of them had hepatitis flare and 1 of these 6 patients achieved HBsAg seroclearance after NA was restarted). Hepatic events developed in 75/695 (10.8%) patients who had NA resumed vs 43/381 (11.3%) patients who did not resume NA (P = .677). Conclusions Hepatitis flare and retreatment were common in HBeAg‐negative CHB patients who stopped NA treatment; whereas HBsAg seroclearance rarely occurred. Stopping NA to achieve functional cure should not be recommended at this moment.

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Section: Discussionsupporting

confidence: 76%

Section: Safety Of Stopping Namentioning

confidence: 78%

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

Wong

Chan

Yuen

et al. 2019

Liver International

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“…47,54,55 Small studies in Europe have reported rates of HBsAg loss as high as 20-30% within 3 years of stopping NAs, whereas studies in Asia have reported lower rates of HBsAg loss (<10%) after similar durations of off-treatment follow-up. [54][55][56][57][58][59] Moreover, clinical relapse, hepatitis flares, and hepatic decompensation can occur when NAs are stopped. 60 (Fig.…”

Section: Current Therapies For Chronic Hbv and Hdv Infectionmentioning

confidence: 99%

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

Cornberg

Lok

Terrault

et al. 2020

Journal of Hepatology

242

122

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Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide clinical trials aiming to 'cure' HBV. Agreement among the conference participants was reached on some key points. 'Functional' but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in > − 30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV 'functional cure', the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.

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“…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).…”

Section: Studies Characteristicsmentioning

confidence: 99%

“…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.…”

Section: Studies Characteristicsmentioning

confidence: 99%

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

Xie

Jin

Song

et al. 2020

Preprint

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BackgroudTo address the possibility of safe cessation of nucleos(t)ide analogues (NAs) therapy in chronic hepatitis B (CHB) and to identify factors associated with off-NAs virological relapse (VR).MethodsA published work search was performed to identify all published studies including patients who ceased NAs and were followed for ≥12 months. A meta-analysis was performed.ResultsTwenty-six studies involving 2573 patients who discontinued NAs were included. The pooled rate of off-NAs VR was 0.63, being lower in initially hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients (0.57 versus 0.62, P = 0.732). The pooled rates of VR were 0.47, 0.55, 0.61, 0.51, 0.73 and 0.64 at 6, 12, 24, 36, 48 and 60 months after NAs cessation, respectively, being relatively lower in initially HBeAg-positive (0.31, 0.45, 0.55, 0.44, 0.48, 0.52) than HBeAg-negative patients (0.50, 0.55, 0.69, 0.57, 0.53, 0.68) ( P = 0.405). The pooled rate of biochemical relapse was 0.44, being lower in initially HBeAg-positive than HBeAg-negative patients (0.43 versus 0.48, P = 0.554). The pooled rates of hepatitis B surface antigen (HBsAg) loss and seroconversion was 0.09 and 0.06, respectively. The pooled rates of VR at 12 months after NAs cessation were significantly different between duration of on-NAs virological response ≤24 months and >24 months in all patients (0.55 versus 0.41, P = 0.011), initially HBeAg-positive patients (0.59 versus 0.41, P = 0.031), and initially HBeAg-negative patients (0.53 versus 0.37, P = 0.025).ConclusionsCessation of NAs therapy seems to be safe in a small subset of CHB patients. On-NAs virological response >24 months reduces the risk of off-NAs VR.

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DARING-B: Discontinuation of Effective Entecavir or Tenofovir Disoproxil Fumarate Long-Term Therapy before HBsAg Loss in Non-Cirrhotic HBeAg-Negative Chronic Hepatitis B

Cited by 77 publications

References 23 publications

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

The safety of stopping nucleos(t)ide analogue treatment in patients with HBeAg‐negative chronic hepatitis B

Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference‡

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

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