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Assessment and management of patients with hepatitis B infection NHS Greater Glasgow and Clyde January 2013

Assessment and management of patients with hepatitis B infection

NHS Greater Glasgow and Clyde

January 2013

Developed by:

Viral Hepatitis Managed Care Network

Version No.


Date of Introduction:

September 2004

Date of Last Review:

Jan 2013

Date of Next Review:

Jan 2016

Updated by:

Dr David Bell , Consultant in Infectious Diseases, Brownlee Centre, Gartnavel General Hospital.

Page 1 of 15


This guideline is largely based upon the recommendation of the European Association for the Study of the Liver 2012 Hepatitis B guidelines (1).

Around 350-400 million people in the world are chronic hepatitis B (CHB) carriers with detectable serum hepatitis B surface antigen (HBsAg) for six months or longer. The prevalence is Scotland is estimated to be around 0.2%, with around 9000 persons thought to have CHB (2).

Natural History of Hepatitis B Virus (HBV) infection

Transmission of HBV occurs through contact with infected blood or body fluids. Worldwide, the most common route of transmission is from an infected mother at the time of birth (vertical transmission) or during childhood (horizontal transmission). Sexual transmission and injecting drug use are also important modes of transmission. Infection early in life is usually asymptomatic and the likelihood of chronic infection is high, 90% for vertical transmission, 8-15% for horizontal transmission (3, 4). Acquisition of HBV infection in adult life usually results in clinical hepatitis and a low rate of chronic carriage, less than 5% (5).

The spectrum of disease and natural history of chronic HBV infection are variable. Chronic HBV infection is a dynamic process, with several stages of infection described, table 1 (6). Patients may move between these stages (not necessarily sequentially or in one direction) and regular monitoring is essential so correct treatment decisions can be made appropriate to the phase of infection.

Introduction This guideline is largely based upon the recommendation of the European Association for the Study

Table 1: Phases of chronic hepatitis B infection (6)

Patients infected at birth or early childhood usually enter a prolonged Immune Tolerant phase with a high levels of HBV DNA, eAg positivity but minimal liver inflammation (normal ALT) and no or slow progression of fibrosis. Treatment is generally not required but may be indicated in pregnancy (see below and GGC HBV in Pregnancy guideline). These patients are highly infectious.

Entry to the Immune Reactive phase is associated with increased immune activity, falls in HBV DNA, rises in ALT and possible seroconversion from eAg+ to eAg-. Rates of e- seroconverion of between 8 and 12% per year are reported. This phase is associated with liver inflammation and progression of fibrosis. Treatment should be considered in those failing to e-seroconvert within 3-6 months.

E-seroconversion from eAg+ to eAb+ is associated with entry into the Inactive Carrier phase, with low or undetectable levels of HBV DNA, normal ALT. Liver inflammation and progression of fibrosis are minimal. The EASL 2012 guideline recommends a minimum follow-up of 1 year showing normal ALT levels at least every 34 months and serum HBV DNA levels < 2000 IU/ml before classifying a patient as inactive HBV carrier (1). Patients who remain in this phase do not usually require treatment and are at low risk of cirrhosis or HCC. Around 1-3% per annum will spontaneously clear their sAg with or without the development of anti-HBs. Inactive carriers require life-long follow up, with periodic ALT and HBV DNA measurement to detect viral re-activation. Immunosuppression of patients in the inactive carrier state may lead to reactivation of the virus.

“HBeAg-negative CHB” develops in 15-20% of Inactive Carriers with viral re-activation and fluctuating levels of HBV DNA and ALT. These patients are at risk of liver inflammation and fibrosis and may require treatment. Patients remain eAg- and most have HBV virions harbouring nucleotide mutations in their pre-core promoter regions resulting in an inability to produce eAg (pre-core mutants).

HBsAg loss occurs rarely during the natural course of infection and is associated with a reduced risk of fibrosis. Immunosuppression, even after loss of HBsAg may lead to viral reactivation.

Morbidity and mortality in CHB are linked to persistence of viral replication and evolution to cirrhosis and/or hepatocellular carcinoma (HCC) (1). Longitudinal studies of untreated patients with CHB indicate that, after diagnosis, the 5-year cumulative incidence of developing cirrhosis ranges from 8% to 20%. The 5-year cumulative incidence of hepatic decompensation is approximately 20% for untreated patients with compensated cirrhosis. Co-infection with HIV, HCV, HDV and alcohol or obesity all affect the natural course of CHB.

New Patient Assessment

History to include:

Assessment of probable route and duration of infection, country of birth

Family History of CHB infection, liver cancer and Cirrhosis

Previous HBV Therapy

Results of HBV tests / vaccinations of close and sexual contacts

Advice on risk factors for transmission: condoms, vaccination of household and

sexual contacts, not to share toothbrush or razors, cover cuts and clean up blood spills etc.

Other medication / drugs / alcohol Future and current fertility and contraception plans

Examination Stigmata of Chronic Liver Disease Liver palpation

Investigations If not already done, the following tests should be arranged:







HIV Test (with verbal consent)




HBV-serology (sAg, cAb, eAg, eAb)




HBV DNA + Genotype


Iron Studies





U&E + Glucose + TFT


Autoantibodies including:

Bone Profile (phosphate)



LFT including gamma GT


Alphafetoprotein (AFP)








Imaging Fibroscan (if available). NB - pregnancy is a contraindication


Liver Ultrasound Scan


Liver Biopsy Liver biopsy is the gold standard for assessing the degree of inflammation and fibrosis. Biopsy is most useful in those who do not meet clear criteria for treatment and those with higher risk for progression (age>40, male, FH of HCC or cirrhosis, alcohol excess, obesity). Risks of ultrasound guided biopsy are low, but this should be discussed and documented in notes. Biopsy should not usually be performed on patients with established cirrhosis.

Immunotolerant: Consider liver biopsy or even therapy in these patients over 30 years of age and/or with a family history of HCC or cirrhosis.

Different scoring methods are available, including ISHAK and METAVIR. The degree

of necroinflammation is reported as a “grade” and fibrosis as a “stage”.

Contact Tracing and Vaccination Advise HBV testing and / or vaccination of household or sexual contacts if this has not already been done. Starting in late 2012, all new HBV cases (chronic or acute)

will be automatically notified to the Sandyford Shared Care initiative who will assist GPs and other health Professionals in arranging contact tracing and vaccination.


Loss of HBsAg is rarely achieved and the aim of treatment is to reduce morbidity and mortality from liver cirrhosis and HCC and prevent further transmission. This can be achieved by sustained suppression of HBV replication (1). There is evidence that sustained suppression of viral replication may lead to histological improvement in patients with established cirrhosis (7, 8). Even after loss of HBsAg, HBV cccDNA remains integrated in hepatocyte DNA and HBV reactivation may occur during immunosuppressant therapy.

Treatment outcomes associated with improved prognosis may be divided into biochemical, virological and serological responses and depend on whether the patient is on or off treatment and which treatment has been taken. These are shown in table 2.


Normalisation of ALT


On Pegylated Interferon: HBV DNA < 2000 IU/ml after 6 months on therapy, at the end of therapy and sustained for at least 12 months after therapy


On Nucleotide analogues: Undetectable HBV DNA (<60 IU/ml) on treatment


For HBeAg+ patients: Loss seroconversion to anti-HBe





For all CHB patients: loss of HBsAg +/- development of anti-HBs

Table 2. Treatment responses in CHB

Indications for treatment

These are based upon serum HBV DNA levels, ALT levels and the severity of liver disease.

Patients should be considered for treatment if they have a combination of:

HBV DNA > 2000 IU/ml


ALT > Upper limit of normal (ULN)


Liver disease severity assessed by biopsy or Fibroscan showing moderate to severe active necro-inflammation and/or at least moderate fibrosis

Indications for treatment should also take into account age, health status, family history of HCC or cirrhosis and extrahepatic manifestations. Treatment should be considered in any

patient with significant fibrosis or cirrhosis or history a family of HCC even if the ALT level is normal or HBV DNA is low.

The EASL 2012 guideline suggests an ALT ULN of 40 IU/ml (1). An ULN for ALT of 19 IU/ml for women and 30 IU/ml for men have been suggested by others (9).

Treatment options

Two types of treatment are used for CHB; pegylated interferon (PEG-INF) or nucleoside/nucleotide analogues (NAs). Both are NHS GGC formulary approved for the treatment of HBeAg-positive or HBeAg-negative CHB. Advantages and disadvantages of both types of treatment are listed in table 3 (1).

patient with significant fibrosis or cirrhosis or history a family of HCC even if the ALT

Table 3. Advantages and disadvantages of PEG-IFN and NAs in the treatment of CHB (1)

Pegylated Interferon Alpha 2a

This is given as a monotherapy for 48 weeks as a weekly SC injection of 180 micrograms. PEG-IFN is contra-indicated in pregnancy and decompensated cirrhosis. Response rates 6 months following 48 weeks of PEG-IFN are shown, table 4 (1).


HBeAg-positive patients

HBeAg-negative patients

HBV DNA < 60 IU/ml (%)

  • 14 19

Anti-HBe seroconversion (%)

  • 32 N/A

ALT normalisation (%)

  • 41 59

HBsAg loss (%)



Table 4. Responses to PEG-IFN (1)

Pre-treatment predictors of response to PEG-IFN in HBeAg-positive patients include (6):

ALT > 2 x ULN HBV DNA < 2 x 10 8 IU/ml Age <50 years Genotype A or B Female Significant necro-inflammatory score on liver biopsy Predicting on treatment response to PEG-IFN

Recent data have demonstrated high negative predictive values (NPV) using

quantitative HBsAg at week 12 and 24 to identify HBeAg-positive patients unlikely to respond to pegylated interferon therapy. These rules were applicable to genotypes A, B, C and D, figure1 (10). Other studies have shown that a combination of HBV DNA and HBsAg levels together may be useful in HBeAg-negative patients (1)

Quantification of HBsAg is available in GGC through the West of Scotland Specialist Virology Centre in Glasgow and should be requested on all patients starting pegylated interferon at baseline and at week 12.

 Recent data have demonstrated high negative predictive values (NPV) using  quantitative HBsAg at week

Figure 1. Performance of stopping rules using quantitative HBsAg in 803 HBeAg-positive patients treated with pegylated interferon (10)

Nucleoside/Nucleotide analogue (NA) therapy

Adefovir, Entecavir, Lamivudine and Tenofovir are taken oral once daily. Data from clinical trials on treatment response after 1 year with NAs in HBeAg-positive and negative patients are shown in table 5 (1). These trials were conducted in different patient populations and the response rates may not be directly comparable.

With prolonged therapy, these response rates are increased. After 5 years of Tenofovir in HBeAg+ patients, a 40% anti-HBe seroconversion rate has been reported with 11% of patients achieving HBsAg loss (11). Similar rates with prolonged Entecavir therapy are reported (12). After 5 years, >90% of eAg-positive or negative patients on either treatment will have an undectable VL. For both drugs, the chances of achieving HBs loss are related to the viral genotype and/or patient ethnicity. HBs loss appears to be much less common in Asian populations and with genotypes B or C (13-15).







100 mg/day

245 mg/day

0.5 mg/day


1mg/day if



Side Effects







phosphate loss

phosphate loss

Treatment responses at 1 year in HBeAg-positive patients


Anti-HBe seroconversion (%)



  • 21 12-18

HBV DNA <60 IU/ml (% )



  • 67 13-21

ALT Normalisation (%)



  • 68 48-54

HBsAg Loss (%)





Resistance at 1 year (%)

  • 24 0



Resistance at 5 years (%)

  • 70 0



Treatment responses at 1 year in HBeAg-negative patients


HBV DNA < 60 IU/ml (%)

  • 72 93

  • 90 51-63

ALT Normalisation (%)



  • 78 72-77

Table 5. Treatment response with NAs in HBeAg-positive and negative patients (1)

Overview of NAs for CHB

Adefovir, Entecavir, Lamivudine and Tenofovir are all GGC Formulary approved for the treatment of CHB, though the Scottish Medicines Consortium (SMC) restricts the use of Adefovir to patients with lamivudine resistance. In clinical practice, Entecavir and Tenofovir are used in preference to other NAs because of their greater potency and high barriers to resistance. There is no evidence to favour dual NA therapy but this may be considered in exceptional circumstances e.g. HIV co-infected or resistant HBV





No specific toxicity monitoring recommended Very low levels of resistance

Pregnancy risk category C Caution in previously Lamivudine treated patients in case of resistance


Drug of choice if required in pregnancy (see below)

Requires monitoring of renal function due to concerns over renal toxicity


No resistance reported

and phosphate loss (16) (see below)



Low genetic barrier to resistance



Low genetic barrier to resistance Requires monitoring of renal function due to concerns over renal toxicity (see below)

In line with the GGC formulary Section 5.3.3, the Board policy is that a Specialist should always recommend the initiation of such drugs but that prescribing is undertaken by GPs. Monitoring of treatment efficacy and for side-effects will be undertaken in the specialist clinic. Where treatment is required to start immediately then the initial supply will be dispensed from secondary care, with the GP providing ongoing prescribing if required, e.g. in late pregnancy. Shared care protocols for the management of chronic HBV are in development and will be available to GPs and Specialist to define these roles.

Treatment Recommendations

Choice of first line therapy is influenced by patient characteristics and informed patient choice. Factors to consider include; route of administration, side effects, likely treatment duration, family planning, ALT, HBV DNA, liver histology or Fibroscan result, genotype and family history. A high level of adherence to NA therapy is critical for virological outcome and to prevent resistance. Ensure patient is HIV negative before starting NA therapy.

Tenofovir is cheaper than Entecavir; the BNF price per year for Tenofovir 245mg daily is £2886 and for Entecavir 0.5 mg daily is £4359. Tenofovir requires more monitoring and may be unsuitable in some patients with renal dysfunction.

  • 1. Pre-cirrhotic CHB HBeAg +ve or ve:

Pegylated interferon alpha-2a 180ug sc weekly for 48 weeks


Tenofovir 245mg orally once daily. Optimum duration remains unknown, although continue for at least 48 weeks if tolerated.


Entecavir 0.5mg orally once daily (1mg daily if known to be Lamivudine resistant). Optimum duration remains unknown, although continue for at least 48 weeks if tolerated.

  • 2. Compensated cirrhosis Usually treatment is with NAs and is likely to be indefinite. Watch carefully for evidence of decompensation if using PEG-IFN.


Decompensated cirrhosis

Should be managed by hepatologists in conjunction with Scottish Liver Transplant Unit (SLTU) if suitable candidate for transplantation.

Consider Tenofovir therapy. Do not use PEG-IFN.

  • 4. Lamivudine Resistant CHB Tenofovir 245mg daily or Entecavir 1mg daily (less good option)

  • 5. Hepatitis D co-infection HBV-HDV co-infection is associated with faster liver disease progression. PEG-IFN is the only effective drug against HDV (1). The optimal duration of therapy is not well defined. NAs do not impact on HDV replication

  • 6. Hepatitis C Virus (HCV) co-infection HCV rather than HBV is often responsible for the chronic hepatitis seen in this group of patients. Patients should receive PEG-INF plus Ribavirin as for HCV. HCV sustained virological response rates are comparable to HCV mono-infected patients (17). There are no data on the use of the newer HCV agents including Telaprevir and Boceprevir in patients with CHB. HBV re-activation during or after clearance of HCV should be treated with NAs.

  • 7. HIV co-infection Co-infected patients should be managed by infectious disease physicians. Tenofovir and emtricitabine used as part of anti-HIV combined therapy (18). If there is evidence of Tenofovir intolerance/toxicity then Entecavir should be added to new anti-HIV regime. Entecavir should never be used unless the patient is on anti-HIV medication at the same time.

  • 8. Immunosuppressed patients Hepatitis B carriers and persons who have previously had hepatitis B infection are at risk of re-activation on receiving some chemo or immunosuppressive therapies (particularly with regimes containing corticosteroids or rituximab). HBsAgpositive patients should be considered for prophylactic treatment with a NA, regardless of HBV DNA level, due to the high risk of reactivation which carries a significant risk of morbidity and mortality. Treatment should continue for at least 12 months after cessation of therapy.

Lamivudine is the most frequently studied NA in this setting, however given the risks of resistance, more potent NAs should be considered, particularly if prolonged treatment is required. One study suggests that Entecavir may be more effective as prophylaxis (19). Little published data exists for tenofovir but theoretically it should be equally efficacious. Where baseline renal function is deranged, in renal transplant patients or treatment carries a high risk of nephrotoxicity (due to tumour lysis syndrome or nephrotoxic

regimes) then Entecavir may be the preferred option. If tenofovir is used dose adjust according to eGFR.

HBsAg-negative patients with positive anti-HBc antibodies and undetectable HBV DNA need close monitoring of ALT and monthly HBV DNA levels during therapy. They should receive NAs treatment upon confirmation of detectable HBV DNA before ALT elevation. When close monitoring of DNA levels is not felt practical, or were there is felt to be a high risk of reactivation (profound immunosupression for a prolonged period of time, including Rituximab regimes and bone marrow transplant) or established advanced liver disease, then pre-emptive prophylactic treatment should be considered.

All patients receiving prophylaxis with a NA should have close observation (1-3 monthly for 6 months) of LFTs and DNA levels on withdrawal of prophylaxis, to monitor for delayed reactivation.

Monitoring of patients not requiring treatment

In most circumstances patients will be seen every 3-6 months with measurement of LFTs, HBV DNA, HBeAg and anti-HBe depending on patient characteristics and HBV status. HCC surveillance should also be considered (see below).

Monitoring of patients on treatment

Pegylated interferon is only dispensed and monitored in secondary care:

Biochemistry and haematology as for PEG-IFN treatment in HCV infection

Quantitative HBV DNA every 3 months during therapy, then 6 months following end of treatment.

HBeAg and anti-HBe after 6 months, at the end of treatment and then 6 months following end of treatment.

Consider quantitative measurement of HBsAg at treatment onset, 12 weeks and end of treatment.


The GGC formulary states that GPs are asked to prescribe medication but that monitoring of treatment efficacy and toxicity is undertaken in the specialist clinic.

Measure LFTs + HBV DNA every three months for one year, then 3-6-monthly.

If HBV DNA has not fallen by > 1log at 3 months or is still detectable at 12 months check compliance and request a resistance test.

HBeAg and anti-HBe every 6 months

Additional monitoring is recommended for patients on Tenofovir or Adefovir due to the risk of renal toxicity

o The SPC for Tenofovir recommends monitoring of renal function and serum phosphate every four weeks for the first year then every three months thereafter (16). In practise less frequent monitoring, with review at 1 month on treatment then every 3 months thereafter is acceptable for patients at low risk of renal toxicity normotensive, not diabetic, no proteinuria, normal eGFR at baseline and not on nephrotoxic medication.


Progressive decline in eGFR, or the presence of hypophosphataemia or new-onset haematuria, glycosuria (in the presence of normoglycaemia) may indicate tenofovir toxicity. The presence of hypophosphataemia should be confirmed on a fasting specimen if possible (phosphate levels fall on eating)


Urine protein leakage is an early feature of Tenofovir renal toxicity. The British HIV Association recommends regular measurement of urine

protein-creatinine (uPCR) ratio for patients taking Tenofovir (20). A rise in the uPCR above the ULN may indicate Tenofovir toxicity. In GGC in ULN is 30 mg/mmol

o The SPC for Adefovir recommends that patients with normal renal function should be monitored for changes in serum creatinine every 3 months and eGFR calculated. In patients at risk of renal impairment, more frequent monitoring should be considered (21).

Treatment Discontinuation

Generally, NA treatment should not be discontinued in patients with significant liver fibrosis

The EASL 2012 guideline states that treatment with NAs may be discontinued in HBeAg-positive patients who achieve anti-HBe seroconversion (1). Treatment should continue for at least 12 months following seroconversion prior to stopping. A number of these patients will require retreatment as they will not sustain their virological or biochemical response.

Screening for Hepatocellular Carcinoma (HCC)

The annual incidence of HCC in a cohort of Asian males with CHB is reported to be 0.5%, with a relative risk for HCC of 100 compared to non-HBV carrier controls (22). The risk of HCC varies depending on multiple factors including current and previous hepatic inflammatory activity, HBV replication liver fibrosis, family history of HCC, age, age at time of infection, co-infection with HIV, HDV or HCV, the presence of other liver diseases and possibly host ethnicity. The 2005 AASLD (American Association for the Study of the Liver) Practice Guideline recommends HCC surveillance using liver ultrasound and serum AFP measurement at intervals of between 6 and 12 month in the following patient groups with CHB (23).

Asian males over 40 years old

Asian females over 50 years old

Africans over 20 years old

All Cirrhotic patients (biopsy proven, or FibroScan or radiological)

Family history of HCC

For the sake of simplicity and to minimize the risk of a missed HCC in the GGC population, an annual USS should be performed on all chronic HBV patients with more frequent scans being performed in those at higher risk.


  • 1. European Association for the Study of the Liver (EASL) Clinical Practice Guidelines: Management of chronic hepatitis B virus infection 2012. Journal of Hepatology 2012: 57; 167185

  • 2. Christian Schnier, Health Protection Scotland. Data presented September 13th 2012 at Royal College Physicians of Edinburgh.

  • 3. Xu, W.M. et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo- controlled study. J. Viral Hepat. 2009: 16; 94103.

  • 4. Davis LG et al. Horizontal transmission of hepatitis B virus. Lancet 1989; l: 889-93.

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  • 7. Afdhal N et al. Factors associated with regression of cirrhosis in patients with chronic hepatitis B infection treated with tenofovir disoproxil fumarate. EASL Conference, Barcelona 2012; Poster #497.

  • 8. Chang TT et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52: 88693.

  • 9. Prati D et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002;137:19

    • 10. Sonneveld MJ et al. Response-guided peginterferon therapy in HBeAg-positive chronic hepatitis B using serum hepatitis B surface antigen levels: a pooled analysis of 803 patients. AASLD 2012 Conference, Boston. Abstract #23.

    • 11. Marcellin P et al. No Detectable Resistance to Tenofovir Disoproxil Fumarate (TDF) Following up to 240 Weeks of Treatment in Patients with HBeAg+ and HBeAg- Chronic Hepatitis B Virus Infection. AASLD Conference San Francisco 2011; Oral Abstract #238

    • 12. Lampertico P et al. Maintained viral suppression and excellent safety profile of entecavir monotherapy in 418 NUC-Naive patients with chronic hepatitis B: A 4- year field practice, multicentre study. EASL Conference Barcelona 2012; Poster #522

  • 13. Heathcote EJ et al. Long Term (4 Year) Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Positive Patients (HBeAg+) with Chronic Hepatitis B (Study 103). AASLD Conference Boston 2010; Poster #477

  • 14. Marcellin P et al. HBsAg kinetics in patients with chronic hepatitis B treated with tenofovir disoproxil fumurate for up to 4 years. EASL Conference Berlin 2011; Poster #740

  • 15. Gish R et al. Loss of HBsAg in Nucleoside-Naïve HBeAg(+) Chronic Hepatitis B Patients Following Treatment with Entecavir or Lamivudine: Evaluation of HBV Genotypes. AASLD Conference Boston 2009; Poster #388

  • 16. Tenofovir Summary of Product Characteristics, February 2012

  • 17. Chu et al. Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment. Journal of Gastroenterology and Hepatology 2008: 23; 512520

  • 18. British HIV Association (BHIVA) guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy, HIV Medicine 2012, 13 (Suppl. 2), 185

  • 19. Li HR et al. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. Journal of Viral Hepatitis, 2011, 18, 877883

  • 20. British HIV Association (BHIVA) guidelines for the routine investigation and monitoring of adult HIV-1-infected individuals. HIV Medicine 2012, 13, 144

  • 21. Adefovir Summary of Product Characteristics, August 2012

  • 22. Beasley RP et al. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981 Nov 21;2(8256):1129-33.

  • 23. Bruix J and Sherman M. AASLD Practice Guideline. Management of Hepatocellular Carcinoma . Hepatology 2005: 42, No. 5.