Copyright
©The Author(s) 2021.
World J Hepatol. Sep 27, 2021; 13(9): 1042-1057
Published online Sep 27, 2021. doi: 10.4254/wjh.v13.i9.1042
Published online Sep 27, 2021. doi: 10.4254/wjh.v13.i9.1042
Table 1 Guidelines for stopping nucleos(t)ide analog therapy
Guidelines | HBeAg-positive CHB | HBeAg-negative CHB |
APASL 2015[11] | HBeAg seroconversion: + undetectable HBV DNA + normal ALT for ≥ 12 mo (or preferably 3 yr). Cirrhotic patients may be stopped with careful monitoring | Undetectable HBV DNA at least 2 yr with documented on three separate occasions, 6 mo apart: Or HBsAg clearance either at least for 1 yr; Or until anti-HBs seroconversion. Cirrhotic patients may be stopped with careful monitoring |
AASLD 2018[10] | HBeAg seroconversion + undetectable DNA + normal ALT for ≥ 12 mo. Not recommended in cirrhosis | HBsAg clearance. Not recommended in cirrhosis |
EASL 2017[9] | HBeAg seroconversion + undetectable DNA for ≥ 12 mo. Not recommended in cirrhosis | HBsAg clearance. Or selected noncirrhotic with undetectable HBV DNA ≥ 3 yr. Not recommended in cirrhosis |
Table 2 Off-therapy virological relapse, clinical relapse, and hepatitis B surface antigen loss in chronic hepatitis B patients
Ref. | Country | n (%) | HBeAg-negative, n (%) | Follow-up time (mo) | Virological relapse rate (%) | Clinical relapse rate (%) | HBsAg loss, n (%) |
Fung et al[67], 2004 | Canada | 27 | 27 | 18 | 44.4 | 25.9 | NR1 |
Enomoto et al[68], 2008 | Japan | 22 | 22 | 48 | 68.7 | 68.7 | NR |
Yeh et al[69], 2009 | Taiwan | 71 | 0 | 15 | 26.8 | 26.8 | 0 |
Fung et al[70], 2009 | Hongkong | 22 | 0 | 20 | 63.6 | 31.8 | NR |
Wang et al[71], 2010 | China | 125 | 125 | 24 | 30.4 | NR | NR |
Kuo et al[72], 2010 | Taiwan | 124 | 0 | > 12 | 66.1 | 66.1 | NR |
Cai et al[73], 2010 | China | 11 | 0 | 22 | 42.8 | 0 | NR |
Liu et al[74], 2011 | China | 61 | 61 | 15 | 50.8 | 45.9 | 8/61 |
Jung et al[75], 2011 | South Korea | 19 | 9 | 12 | 31.6 | 21 | 0 |
Chan et al[76], 2011 | Hongkong | 53 | 53 | 47 | 69.8 | NR | 9/53 |
Liang et al[77], 2011 | Hongkong | 84 | 43 | 44 | 14.3 | NR | |
Chaung et al[78], 2012 | United States | 39 | 0 | 14 | 89.7 | 38.5 | 0 |
Hadziyannis et al[15], 2012 | Greece | 33 | 33 | 69 | 45.4 | 45.4 | 13/33 |
Ha et al[79], 2012 | China | 145 | 145 | 16 | 65.5 | 64.1 | NR |
Song et al[80], 2012 | South Korea | 48 | 0 | 18 | 41.6 | NR | NR |
He et al[81], 2013 | China | 66 | 66 | 17 | 28.8 | NR | 2/66 |
Kim et al[82], 2013 | Korea | 45 | 45 | 26 | 73.3 | 53.3 | NR |
Jeng et al[83], 2013 | Taiwan | 95 | 95 | > 12 | 57.9 | 45.3 | 0/95 |
Kwon et al[84], 2013 | South Korea | 16 | NR | 32 | 25 | 25 | 2/16 |
Ridruejo et al[85], 2014 | Argentina | 35 | 0 | 15 | 25.7 | NR | 18/35 |
Sohn et al[86], 2014 | South Korea | 95 | 54 | 22 | 83.1 | NR | 0/95 |
Patwardhan et al[87], 2014 | United States | 33 | 33 | 36 | 63.6 | 48.5 | 0/33 |
He et al[88], 2014 | China | 97 | 0 | 32 | 8.2 | 1 | 11/97 |
Chen et al[40], 2014 | Taiwan | 188 | 105 | 49 | 66.5 | NR | 33/185 |
Jiang et al[89], 2015 | China | 72 | 39 | 13 | 65.3 | 41.7 | NR |
Seto et al[90], 2015 | Hongkong | 184 | 184 | 12 | 91.8 | 22.8 | 0 |
Peng et al[91], 2015 | China | 65 | 21 | 12 | 43.1 | 27.7 | 1/65 |
Jeng et al[92], 2016 | Taiwan | 85 | 85 | 155 | 69 | 52 | 2/85 |
Qiu et al[93], 2016 | China | 112 | 0 | 52 | 48.2 | NR | 1/112 |
Yao et al[94], 2017 | Taiwan | 119 | 119 | 6 yr | 25.2 | 12.7 | 44/1192 |
Cao et al[95], 2017 | China | 82 | 22 | 91 | 70.7 | 34.1 | 5/82 |
Chen et al[96], 2018 | Taiwan | 143 | 104 | 104 | 67.1 | 48.9 | 7/143 |
Hung et al[97], 2017 | Taiwan | 73 | 73 | 6 yr | 54.8 | 6.8 | 20/73 |
Berg et al[42], 2017 | German | 21 | 21 | 144 | 52 | 23 | 4/21 |
Jeng et al[33], 2018 | Taiwan | 691 | 691 | 6 yr | 79.2 | 60.6 | 42/691 |
Liem et al[39], 2019 | Canada | 45 | 27 | 72 | 71 | 13 | 1/45 |
Kaewdech et al[12], 2020 | Thailand | 92 | 70 | 48 | 63 | 33.7 | 2/92 |
Table 3 Factors predictive of hepatitis B virus relapse
Baseline at pretreatment | On-treatment | End of treatment |
Virological relapse | ||
High age[40,44] | Short consolidation duration[38] | High HBsAg level[40,41] |
Male sex[40] | High HBcrAg level[12] | |
High HBsAg level[44] | High HBV RNA level[12] | |
Clinical relapse | ||
High HBsAg level[44] | Short consolidation duration[44] | High HBsAg level[13,40,41] |
High HBcrAg level[12,13,52] | ||
High HBV RNA level[12,52] |
Table 4 Factors predictive of hepatitis B surface antigen clearance
Table 5 Hepatitis B core-related antigen level and clinical application
Ref. | n (%) | End of treatment HBcrAg level (log10 U/mL) | Clinical application |
Shinkai et al[98], 2006 | 22 | < 3.4 | Predictive factor for absence of the off-therapy relapse |
Matsumoto et al[47], 2007 | 34 | < 3.2 | Predictive factor for absence of the off-therapy relapse |
Jung et al[99], 2016 | 113 | ≤ 3.7 | Virological relapse within 1 yr of NA cessation |
Hsu et al[48], 2019 | 135 | NR | Predictive factors of HBsAg loss and lower clinical relapse |
Kaewdech et al[12], 2020 | 92 | < 3 | Low risk of off-therapy relapse |
Papatheodoridi et al[54], 2020 | 57 | < 2 | Predictive factor of HBsAg loss, not required retreatment |
Sonneveld et al[13], 2020 | 572 | < 2 | Higher risk of sustained response and HBsAg loss |
Table 6 Summary of follow-up interval and retreatment criteria
Ref. | Follow-up interval | Criteria of retreatment |
Berg et al[42], 2017 | Every 2 wk in the first 3 mo, every 4 wk until week 48, and every 12 wk thereafter until week 144 | Two consecutive total bilirubin > 1.5 mg/dL plus ALT > ULN |
Two consecutive PT ≥ 2.0 seconds (INR ≥ 0.5) prolonged from baseline with adequate vitamin K therapy plus ALT > ULN | ||
Two consecutive ALT > 10 × ULN | ||
ALT > 2 × but ≤ 5 × ULN persisting for ≥ 12 wk plus HBV DNA > 20000 copies/mL | ||
ALT 5 × but ≤ 10 × ULN persisting for ≥ 4 wk | ||
Papatheodoridi et al[63], 2018 | Every mo in the first 3 mo then at least every 3 mo until month 12 | Greece cohort: (1) ALT > 10 × ULN; (2) ALT > 5 × ULN plus total bilirubin > 2 mg/dL; (3) ALT > 3 × ULN plus HBV DNA > 100000 IU/mL; and (4) ALT > ULN plus HBV DNA > 2000 IU/mL on three sequential occasions |
Taiwanese cohort: (1) ALT > 2 × ULN twice 3 mo apart plus HBV DNA > 2000 IU/mL; (2) Total bilirubin > 2 mg/dL; and (3) PT ≥ 3 seconds of control range | ||
Liem et al[39], 2019 | Wk 4, 6, 12, 18, 24, 36, 48, 60, and 72 | HBeAg seroreversion |
HBV DNA > 2000 IU/mL plus ALT > 600 IU/mL | ||
HBV DNA > 2000 IU/mL plus ALT > 5 × ULN (40 IU/mL) on two consecutive visits | ||
HBV DNA > 2000 IU/mL plus ALT > 200 IU/mL but < 600 IU/mL for > 6–8 wk | ||
HBV DNA > 20000 IU/mL on two consecutive visits at least 4 wk apart | ||
García-López et al[60], 2020 | Monthly in the first 6 mo then every 3-4 mo until 24 mo | Two consecutive ALT > 10 × ULN regardless of HBV DNA level |
ALT > 5-10 × ULN and HBV DNA > 2000 IU/mL persisting for ≥ 4 wk | ||
ALT > 2-5 × ULN and HBV DNA > 2000 IU/mL persisting for ≥ 6 mo | ||
Need for immunosuppressive treatment |
- Citation: Kaewdech A, Sripongpun P. Challenges in the discontinuation of chronic hepatitis B antiviral agents. World J Hepatol 2021; 13(9): 1042-1057
- URL: https://www.wjgnet.com/1948-5182/full/v13/i9/1042.htm
- DOI: https://dx.doi.org/10.4254/wjh.v13.i9.1042