Hepatitis B Surface Antigen Loss: Too Little, Too Late and the Challenge for the Future
Geoffrey Dusheiko'Correspondence information about the author Geoffrey DusheikoEmail the author Geoffrey Dusheiko
Liver Unit, Kings College Hospital and University College London Medical School, London, UK
Bo Wang
Liver Unit, Kings College Hospital, London, UK
PlumX Metrics
DOI: https://doi.org/10.1053/j.gastro.2019.01.015 |
-
See “Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis,” by Yeo YH, Ho HJ, Yang H-I, et al, on page 635.
Detectable hepatitis B surface antigen (HBsAg) is the serological hallmark of persistent hepatitis B virus (HBV) infection and disease. Loss of HBsAg signifies a favorable outcome of the natural history, particularly if HBsAg loss occurs before the accrual of significant liver disease. Loss of HBsAg has been defined, for reference, as a functional “cure.” However, HBsAg is infrequently cleared in those with chronic hepatitis B.
In the current issue of Gastroenterology, Yeo et al1 have performed a systematic review and meta-analysis of HBsAg clearance rates and predictors of clearance. Of 42,588 patients, 3194 cleared HBsAg. The pooled annual rate of HBsAg seroclearance was 1.02% (95% confidence interval, 0.79–1.27). Favorable factors for HBsAg loss included hepatitis B e antigen (HBeAg) negativity, a lower quantitative HBsAg level, and lower HBV DNA concentrations at baseline. Numerically, genotype A had the highest HBsAg seroclearance rates. No marked regional differences were noted, but seroclearance rates were numerically higher in community versus health service-based cohorts. Treatment had little effect, although higher HBsAg seroclearance rates were observed in interferon-treated patients than nucleos(t)ide analogue (NUC) recipients.作者: StephenW 时间: 2019-2-7 13:03
Several potential strategies exist to achieve higher rates of HBsAg loss with treatment of a finite duration, which suggest several editorialized projections of where the field may go.
•
Covalently closed circular DNA is not eliminated by treatment with NUCs, which have less effect on HBV RNA and HBsAg, despite inhibiting HBV replication.
•
Novel capsid assembly modulators deepen inhibition of HBV replication by disrupting crucial early and late states of the HBV life cycle; these agents cause a decrease in HBV DNA and HBV RNA, but have a limited effect on HBsAg after 28 days and will require a longer duration of therapy to reduce HBsAg.
•
Sequential combinatorial therapy ideally should cause a precipitous decrease in HBsAg that, when followed by an immunomodulatory therapy, leads to sustained HBsAg loss.
•
Indeed, GalNac small interfering RNA knockdown in transgenic and transduced mice of HBsAg followed by an adjuvant therapeutic vaccine provides an elegantly choreographed proof of concept.25 These data require further clinical experimentation in humans with chronic hepatitis B.
•
Nucleic acid polymers, which block assembly and release of subviral particles, followed by pegylated interferon result in marked HBsAg reduction (and anti-HBs development), but require further validation and safety testing.26
•
Several immunomodulatory strategies including RIG-1 agonism or oral Toll-like receptor agonists or check point inhibition could trigger effective innate and adaptive immune responses after HBsAg reduction.
•
These strategies will need tailoring to the immunologic phenotype in patients with high and lower levels of HBV replication, to adjudge their effectiveness in different populations and at different stages of disease.作者: StephenW 时间: 2019-2-7 13:05