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Pegint in eAg-ve CHB: HBsAg levels & genotype
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Pegint in eAg-ve CHB: HBsAg levels & genotype

Daniel Shouval⇑
Liver Unit, Hadassah-Hebrew University Hospital, Jerusalem, Israel

The putative impact of genotyping on HBsAg levels and endpoint
of interferon treatment in HBeAg negative patients with
chronic hepatitis B
The hepatitis B surface antigen (HBsAg) is produced by translation
of mRNAs of transcriptionally active HBV cccDNA as well
as from integrated HBV sequences coding for the surface protein.
The clinical utility of HBsAg quantification in monitoring the natural
history of chronic hepatitis B (CHB) and in evaluation of
response to anti-viral treatment continues to capture the attention
of the hepatology community for more than a decade [1–
6]. Although at least three standardized immuno-assays for quantification
of HBsAg are now commercially available [7], its utilization
is frequently restricted to academic institutions and research
centers. Both HBV-DNA and HBsAg levels fluctuate during the
various phases of chronic HBV infection, being high in the initial
immune-tolerant phase and usually fading over age except during
periods of HBV reactivation. Serum levels of circulating HBsAg
are controlled, at least in part, by the amount of intra-hepatic
cccHBV-DNA, as well as by specific immune response(s) against
the envelope proteins. In general, both HBV-DNA and HBsAg levels
are higher in treatment-naive HBeAg positive as compared to
anti-HBe positive CHB patients. In recent years various studies
evaluated the utility of HBsAg quantification in assessment of
anti-viral response to interferon as well as to nucleot(s)ide analogues.
Indeed, it has repeatedly been shown that decreasing
HBsAg levels can predict clearance of HBsAg and anti-HBs seroconversion
in the relatively small number of patients who resolve
the persistent viral infection. Overall, there is already a consensus
that in addition to measurements of viral load through HBV-DNA
monitoring, HBsAg quantification may be helpful in the prediction
of response or non-response to anti-viral treatment for both
HBeAg positive and HBeAg negative CHB patients (reviewed in
[5]). However, it soon became clear that there seem to be significant
geographic variations in the kinetic as well as the positive
and negative predictive values of threshold HBsAg levels, which
forecast response or non-response to anti-viral treatment especially
in HBeAg negative CHB patients treated by pegylated interferon
[8]. The heterogenous results obtained in different parts of
the world suggest that there may be some unrecognized factor(s),
which may have an impact on HBsAg levels, before, during and
after completion of anti-viral therapy.
In the present issue of the Journal, Brunetto and an experienced
group of investigators in the field, report the results of
a new retrospective analysis of an old multi-center study on
the impact of HBV genotypes on the five year kinetics of HBsAg
levels in HBeAg negative CHB patients with genotypes A, B, C,
and D, treated with pegylated interferon a2a with or without
lamivudine [9]. Two cohorts of patients were evaluated: Cohort
1 included 117 patients with available serum samples collected
at baseline, week 12, 24, 48, 72 or end of treatment (EOT) as
well as at 5 years after completion. Cohort 2 included 199
patients with available serum samples at baseline, EOT and at
5 years. Long-term virologic response was defined as a viral load
6104 copies/ml corresponding to 1.78  103 IU/ml at 5 years.
The major findings of this study suggest that: (1) Baseline
HBsAg levels and HBsAg kinetics vary significantly between
genotypes tested. For example, baseline HBsAg concentrations
were highest in genotype A patients followed by genotype D
and lowest for genotypes B and C. In contrast, baseline viral load
and ALT levels were similar across genotypes. (2) Patients with
genotypes A, D, and B had a heterogenous response to interferon
therapy manifested by different slops of HBsAg decline in
responders and non-responders while the mean decline of
HBsAg concentration was more pronounced across genotypes
A, B, and D in responders with long-term viral response as compared
to non-responders. In contrast, the almost absent decline
in HBsAg levels along time in genotype C patients did not
enable distinction between responders and non-responders. (3)
The early on-treatment timeframe for recognition of responders
following treatment initiation was observed between week 12–
24 of treatment for genotype A and between baseline and week
12 for genotype B. Consequently, these observations may facilitate
improved definition of treatment stopping rules as suggested
recently for interferon treated genotype D patients with
lack of HBsAg decline and <2 log10 decrease in viral load at
week 12 [10]. (4) HBsAg concentration cut-off levels for identification
of treatment response as determined by ROC analysis
were highest for genotype D at 1000 IU/ml followed by
400 IU/ml for genotype A, 75 IU/ml for genotype C and 50 IU/
ml for genotype B. Genotype specific positive predictive
cut-off values (PPV) of HBsAg concentration at week 48 and for
5 years post treatment were relatively high for all genotypes
tested except for genotype B treated patients. Negative predictive
values (NPV) were high irrespective of genotype (see Table 2
Comment: The interpretation of this important analysis is
indeed complex. Until recently, most reports on utilization of
HBsAg quantification did not include a detailed analysis of pre,
intra and post treatment response across genotypes. The results
of the present study suggest that interpretation obtained
through ‘‘simple’’ HBsAg quantification in such patients may
not be sufficient and possibly misleading for definition of new
stopping rules for treatment. The newly described genotypic
cut-off values and variable kinetics of HBsAg may improve our
ability to predict the response to and stop (or prolong) of interferon
treatment. Yet, as the authors themselves state in their
balanced discussion, it seems pre-mature to utilize genotype
specific quantification for treatment decisions in HBeAg negative
CHB patients. Although original but also intriguing these
results require confirmation by a much larger sample size with
balanced representation of genotypes before incorporating the
conclusions into clinical practice guidelines. The paper by Brunetto
et al. [9] adds new and important information but is not
easy to read. It contains a wealth of additional data not discussed
above. The limitations of the analysis are also described
in detail in the discussion. HBsAg quantification in clinical practice
is still a research tool, which requires more attention from
the scientific community. Thus, despite the availability of three
excellent commercial assays, the answer to a recent editorial
entitled ‘‘Is HBsAg quantification ready for prime time?’’ (7)
Tags: hbsag
Nice article
thanks for sharing
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