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Hepatitis
Entecavir and Liver Stiffness
The impact of entecavir therapy on the liver was measured using stiffness of >30%. Liver stiffness additionally correlated with serum
transient elastography, a non-invasive technology that records liver alanine transaminase (ALT) levels. Both cirrhotic and non-cirrhotic
stiffness as an indirect measure of fibrosis. A prospective study patients experienced a decline in ALT, although stiffness was still
enrolled 118 hepatocellular carcinoma-free patients with chronic significantly higher in the former group.
hepatitis B virus (HBV) who were treated with 0.5mg/day of
entecavir for 12 months. Liver stiffness was evaluated at baseline While a decline in liver stiffness is a positive outcome, the authors
and month 12. At the end of the study, 92% of patients achieved cautioned that more studies are required to determine whether
undetectable HBV DNA (<12IU/ml) and 48% had a reduction in liver elastography is an exclusive marker of fibrosis.
47
n
Figure 6: Liver Injury Induces a Host of
A Japanese study of entecavir in 19 NUC-naïve patients over three years
Inflammatory Responses
confirmed that viral suppression is correlated with Knodell necro-
inflammatory and fibrosis score improvements (see Figures 7 and 8).
HCV proteins
Protein adducts Additionally, compliance with entecavir appeared to correlate with
MHCI/II Hepatocyte Kupffer cell
Biliary cell
histological improvement.
56
T cell
TLR-4–CD14
Activation Activation
LPS
Recruitment
Ratziu concluded that reversing liver fibrosis requires long-term
Free radicals
IL-6
TGF-β1 treatment with potent antiviral agents with a high genetic barrier to
IFN-γ
Free radicals
TNF-α
CD40
TNF-α
TGF-β1
Endothelin-1 resistance. Moreover, long-term studies with entecavir – one of the
CCL21
IL-6
TNF-α
PDGF
EGF
IGF
recommended first-line therapies in the new EASL clinical practice
IGF
guidelines – has demonstrated near normalisation of necro-
Free radicals
Hepatic stellate cell
inflammation and reversal of fibrosis. It remains to be determined
MCP-1
(HSC)
Endothelin-1
whether a liver with advanced cirrhosis can completely regress
Quiescent HSC activation
Activated HSC
PAF
Angiotensin II
to ‘normal’.
IL-10
(+)
IL-8
TGF-β1
Impact of Avoiding Resistance
RANTES
A virological perspective on reversing the effects of chronic HBV
48
was provided by Professor Locarnini. Antiviral drug resistance isAdapted from Bataller and Brenner, 2005.
defined as the reduced susceptibility of a virus to the inhibitory
Advanced fibrosis was previously thought to be permanent, explained effect of a drug, resulting from a process of adaptive mutations in
Ratziu. However, there is now evidence of a dynamic balance between the HBV polymerase gene.
57
The EASL clinical practice guidelines
fibrosis and inflammation, and the liver is capable of self-repair using emphasise the importance of obtaining evidence of resistance and
fibrolytic factors, which compete with fibrogenic factors.
48,53
HBV DNA the definition of types of response (see ‘EASL Clinical Practice
suppression is important to allow self-repair of the liver.
32
Guidelines’, p.28).
The lamivudine registration trial was the first study to show significant The emergence of resistant viruses compromises treatment goals set
reversal of liver injury. Treatment with lamivudine resulted in at least a out by the clinical practice guidelines through:
two-point improvement in histological activity index for necro-
inflammation in 56–57% of patients at both one and three years. Sixty- • virological breakthrough;
58
three per cent of patients had an improvement of at least one point in • ALT elevation or flares;
58,59
histological activity index fibrosis score at three years. Furthermore, the • decreased HBeAg seroconversion;
60
proportion of patients with resistant mutations and the duration of • archiving of resistant variants (cccDNA);
61
and
exposure to the mutant directly correlated with a reduction in • escape of resistant viruses from vaccination.
62
histological benefit.
54
Similar results were seen in adefovir-treated
patients for up to five years, when more than 70% had ≥1-point This may lead to progression of liver disease, including hepatic
improvement in histological activity index score for liver fibrosis.
13
decompensation and HCC.
57
These risks are highlighted in a classic
However, treatment with adefovir led to cases of resistance. placebo-controlled study by Liaw et al., assessing lamivudine
treatment. Over three years, 21% of those randomised to placebo had
The registration trials for entecavir (which has a lower rate of disease progression. Of those treated with lamivudine, only 5% of
resistance) consisted of two years of double-blind trials then an open- patients who retained the wild-type HBV experienced disease
label extension trial in both HBeAg-positive and -negative patients. progression; however, that compared with 13% of patients whose HBV
Patients had a total of three liver biopsies. Over the long term (median gained resistance to lamivudine (see Figure 9).
63
280 weeks), 96% of patients experienced histological improvement of
≥2-point decrease in Knodell necro-inflammatory score, while 88% Mechanisms of Drug Resistance
had ≥1-point decrease in Ishak fibrosis score.
55
A poster at EASL 2009 Key factors that drive the emergence and selection of resistance can
also evaluated the impact of entecavir on fibrosis using transient be divided into three groups, explained Professor Locarnini: the virus,
elastography (see ‘Entecavir and Liver Stiffness’, above). the drug and the patient.
32 EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
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