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Right First Time – Therapeutic Strategy for Chronic Hepatitis B
No randomised controlled trials have thus far demonstrated an effect of Figure 3: Virological Response Rates to
antiviral treatment on death, liver decompensation, cirrhosis or HCC, or
Nucleos(t)ide Analogues
resolved hepatitis. “This is not surprising,” said Lok, “because most
randomised controlled trials are not designed with clinical outcomes as
Partial virological response to NUC*
end-points.”* Furthermore, the role of intermediate markers as
100
surrogate end-points has never been adequately tested. The definition
87%
Week 24
Week 48
80
of a surrogate end-point is “a biomarker intended to substitute for a
68%
HBeAG-positive
clinical endpoint that should predict clinical benefit”.
24
To be useful, a
55%
60
surrogate marker should meet the following criteria:
25
be easier to HBeAG-negative
assess than the end-point and occur more frequently; be in the causal
40
37%
29%
33%
pathway to the end-point; and react to an intervention in a
24%
20%
corresponding way to the end-point.
P
atients with detectable
HBV DNA by PCR (%)
20
10%
7%
0
End-points as Surrogates LAM LDT ADV ETV TDF
Baseline
Lok examined whether the measurements defined in the EASL clinical HBV DNA
9.5 7.4 9.5 7.7 8.9 7.0 9.6 7.6 8.6 6.9
(log cp/ml)
practice guidelines met the definitions of surrogate markers. HBsAg is
*Viraemia quantified by Roche Cobas Amplicor PCR assay <300cp/ml for
easier to measure than clinical outcomes and occurs in the pathway of
LAM, LDT and ETV and by Roche Taq-Man PCR assay <400cp/ml for TDF, ADV
the disease. There is also evidence from a cohort study of 309 patients
It should be noted that direct comparison between the different nucelos(t)ide analogues
that HBsAg clearance correlates with lower rates of HCC,
(NUCs) is difficult since those data are derived from several different studies with varying
criteria, end-points and baseline characteristics.
decompensation and liver-related death.
26
There is also evidence that it 6
Adapted from Lampertico,2009.
is associated with decreased HBV replication and liver injury.
22
HBeAg
seroconversion is likewise easier to measure than clinical outcomes and Lok concluded that sustained HBsAg loss with or without
there is evidence that patients with persistent HBeAg have a worse seroconversion is the primary end-point, but will not be achieved in the
clinical outcome. Evidence that HBeAg seroconversion is inversely majority of patients. It is important therefore to have secondary aims,
correlated with risk of HCC was documented in an 8.5-year study of particularly for HBeAg-positive patients, where HBeAg seroconversion is
11,893 Taiwanese men.
27
A second Taiwanese study linked persistent an alternative target. Undetectable HBV DNA maintained during
HBeAg with a higher risk of progression to cirrhosis,
28
while a 1996 study treatment and sustained after cessation of treatment will improve
linked IFN-α-induced loss of HBeAg with increased survival.
29
outcomes in the majority of patients.
Suppression of HBV DNA also meets the first two criteria for a surrogate
marker. There is evidence that persistently high serum HBV DNA is Resistance
associated with an increased risk of HCC,
30
while sustained viral Avoiding resistance is a core focus of the new clinical practice
suppression prevents disease progression.
31
The histological activity guidelines and generated much discussion at EASL 2009. “There is
index has also been shown to be correlated with serum HBV DNA levels already a large pre-existing pool of resistant HBV strains,” said Professor
across five trials of 1,090 patients.
32
Zoulim at the introduction of the EASL–ViRgil Joint Workshop on
resistance, “largely because of prior worldwide exposure to lamivudine.”
Are the End-points Achievable? The development of new agents and improvements in virological
HBsAg loss occurs very rarely after one year of NUC treatment: 0–3% monitoring have helped to control the disease. Furthermore, a better
in HBeAg-positive patients and 0–<1% in HBeAg-negative patients.
33
understanding of the kinetics of resistance ensures a more specific
However, Lok observed that in clinical practice NUC treatment is likely to approach to treatment. Upon initiation of antiviral treatment, there is
be prescribed beyond one year. After two to five years of treatment typically a fall in HBV DNA to undetectable levels. At this point a very
there is an increase in the rate of HBsAg loss with NUC treatment. This sensitive assay may be able to detect early indications of genotypic
ranges from 1.3 to 6% for HBeAg-positive patients and from 0 to 5% in resistance, especially with older drugs. If treatment is continued and not
HBeAg-negative patients. The rate of HBsAg loss following pegIFN-α adapted at this time, there may be viral breakthrough (see ‘EASL Clinical
treatment is 11% irrespective of HBeAg status, but is genotype- Practice Guidelines’, p.28) with a consequent rise in alanine
dependent.
12,14,21,33,34
These are still relatively low losses. The rates of aminotransferase (ALT) levels.
HBeAg loss are higher. Treatment with NUCs for one year results in
around 20% of patients achieving HBe seroconversion, while treatment Major Issues with Resistance
for up to five years yields rates of 26–50%.
14,33,35
It is not known whether “The primary form of persistent HBV is cccDNA, a very stable form of
a further five years of treatment would lead to seroconversion in the DNA and the equivalent of a mini-chromosome,” said Professor Zoulim
non-responders. Maintaining undetectable serum HBV DNA is a more (see Figure 4). NUCs inhibit the reverse transcriptase activity of the DNA-
commonly defined end-point. After five years of treatment with adefovir, dependent polymerase but do not have a direct effect
39% of HBeAg-positive patients had undetectable HBV DNA compared on cccDNA. The mechanisms of resistance or treatment failure are
with 94% of entecavir patients. At two years the rates for telbivudine and complex, but can consist of two groups. The first includes primary non-
tenofovir were 56 and 78%, respectively.
12,14,15
In HBeAg-negative patients response and partial response, typically due to host factors – drug
the rates of HBV DNA suppression are higher because of lower pre- metabolism and compliance – and drug factors such as antiviral
treatment viral load: adefovir at 67% (five years), telbivudine 82% (two potency. The second is secondary treatment failure, which is associated
years), tenofovir 90% (two years) and entecavir 90% (one year).
12,13,15,36
The with antiviral drug resistance and selection of resistant mutants. There
figures are much lower for pegIFN-α. are also drug factors associated with secondary treatment failure,
*Clinical outcomes as end-points are difficult to implement because of the requirement for large numbers of patients, prolonged duration of therapy, prohibitive cost and ethical approval.
EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW 29
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