Book on hepatitis from page 322 to 327

Book on hepatitis from page 322 to 327

2005).
322  Hepatology 2012
Cirrhosis
Higher rates of cirrhosis have been demonstrated in HBV/HCV-coinfected patients.
In comparison to patients with HBV monoinfection, higher rates of cirrhosis (44%
vs. 21%) and decompensated liver disease (24% vs. 6%) were demonstrated in
coinfected patients (Fong 1991). Compared to HCV monoinfected patients a higher
rate of cirrhosis (95% vs. 49%) and more decompensated liver disease (Child-Pugh
class C 37% vs. 0%) were found in HBV/HCV-coinfected patients (Mohamed Ael
1997).
Hepatocellular carcinoma
In many studies coinfection with HBV and HCV has been shown to be associated
with an increased risk of HCC development (Kaklamani 1991, Mohamed Ael 1997).
In one longitudinal study incidence of HCC was 6.4 per person years in
HCV/HBV-coinfected patients compared to 2.0 in HBV and 3.7 in HCV
monoinfection. The cumulative risk of developing HCC after 10 years was 45% in
HBV/HCV-coinfected patients compared to 16% in HBV-  and 28% in HCV-monoinfected patients (Chiaramonte 1999). HBV/HCV-coinfected patients should
undergo a screening routine for HCC with liver ultrasound and α-fetoprotein levels
in serum at least every 6 months.
Treatment of HBV and HCV coinfection
Currently there are no well-established treatment guidelines for HBV/HCV-coinfected patients. Generally, treatment guidelines for monoinfected patients
should be applied to coinfected patients. In patients with HBV/HCV coinfection
treatment should be initiated when inclusion criteria for standard treatment
guidelines of HBV and HCV monoinfection are met (see Chapter 9 on therapy of
HBV and Chapter 13 on treatment of HCV). As with HBV and HCV
monoinfection, treatment of coinfected patients should be started in patients with
active chronic hepatitis or cirrhosis before liver decompensation occurs. Due to the
variety of virological profiles in HBV/HCV coinfection it is important to assess the
dominant virus prior to initiating therapy.
Due to loss of viral suppression from the successfully treated dominant virus,
deterioration of liver disease has been reported (Yalcin 2003), thus caution must be
exercised upon initiation of therapy.
In coinfected patients with dominance of HCV infection, treatment with IFN
(Weltman 1995, Villa 2001, Utili 1999) and IFN plus ribavirin (Chuang 2005, Hung
2005, Liu 2003) has been well-studied and proven effective. However, more recent
studies show that combination therapy with pegylated IFN and ribavirin are even
more efficient in inducing virological results (see Table 2).
HCV RNA response was similar to results seen in HCV monoinfection with up to
83% in HCV genotype 2/3 and 72% in HCV genotype 1 achieving sustained
virological response (Liu 2009). In one small study including 17 HCV/HBV-coinfected patients these successful results were not confirmed (Senturk 2008).
Importantly, HBV replication may become detectable in up to 36% of patients with
undetectable pretreatment HBV DNA levels (Potthoff 2009, Liu 2009). Thus, close
monitoring of both viruses is recommended during and after combination therapy.
HBV/HCV Coinfection  323
Table 2. Peg-IFN plus ribavirin treatment trials in HBV/HCV-coinfected patients.
Patients (n)  HCV SVR (%) HBV DNA
negative (%)
HBsAg loss
(%)
HBV
reactivation #
(%)
Reference
19  74  33  0  31  Potthoff, 2008
161  72*, 83**   56  11  35  Liu, 2009
17  6  na  na  na  Senturk, 2008
50  40*, 75**  100  0  24  Yu, 2009
*HCV GT1,** HCV GT2/3, na=not applicable, # HBV DNA negative pretreatment
In patients with dominance of HBV disease IFN +/- HBV polymerase inhibitors
are an option, although until now there is only data for lamivudine in a small cohort
of 8 HBV (HBeAg and HBV DNA-pos) and HCV (HCV RNA-pos) coinfected
patients (Marrone 2004). In this study, clearance of HBeAg was found in 3/8, two
patients showing HBeAg seroconversion, and clearance of HBV DNA was observed
in 3/8 at the end of therapy. HBV DNA became detectable again in 2 patients at the
end of follow-up. HCV clearance was observed in 50%. Based on these
observations nucleos(t)ide analogs such as tenofovir, adefovir, entecavir  and
telbivudine showing a higher genetic barrier in combination with PEG-IFN are a
possible treatment option. However, studies are needed to estimate the treatment
value of these newer drugs in this clinical scenario.
Conclusion
Coinfection with HBV and HCV is not uncommon, especially within areas of high
hepatitis B prevalence. HBV/HCV coinfection is a challenge for clinicians due to
the complex interaction of HBV and HCV, and the propensity for developing severe
liver disease. No treatment standard has been established for HBV/HCV-coinfected
patients. Treatment decisions must be made based upon identification of the
dominant virus. Combination therapy of PEG-IFN plus ribavirin has been shown to
be highly effective in inducing virological response of HCV in patients with
HBV/HCV coinfection. The availability of direct acting antivirals against HCV will
open new pathways in treatment, which should be replicated in HBV/HCV
coinfection. However, to date, in coinfection of HBV/HCV no treatment experience
with these new agents has been reported. Finally, caution must be exercised in
treating coinfected patients, as flares of the untreated virus may occur.
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326  Hepatology 2012
20. Assessment of Hepatic Fibrosis in
Chronic Viral Hepatitis
Frank Grünhage and Frank Lammert
Introduction
Non-invasive methods for the assessment of liver fibrosis are increasingly being
used versus invasive liver biopsy thanks to patient acceptance and the low but ever-present morbidity of biopsies. Non-invasive tests should be able to discriminate
between non-significant (stages F0-F1) and significant (stages ≥F2) fibrosis to help
either delay or initiate antiviral treatment. In addition, non-invasive markers should
be able to reliably predict liver cirrhosis in order to initiate further diagnostics to
exlude portal hypertension and to initiate surveillance strategies with progressive
fibrosis. Non-invasive strategies are also warranted for monitoring the disease while
on therapy and ideally document a regression of fibrosis in the long term.
Yet, despite recent advances in the use of surrogate markers and the development
of new technical developments such as elastography, liver histology remains the
gold standard for fibrosis staging (Goodman 2007). Currently an intense debate
regarding non-invasive tests is going on and a number of participants of this
discussion have suggested to not accept the claim of liver histology as the gold
standard and define the role of histology as the best available standard (Bedossa
2009). Nevertheless, until today most experts agree that non-invasive techniques
will not replace liver biopsies completely although they will help reduce the number
of biopsies required (Leroy 2007,  Pinzani 2005,  Sebastiani 2006). While non-invasive fibrosis tests are suitable for the diagnosis of liver cirrhosis, they have been
questioned for clinical practice as they lack the potential to discriminate the stages
of fibrosis. This specific dogma is now being questioned, and entirely non-invasive
algorithms have been developed that include a differentiation of the stages of
fibrosis (Boursier 2011a, Boursier 2011b).
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  327
Mechanisms of liver fibrosis in chronic viral
hepatitis
Liver fibrosis is characterised by the loss of hepatocytes, destruction of hepatic
(micro)architecture, proliferation of hepatic (myo)fibroblasts, and excess deposition
of extracellular matrix components (Friedman 2008). Endstage liver fibrosis
(cirrhosis) may include insufficient detoxification, hepatocellular carcinoma, portal
hypertension, renal and pulmonary failure, and is associated with excess mortality.
In chronic viral hepatitis, fibrosis develops as a consequence of the host
immunological response. This immunological response activates antiviral defence
mechanisms that aim to clear infected hepatocytes. The mechanisms underlying
fibrogenesis in HBV or HCV are complex (Friedman 2007).
A key feature of hepatic fibrosis is the activation and proliferation of hepatic
stellate cells. Quiescent hepatic stellate cells store vitamin A and reside in the
subendothelial space of Disse. Chronic liver injury leads to activation of these cells,
which become contractile, produce extracellular matrix components and secrete pro-inflammatory cytokines and chemokines like transforming growth factor ß. The
activation of these cells is believed to represent the key event in hepatic fibrogenesis
(Friedman 2008). Hepatic stellate cell activation depends on signalling by Kupffer
cells, endothelial cells, hepatocytes, and platelets. The deposition of the
extracellular matrix is constantly opposed by degradation of these proteins. In
progressive liver fibrosis, this balance is skewed in favour of excess extracellular
matrix deposition. Matrix metalloproteinases and their regulators (tissue inhibitors
of metalloproteinases, TIMPs) control matrix deposition and degradation. In liver
fibrogenesis, TIMP-1 is also produced by activated hepatic stellate cells.
Liver histology, by helping visualise the fibrosis, has been considered the gold
standard for assessment and measurement of progression of fibrosis. However, the
disadvantages of this method have motivated researchers and clinicians to look into
more non-invasive strategies. These strategies are based either on single serum
surrogate markers, compositional scores derived from combinations of different
surrogate markers, or modifications of imaging techniques.
Liver biopsy – the gold standard for staging of
liver fibrosis
In the majority of liver centres worldwide, liver biopsy is performed as a “blind” or
ultrasound-guided puncture, as either an out-  or in-patient procedure. Liver
punctures are considered to be relatively safe procedures with complication rates
ranging from 0.75% up to 13.6% (Myers 2008, Piccinino 1986, van der Poorten
2006). The most frequent complications are minor bleeding or pain. After efficient
substitution with clotting factors, percutaneous liver biopsy is also possible in
patients with inherited bleeding disorders with no obvious increase of complication
rates (DiMichele 2003,  Schwarz 2008). Procedure-related mortality rates are
reported to range from 0.001 to 0.003% (Piccinino 1986). Of note, excess rates with
severe bleedings and biopsy related deaths have been reported after percutaneous
biopsy in populations with advanced fibrosis, cirrhosis, or hepatic tumors (Terjung
2003). Thus, liver biopsies in these patients should always be performed as in-