Roadmap to functional cure of chronic hepatitis B: An expert consensus

“…In clinical practice, the existing antiviral drugs of CHB mainly include 2 types, one is immunomodulators, such as peginterferon-a a2a/b (Peg-IFN-a), and another is the drug with direct antiviral effects, such as nucleos(t)ide analogues (NAs). However, due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes and the lack of therapeutic drugs directed against cccDNA, complete elimination of the virus from the host, i.e., complete sterilizing cure, is almost impossible to achieve clinically [5][6][7]. Therefore, the concept of functional cure, also referred to as clinical or immunologic cure, was recently proposed and widely recognized in the clinic [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…The clinical efficacy index of hepatitis B functional cure mainly refers to hepatitis B surface antigen (HBsAg). The HBsAg load at the initial treatment is the baseline antigen level, and the standard of functional cure is HBsAg load lower than or equal to 0.05 IU/mL [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…A recent prospective study [10] showed that lower baseline HBsAg level can predict CHB patients' response after their discontinuation of medication. In particular, researchers [7] integrated existing research results and proposed a roadmap for the sequential combination therapy of direct antiviral drug (DAA) (e.g., NAs) and immunomodulators (e.g., Peg-IFN-a) based on HBsAg kinetics. Therefore, the kinetic analysis of HBsAg during treatment has received increasing attention.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B Surface Antigen (HBsAg) Kinetics in Chronic Hepatitis B Patients during Peginterferon Treatment

et al. 2020

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Background: Hepatitis B surface antigen (HBsAg) loss/seroconversion is considered to be an ideal endpoint for antiviral therapy and a final therapeutic target for chronic hepatitis (CHB). This study aimed to evaluate the HBsAg kinetics in CHB patients during peginterferon-a (Peg-IFN-a) treatment. Material/Methods: A retrospective cohort study was performed using a case database, which included 151 patients who received Peg-IFN-a treatment and with HBsAg load of no less than 4 time points from May 1, 2018 to January 31, 2019. The HBsAg kinetic pattern was analyzed by Q-type clustering, and a clinical prognostic empirical model was constructed based on the HBsAg kinetic pattern of uncured patients. Results: Changes of HBsAg in 13 functionally cured patients were attributed to 3 kinetic patterns by cluster analysis, and there was a significant positive correlation between functionally cure time and baseline HBsAg. For uncured 116 patients with treatment duration longer than or equal to 56 days, 5 HBsAg kinetic patterns were obtained by cluster analysis, and the clinical prognosis empirical model was established. Finally, 13 new functionally cured patients preliminarily confirmed the rationality of the proposed empirical model. Conclusions: According to empirical model, we recommend that the therapeutic regime should be timely adjusted to improve sustained response rate and reduce patients' medical burden for patients with second (Z type) and fifth (Z+W type) kinds of patterns. While for the rest of patterns' patients, it is recommended to continue treatment for a longer period of time to achieve the desired therapeutic goal.

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“…For instance, PEG-IFN and the tenofovir disoproxil fumarate (TDF) combination increased HBeAg seroconversion and loss of HBsAg in some HBeAg + , HBV DNA low CHB patients [6] . In some patients who displayed a low-level of serum HBsAg under long-term antiviral drug treatment, HBsAg loss was observed after they received add-on PEG-IFN treatment [7] . At the same time, several monoclonal antibodies targeting HBsAg have been developed and are being evaluated at different pre-clinical or clinical stages [8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

Shi

Wang

et al. 2019

eBioMedicine

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a b s t r a c tBackground: Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. Methods: Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. Findings: A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8 + T cells and increased TNF-α, granzyme B production. Interpretation:The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB. Research in context section Evidence before this studyPersistence of HBV cccDNA and various host immune defects were shown as the two main obstacles for HBV clearance. Blocking a single target will not be sufficient to achieve functional cure of CHB. A very small percentage of CHB patients could attain "functional cure" by antiviral treatment fol- * Corresponding authors. .cn (Z. Yuan). lowed by interferon therapy. Therapeutic vaccination for CHB showed substantial efficacy. A humanized HBsAb G12 could efficiently block HBV infection and decrease HBsAg level in mice model. Added value of this studyThis research showed that when both serum viral DNA and HB-sAg load became low or undetectable by antiviral and HBsAb treatment, therapeutic vaccine (mYIC) add on induced effective, host humoral and intrahepatic cellular anti-HBV immune responses, with more rapid and efficient clearance of HBV and HBsAg.

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Roadmap to functional cure of chronic hepatitis B: An expert consensus

Cited by 67 publications

References 94 publications

Is the life‐long entecavir treatment really inevitable in chronic hepatitis B patients?

Is the life‐long entecavir treatment really inevitable in chronic hepatitis B patients?

Hepatitis B Surface Antigen (HBsAg) Kinetics in Chronic Hepatitis B Patients during Peginterferon Treatment

Evaluation of antiviral - passive - active immunization (“sandwich”) therapeutic strategy for functional cure of chronic hepatitis B in mice

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