Incidences and Determinants of Functional Cure During Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B

Hsu, Yao‐Chun; Yeh, Ming‐Lun; Wong, Grace Lai–Hung; Chen, Chien‐Hung; Peng, Cheng Yuan; Buti, María; Enomoto, Masaru; Xie, Qing; Trinh, Huy N.; Preda, Carmen Monica; Liu, Li; Cheung, Ka Shing; Yeo, Yee Hui; Hoang, Joseph; Huang, Chung‐Feng; Riveiro‐Barciela, Mar; Kozuka, Ritsuzo; Istrătescu, Doina; Tsai, Pei‐Chien; Accarino, Elena Vargas; Lee, Dong-Hyun; Wu, Jia‐Ling; Huang, Jiun-Chi; Dai, Chia‐Yen; Cheung, Ramsey; Chuang, Wan‐Long; Yuen, Man‐Fung; Wong, Vincent Wai‐Sun; Yu, Ming‐Lung; Nguyen, Mindie H.

doi:10.1093/infdis/jiab241

Cited by 49 publications

(43 citation statements)

References 47 publications

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“…A large multinational multicenter long-term ETV/TDF therapy cohort study in 4769 patients demonstrated a 10-year HBsAg loss rate of 2.1% and an annual incidence of only 0.22% [40].…”

Section: Ultimate Goal Of Hbsag Loss Rarely Achievedmentioning

confidence: 99%

Current Trend in Antiviral Therapy for Chronic Hepatitis B

Chien

Liaw

2022

Viruses

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Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.

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“…A large multinational multicenter long-term ETV/TDF therapy cohort study in 4769 patients demonstrated a 10-year HBsAg loss rate of 2.1% and an annual incidence of only 0.22% [40].…”

Section: Ultimate Goal Of Hbsag Loss Rarely Achievedmentioning

confidence: 99%

Current Trend in Antiviral Therapy for Chronic Hepatitis B

Chien

Liaw

2022

Viruses

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“…11 This estimation is supported by a most recent large international multicenter cohort study in 4769 patients with CHB, which showed a 10-year cumulative HBsAg loss rate of only 2% with a steady annual incidence of 0.2% (0.17%-0.28%) during 26,614 person-years of ETV/TDF therapy. 12 Indeed, indefinite long-term or even life-long Nuc therapy is required to achieve HBsAg loss, a desirable but unrealistic ultimate goal of "functional cure." This strategy has been the mainstream recommendation in the existing guidelines of all major liver association.…”

Section: Current Status Of Antiviral Therapy In Chronic Hbv Infectionmentioning

confidence: 99%

“…[25][26][27][28][29][30][31] It has been proposed that immune restoration during Nuc therapy and/or HBV reactivation elicited immune response may facilitate further HBsAg decline toward HBsAg loss. 19,32 A recent study of Nuc therapy in patients with HBV DNA <2000 IU/ml showed a 10-year HBsAg loss rate of only 1.26%, 12 12-44 times lower than that in untreated inactive carriers with HBV DNA <2000 IU/ml. 1,2,33,34 These findings strongly suggest that unnecessary Nuc therapy or retreatment may deprive the patients of HBsAg loss.…”

Section: High Hbsag Loss Rate Justifies Finite Nuc Therapy As An " Ac...mentioning

confidence: 99%

Finite nucleos(t)ide analogue therapy in hepatitis B e antigen‐negative chronic hepatitis B: From an “option” to an “active recommendation”

Liaw

Chien

2022

The Kaohsiung J of Med Scie

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Nucleos(t)ide analogue (Nuc) including entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide may suppress hepatitis B virus (HBV) DNA profoundly but have no direct action on covalently closed circular DNA, which is a very stable template for HBV production. Therefore, decades of long-term Nuc therapy are required to maintain HBV suppression and to achieve hepatitis B surface antigen (HBsAg) loss in hepatitis B e antigen (HBeAg)-negative patients. However, there are concerns including financial burden, adherence, and willingness for indefinite long-term Nuc therapy. Patients lost to follow-up and hence not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. Cessation of Nuc therapy in HBeAgnegative patients was initially considered in early 2000s. Earlier findings in Asian patients that finite Nuc therapy over 2-3 years is feasible and safe have founded Asian-Pacific Association for the Study of Liver stopping rule since 2008. Subsequent studies have confirmed the feasibility and safety of the strategy of finite Nuc therapy, which has finally been accepted as "an option" by American and European liver associations since 2016. More recent large studies since 2018 have further confirmed the pivotal findingof greatly increased HBsAg loss rate (~5-year 39%) after stopping Nuc therapy. With the high HBsAg loss rate as the main justification, the paradigm shift from indefinite longterm therapy to finite Nuc therapy in HBeAg-negative patients has been changing from an "option" to an "active recommendation" aiming to achieve HBsAg loss. More studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and to start retreatment.

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“…It is difficult to achieve the goal of HBsAg seroclearance with standard antiviral treatments. Functional cure occurs at an average annual rate of 0.22% in CHB patients during first-line oral NAs antiviral treatment ( 42 ). PEG-IFN treatment can acquire an average HBsAg clearance annual rate of 3% ( 43 – 45 ), 5-year cumulative rate of 14% and 10-year cumulative rate of 32% ( 46 ) in CHB patients.…”

Section: Immune Mechanisms Of Current Drugs and Emerging Therapies Ta...mentioning

confidence: 99%

Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection

Gao

et al. 2022

Front. Immunol.

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It is considered that chronic hepatitis B patients have obtained functional cure if they get hepatitis B surface antigen (HBsAg) seroclearance after treatment. Serum HBsAg is produced by cccDNA that is extremely difficult to clear and dslDNA that is integrated with host chromosome. High HBsAg serum level leads to failure of host immune system, which makes it unable to produce effective antiviral response required for HBsAg seroclerance. Therefore, it is very difficult to achieve functional cure, and fewer than 1% of chronic hepatitis B patients are cured with antiviral treatment annually. Some chronic hepatitis B patients are coinfected with other chronic viral infections, such as HIV, HCV and HDV, which makes more difficult to cure. However, it is found that the probability of obtaining HBsAg seroclearance in patients with coinfection is higher than that in patients with HBV monoinfection, especially in patients with HBV/HIV coinfection who have an up to 36% of HBsAg 5-year-seroclerance rate. The mechanism of this interesting phenomenon is related to the functional reconstruction of immune system after antiretroviral therapy (ART). The quantity increase and function recovery of HBV specific T cells and B cells, and the higher level of cytokines and chemokines such as IP-10, GM-CSF, promote HBsAg seroclearance. This review summarizes recent studies on the immune factors that have influence on HBsAg seroconversion in the chronic hepatitis B patients with viral coinfection, which might provide new insights for the development of therapeutic approaches to partially restore the specific immune response to HBV and other viruses.

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Incidences and Determinants of Functional Cure During Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B

Cited by 49 publications

References 47 publications

Current Trend in Antiviral Therapy for Chronic Hepatitis B

Current Trend in Antiviral Therapy for Chronic Hepatitis B

Finite nucleos(t)ide analogue therapy in hepatitis B e antigen‐negative chronic hepatitis B: From an “option” to an “active recommendation”

Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection

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