EDITORIAL

1 60
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3 Hepatitis B Surface Antigen Loss: Too Little, Too Late and the 62
4 63
5 Challenge for the Future 64
6 65
7 important to emphasize that the clinical outcomes are likely 66
8 See “Factors associated with rates of HBsAg to be more favorable if HBsAg loss occurs at a young age. In 67
9 seroclearance in adults with chronic HBV a study in New Zealand, spontaneous HBsAg loss occurred 68
10 infection: a systematic review and meta- in 33% of patients after 12,702 person-years of follow-up 69
11 analysis,” by Yeo YH, Ho HJ, Yang H-I, et al, on (1.14 per 100 person-years); liver stiffness measurements 70
12 page 000.
were lower if HBsAg loss occurred before the age of 50 71
13 years.3 Conversely HBsAg loss, after the onset of significant 72
14 hepatic fibrosis, does not obviate the risk of hepatocellular 73
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16
17
D etectable hepatitis B surface antigen (HBsAg) is the
serological hallmark of persistent hepatitis B virus
(HBV) infection and disease. Loss of HBsAg signifies a
carcinoma.4 In the REVEAL-HBV studies the incidence of
hepatocellular carcinoma was 93.7 in 100,000 person-years
in those who achieved HBsAg clearance compared with
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18 favorable outcome of the natural history, particularly if 106.2 in 100,000 person-years in those who did not.2 The 77
19 HBsAg loss occurs before the accrual of significant liver independent effect of undetectable or low HBV DNA and 78
20 disease. Loss of HBsAg has been defined, for reference, as a HBsAg clearance on hepatocellular carcinoma risk can be 79
21 functional “cure.” However, HBsAg is infrequently cleared in difficult to tease out, but there may be added value to HBsAg 80
22 those with chronic hepatitis B. loss in NUC-treated patients.5 81
23 In the current issue of Gastroenterology, Yeo et al1 have Given the low rates of HBsAg loss with treatment, what 82
24 performed a systematic review and meta-analysis of HBsAg therapeutic interventions may enhance HBsAg seroclear- 83
25 clearance rates and predictors of clearance. Of 42,588 pa- ance? Several strategies are being used, including cessation 84
26 tients, 3194 cleared HBsAg. The pooled annual rate of of NUCs. In a recent controlled trial of cessation of tenofovir, 85
27 HBsAg seroclearance was 1.02% (95% confidence interval, 19% of patients achieved HBsAg loss after 144 weeks 86
28 0.79–1.27). Favorable factors for HBsAg loss included hep- follow-up.6 Withdrawal often results in viral relapse, how- 87
29 atitis B e antigen (HBeAg) negativity, a lower quantitative ever, and such a strategy will only be applicable in patients 88
30 HBsAg level, and lower HBV DNA concentrations at baseline. without severe liver disease.7–9 Quantitative HBsAg may be 89
31 Numerically, genotype A had the highest HBsAg seroclear- valuable in selecting patients who could benefit and who 90
32 ance rates. No marked regional differences were noted, but may require retreatment.10,11 91
33 seroclearance rates were numerically higher in community Pegylated interferon treatment may also enhance the 92
34 versus health service-based cohorts. Treatment had little risk of HBsAg loss, as highlighted in the analysis. Both 93
35 effect, although higher HBsAg seroclearance rates were switch to and add-on strategies combining interferon and 94
36 observed in interferon-treated patients than nucleos(t)ide NUCs have been assessed.12 Again, a low quantitative HBsAg 95
37 analogue (NUC) recipients and HBV DNA is favorable, and an early response seems to 96
38 The authors’ detailed analysis extracts a comprehensive determine the rates of HBsAg loss. Newer markers including 97
39 body of data and is the last word on the subject. Although quantitative hepatitis B core-related antigen and HBV pre- 98
40 there was substantial statistical heterogeneity in the pooled genomic (pgRNA) could be used to predict the sequence of 99
41 cohorts, the data verify that HBsAg seroclearance rates are HBeAg and HBsAg loss during treatment.13,14 100
42 low in both untreated and treated patients. It should not If HBsAg seroclearance is associated with improved 101
43 come as a surprise that HBsAg loss is a rare event, based on prognosis, what are the mechanistic considerations we need 102
44 prior data.2,3 Although the cumulative incidence rate to understand to improve rates of loss? HBV envelope 103
45 increased to 17.9% at 15 years (95% confidence interval, variability may play a role, because more frequent muta- 104
46 6.18–23.24), the confidence intervals are wide. The inclu- tions in the major hydrophilic region have been observed in 105
47 sion of treated patients may be somewhat problematic, those who have lost HBsAg (such mutations may have a key 106
48 because untreated patients are likely to have low baseline role in immune recognition and antigenicity).15 Patients 107
49 levels of HBV DNA, whereas treated patients have more with detectable basal core promoter/precore variants and 108
50 active disease. The fact that those with decreasing HBsAg higher viral diversity showed a lower probability of HBsAg 109
51 levels are more likely to become undetectable for HBsAg is loss during NUC therapy.16 Increased natural killer cell 110
52 something of a self-fulfilling prophecy. functionality and HBV-specific T-cell responsiveness have 111
53 What are the implications and how can this substantive been shown in patients experiencing HBsAg seroclearance 112
54 analysis be leveraged? HBsAg loss is regarded as the ideal after stopping NUC therapy.17,18 113
55 end point of therapy; however, although considered a Finally, what is the source of the enduring HBsAg, 114
56 functional cure of chronic hepatitis B, it is recognized that especially in patients without a detectable viral load? It is 115
57 HBV viral genomes endure in the liver even if HBsAg is apparent that HBsAg can be transcribed from covalently 116
58 undetectable. What then is the value of HBsAg loss? It is closed circular DNA and integrated viral genomes. Loss of 117
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120 HBeAg is usually associated with a 3–4 log10 decrease in further clinical experimentation in humans with chronic 179
121 HBV DNA, whereas HBsAg concentrations are reduced by hepatitis B. 180
122 only 1 log10. In HBeAg-negative patients, the relatively 181
 Nucleic acid polymers, which block assembly and
123 smaller reduction of S gene messenger RNA than of pgRNA 182
release of subviral particles, followed by pegylated
124 (suggesting transcription from integrated sequences) could 183
interferon result in marked HBsAg reduction (and anti-
125 explain why HBsAg remains high.19 HBsAg expression has 184
HBs development), but require further validation and
126 been found to correlate negatively with methylation of HBV 185
safety testing.26
127 DNA in HBsAg transgenic mice. Interestingly, loss of HBsAg 186
128 expression ameliorates cell stress and liver integrity.20,21  Several immunomodulatory strategies include RIG-1 187
129 Integrated viral genomes and integrant-derived RNAs agonism or oral Toll-like receptor agonists or check 188
130 are abundant in malignant liver tissue, suggesting that point inhibition could trigger effective innate and 189
131 integrant RNAs are a significant source of HBV envelope adaptive immune responses after HBsAg reduction. 190
132 protein independent of viral replication, explaining why 191
treatment with interferon or NUCs fail to achieve a loss of  These strategies will need tailoring to the immunologic
133 phenotype in patients with high and lower levels of HBV 192
134 HBsAg. RNA interference-based treatment of chronically 193
infected patients and chimpanzees reveals that integrated replication, to adjudge their effectiveness in different
135 populations and at different stages of disease. 194
136 HBV DNA is a major source of HBsAg, particularly in HBeAg- 195
137 negative patients.22,23 This “underrecognized” source of 196
HBsAg, hiding in plain sight, has therapeutic implications. A GEOFFREY DUSHEIKO Q4
138 197
deeper understanding will be required to identify differ- Liver Unit
139 198
ences in the composition and source of subviral particles of Kings College Hospital and
140 University College London Medical School 199
141 HBsAg derived from covalently closed circular DNA versus 200
integrated HBV DNA.24 London, UK
142 201
143 The estimated HBsAg loss reported in this meta-analysis BO WANG 202
144 by Yeo et al,1 and the results reported in trials of pegylated Liver Unit 203
145 interferon and NUCs, or after NUC cessation, provide a Kings College Hospital 204
146 benchmark against which future clinical trials on functional London, UK 205
147 cure will be designed. We are entering a new era, where the 206
148 objective of achieving higher rates of HBsAg loss at an early 207
stage of disease is the goal. High HBsAg antigen loads References
149 208
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278 tenofovir disoproxil fumarate therapy in HBeAg-positive Reprint requests 337
chronic hepatitis B. Gut 2016;66:2013–2023. Address requests for reprints to: Geoffrey Dusheiko, Liver Unit, Kings College
279 Hospital, University College London Medical School, London, UK. e-mail: Q1 338
280 17. Zimmer CL, Rinker F, Honer Zu Siederdissen C, et al. g.dusheiko@ucl.ac.uk. 339
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nucleos(t)ide analogue treatment in chronic hepatitis B
282 Conflicts of interest 341
is associated with liver damage and HBsAg loss. J Infect Q2
283 The author discloses no conflicts.
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Dis 2018;217:1656–1666.
284 © 2019 by the AGA Institute 343
18. Rinker F, Zimmer CL, Honer Zu Siederdissen C, et al.
285 0016-5085/$36.00 344
Hepatitis B virus-specific T cell responses after stopping https://doi.org/10.1053/j.gastro.2019.01.015
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