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Hepatitis
Figure 4: Hepatitis B Virus Life-cycle substitution at position 204 reduces the pocket size and creates a steric
clash with lamivudine and entecavir that renders the drugs less active
11
9
on the viral enzyme.
ER/Golgo
1
–/+ DNA
10
Selection of Mutants
2
3 8 – DNA
Several factors are involved in the selection of mutants: host cellular
factors, such as hepatocyte half-life; viral factors, such as persistence of
cccDNA cccDNA, error rate and proofreading ability; and selective pressure of
7
RNA
RNA 4
drugs. Professor Zoulim added that the rapidity of selection of escape
Core protein
Polymerase mutants is mainly due to the ability to replicate and the clearance of
Hepatocyte wild-type HBV from the liver.
42
Resistance to HBV may also occur
e
6
5 because it has a compact genome with overlapping genes (see Figure
cap A
n
Viral mRNAs RNA pregenome
5). A mutation in the viral polymerase can induce a mutation in the
overlapping surface genes, allowing the virus to escape detection or
Figure 5: Hepatitis B Virus Genome
gain infectivity.
Pre-existing mutants provide a pool from which primary resistance
mutations can be selected. For many drugs, the virus requires
OR
F Pre S2
secondary resistance mutations to regain fitness and increase viral load.
r
e
S
1
HBsAg
O
R
F
P
This accumulation puts the emphasis on preventing or tackling
gene
mutations as soon as they arise.
43,44
O
R
F
S
Only one mutation is required for the development of lamivudine
5’
resistance. A low barrier of resistance and rapidity of replication allows
resistant strains to flourish. With adefovir, although there is only one
–+
mutation required, it takes longer than lamivudine to generate viral
breakthrough, possibly because of the lower fitness of that particular
Partially dsDNA
mutant.* With entecavir at least three mutations are required for
resistance, equating to a high genetic barrier to resistance. Professor
Zoulim speculated on the open question of whether these mutations
can be acquired sequentially or must all appear at the same time.
O 5’
3’
R
F
C
O
o
R 3’
r
e
F Sometimes a single mutation can confer multidrug resistance; for
P
P
ORF X
example, Professor Zoulim stated that the 181 mutation can lead to
r
e
C
Polymerase
gene
resistance to adefovir and reduce activity against lamivudine. Sequential
or cumulative use of monotherapies with low barriers to resistance can
create a mounting sequence of mutation followed by selection for
fitness.
45
This can also lead to multidrug resistance, as with HIV, creating
namely the genetic barrier to resistance offered by an long-term problems for treatment worldwide.
37
agent.
37,38
Secondary treatment failure is the evolution of the viral
population to acquire a sufficient number of critical drug-resistant In summary, resistant mutations pre-exist in the HBV pool prior to
mutations to overcome the antiviral activity of the drug regimen. therapy. Their success depends on fitness, infectivity, replication rate,
level of resistance and replication space available in the liver. A weak
Professor Zoulim described a study of partial response to adefovir. The treatment regimen and insufficient monitoring can lead to resistance
patient population was split into four quartiles: Q1, the first quartile, were selection. Therefore, Professor Zoulim concluded, clinicians should
very good responders (>5 log
10
decrease in HBV DNA levels at week 48), use high-potency drugs with a high genetic barrier to resistance as
while Q4 had the poorest response (<2 log
10
decrease). A phenotypic initial therapy.
analysis on viral strains showed that the virus from patients in Q1
responded equally well to adefovir in vitro as the virus from Q4. Drug Resistance Testing
Therefore, the partial response to adefovir was not due to the selection Stephen Locarnini (Australia) emphasised the increasing importance of
of drug-resistant mutants, but was related to host factors.
39
drug resistance testing and the need for better understanding of test
results. This will enable the development of a rational framework to help
Professor Zoulim noted that drug resistance is caused by the selection manage virological breakthrough in everyday clinical practice. Professor
of drug-resistant mutations. Certain mutations at different points in the Locarnini discussed the acceptable viral DNA level, where disease
genome can confer resistance to one or many different drugs. For progression is stopped or reversed and resistance is halted. The goal
example, a mutation at amino acid 181 can lead to reduced should be ‘undetectable HBV DNA’ as determined by realtime PCR at the
susceptibility to lamivudine and adefovir.
40,41
Changes in the end of the first year of treatment. Standardisation of definition is vital, he
conformation of the polymerase catalytic site due to the amino acid urged, and the EASL clinical practice guidelines are a good starting point
*A single mutation conferring resistance may occur at one of two sites.
30 EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
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