2.1 Epidemiology and public health burden
2.2 Natural history
- (1)The “immune tolerant” phase is characterized by HBeAg positivity, high levels of HBV replication (reflected by high levels of serum HBV DNA), normal or low levels of aminotransferases, mild or no liver necroinflammation and no or slow progression of fibrosis [3,
- (2)The “immune reactive phase” is characterized by HBeAg positivity, a lower level of replication (as reflected by lower serum HBV DNA levels), increased or fluctuating levels of aminotransferases, moderate or severe liver necroinflammation and more rapid progression of fibrosis compared to the previous phase [3,
- (3)The “inactive HBV carrier state” may follow seroconversion from HBeAg to anti-HBe antibodies. It is characterized by very low or undetectable serum HBV DNA levels and normal aminotransferases. As a result of immunological control of the infection, this state confers a favourable long-term outcome with a very low risk of cirrhosis or HCC in the majority of patients. HBsAg loss and seroconversion to anti-HBs antibodies may occur spontaneously in 1–3% of cases per year, usually after several years with persistently undetectable HBV DNA [].
- (4)“HBeAg-negative CHB” may follow seroconversion from HBeAg to anti-HBe antibodies during the immune reactive phase and represents a later phase in the natural history of CHB. It is characterized by periodic reactivation with a pattern of fluctuating levels of HBV DNA and aminotransferases and active hepatitis. These patients are HBeAg-negative, and harbour HBV variants with nucleotide substitutions in the precore and/or the basal core promoter regions unable to express or expressing low levels of HBeAg. HBeAg-negative CHB is associated with low rates of prolonged spontaneous disease remission. It is important and sometimes difficult to distinguish true inactive HBV carriers from patients with active HBeAg-negative CHB in whom phases of spontaneous remission may occur. The former patients have a good prognosis with a very low risk of complications, while the latter patients have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and subsequent complications such as decompensated cirrhosis and HCC. A careful assessment of the patient is needed and a minimal follow-up of one year with serum alanine aminotransferase (ALT) and HBV DNA levels every 3 months usually allows detection of fluctuations of activity in patients with active HBeAg-negative CHB [].
- (5)In the “HBsAg-negative phase” after HBsAg loss, low-level HBV replication may persist with detectable HBV DNA in the liver []. Generally, HBV DNA is not detectable in the serum while anti-HBc antibodies with or without anti-HBs are detectable. HBsAg loss is associated with improvement of the outcome with reduced risk of cirrhosis, decompensation and HCC. The clinical relevance of occult HBV infection (detectable HBV DNA in the liver with low-level [<200 international units (IU)/ml] HBV DNA in blood) is unclear []. Immunosuppression may lead to reactivation in these patients [17,18].
|Grading of evidence|
|High-quality evidence||Further research is very unlikely to change our confidence in the estimate of effect||A|
|Moderate-quality evidence||Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate||B|
|Low- or very low-quality evidence||Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any estimate of effect is uncertain||C|
|Grading of recommendation|
|Strong recommendation warranted||Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost||1|
|Weaker recommendation||Variability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted.||2|
|Recommendation is made with less certainty; higher cost or resource consumption|
- •How should liver disease be assessed before therapy?
- •What are the goals and end-points of treatment?
- •What are the definitions of response?
- •What is the optimal approach to first-line treatment?
- •What are the predictors of response?
- •What definitions of resistance should be applied and how should resistance be managed?
- •How should treatment be monitored?
- •When can treatment be stopped?
- •How should special groups be treated?
- •What are the current unresolved issues?
4.1 Pretherapeutic assessment of liver disease
- (1)The assessment of the severity of the liver disease should include: biochemical markers, including aspartate aminotransferase (AST) and ALT, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase, prothrombin time and serum albumin; blood counts; and hepatic ultrasound (A1). Usually, ALT levels are higher than those of AST. However, when the disease progresses to cirrhosis, the ratio may be reversed. A progressive decline in serum albumin concentrations and prolongation of the prothrombin time, often accompanied by a drop in platelet counts, are characteristically observed after cirrhosis has developed.
- (2)HBV DNA detection and HBV DNA level measurement is essential for the diagnosis, decision to treat and subsequent monitoring of patients (A1). Follow-up using real-time PCR quantification assays is strongly recommended because of their sensitivity, specificity, accuracy and broad dynamic range [26,27,28,29] (A1). The World Health Organization (WHO) has defined an international standard for normalisation of expression of HBV DNA concentrations []. Serum HBV DNA levels should be expressed in IU/ml to ensure comparability; the same assay should be used in the same patient to evaluate antiviral efficacy (A1).
- (3)Other causes of chronic liver disease should be systematically looked for including coinfection with HDV, HCV and/or HIV. Co-morbidities, including alcoholic, autoimmune, metabolic liver disease with steatosis or steato-hepatitis should be assessed (A1).
- (4)A liver biopsy is recommended for determining the degree of necroinflammation and fibrosis in patients with either increased ALT or HBV DNA levels >2000 IU/ml (or both) since hepatic morphology can assist the decision to start treatment (A1). Biopsy is also useful for evaluating other possible causes of liver disease such as steatosis or steato-hepatitis. Although liver biopsy is an invasive procedure, the risk of severe complications is very low (1/4,000–10,000). It is important that the size of the needle biopsy specimen be large enough to precisely analyse the degree of liver injury and fibrosis [] (A1). A liver biopsy is usually not required in patients with clinical evidence of cirrhosis or in those in whom treatment is indicated irrespective of the grade of activity or the stage of fibrosis (A1). There is growing interest in the use of non-invasive methods, including serum markers and transient elastography, to assess hepatic fibrosis to complement or avoid a liver biopsy [32,33,34,35,36].
4.2 Goal of therapy
4.3 End-points of therapy
- (1)In HBeAg-positive and HBeAg-negative patients, the ideal end-point of therapy is sustained HBsAg loss with or without seroconversion to anti-HBs. This is associated with a complete and definitive remission of the activity of chronic hepatitis B and an improved long-term outcome (A1).
- (2)In HBeAg-positive patients, durable HBe seroconversion is a satisfactory end-point because it has been shown to be associated with improved prognosis (A1).
- (3)In HBeAg-positive patients who do not achieve HBe seroconversion, and in HBeAg-negative patients, a maintained undetectable HBV DNA level on treatment with NUCs or a sustained undetectable HBV DNA level after interferon therapy is the next most desirable end-point (A1).
4.4 Definitions of response
- (1)On interferon alpha therapy:
- •Primary non-response is defined as less than 1 log10 IU/ml decrease in HBV DNA level from baseline at 3 months of therapy.
- •Virological response is defined as an HBV DNA concentration of less than 2000 IU/ml at 24 weeks of therapy.
- •Serological response is defined by HBe seroconversion in patients with HBeAg-positive CHB.
- (2)On NUC therapy:
- •Virological response is defined as undetectable HBV DNA by real-time PCR assay within 48 weeks of therapy.
- •Partial virological response is defined as a decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA by real-time PCR assay. A partial virological response should be assessed to modify therapy at 24 weeks of treatment for moderately potent drugs or drugs with a low genetic barrier to resistance (lamivudine and telbivudine) and at 48 weeks of treatment for highly potent drugs, drugs with a higher genetic barrier to resistance or drugs with a late emergence of resistance (entecavir, adefovir and tenofovir).
- •Virological breakthrough is defined as a confirmed increase in HBV DNA level of more than 1 log10 IU/ml compared to the nadir (lowest value) HBV DNA level on therapy; it usually precedes a biochemical breakthrough, characterized by an increase in ALT levels. The main causes of virological breakthrough on NUC therapy are poor adherence to therapy and selection of drug-resistant HBV variants (resistance) (A1).
- •HBV resistance to NUCs is characterized by selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered NUC(s). Resistance may result in primary treatment failure or virological breakthrough on therapy (A1).
4.5 Results of current therapies
- (1)In HBeAg-positive patients, virological response rates at one year (undetectable HBV DNA, defined variously in the different trials and differently from the present guidelines) were 25%, 36–40%, 21%, 67%, 60% and 74% with pegylated interferon alpha-2a/2b, lamivudine, adefovir, entecavir, telbivudine and tenofovir, respectively (Fig. 1) [38,39,40,41,42,43,44]. HBe seroconversion rates were of the order of 30% with conventional and pegylated interferon alpha and approximately 20% for NUCs. HBe seroconversion rates increase with continued NUCs treatment, but are affected if resistance occurs (B1). Loss of HBsAg rates after one year were 3–4% with pegylated interferon alpha, 1% with lamivudine, 0% with adefovir, 2% with entecavir, 0% with telbivudine, and 3% with tenofovir.
- (2)In HBeAg-negative patients, virological response rates at one year (undetectable HBV DNA, defined variously in the different trials and differently from the present guidelines) were 63%, 72%, 51%, 90%, 88% and 91% with pegylated interferon alpha-2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir, respectively (Fig. 2) [41,45,46,47,48,49]. Loss of HBsAg rates after one year were 3% with pegylated interferon alpha and 0% with lamivudine, adefovir, entecavir, telbivudine or tenofovir.
4.6 Indications for treatment
- •Serum HBV DNA levels.
- •Serum aminotransferase levels.
- •Histological grade and stage.
- •Immunotolerant patients: most patients under 30 years of age with persistently normal ALT levels and a high HBV DNA level (usually above 107 IU/ml), without any suspicion of liver disease and without a family history of HCC or cirrhosis do not require immediate liver biopsy or therapy. Follow-up is mandatory (B1).
- •Patients with mild CHB: patients with slightly elevated ALT (less than 2 times ULN) and mild histological lesions (less than A2F2 with METAVIR scoring) may not require therapy. Follow-up is mandatory (B1).
- •Patients with compensated cirrhosis and detectable HBV DNA may be considered for treatment even if ALT levels are normal and/or HBV DNA levels are below 2000 IU/ml (i.e. approximately 10,000 copies/ml) (B1).
- •Patients with decompensated cirrhosis require urgent antiviral treatment. Rapid and profound viral suppression and efficacious prevention of resistance are particularly needed in this group. Significant clinical improvement can be associated with control of viral replication, but patients with very advanced liver disease may not always benefit if treated at this late stage and should be considered for liver transplantation (A1).
4.7 Predictors of response
- (1)For interferon alpha-based treatment:
- •Pre-treatment factors predictive of HBe seroconversion are low viral load (HBV DNA below 107 IU/ml or 7 log10 IU/ml), high serum ALT levels (above 3 times ULN), and high activity scores on liver biopsy (at least A2) [50,51,52] (B2).
- •During treatment, an HBV DNA decrease to less than 20,000 IU/ml at 12 weeks is associated with a 50% chance of HBe seroconversion in HBeAg-positive patients and with a 50% chance of sustained response in HBeAg-negative patients [53,54].
- •During treatment, HBeAg decrease at week 24 may predict HBe seroconversion [54,55] (B2).
- •Further studies are needed to determine the role of HBsAg quantitation to predict sustained virological response and HBsAg loss.
- •HBV genotype A and B have been shown to be associated with a better response to interferon alpha than genotypes C and D []. However, the HBV genotype has a poor individual predictive value and currently, genotype alone should not override the choice of treatment (B2).
- (2)For NUCs treatment:
- •Pre-treatment factors predictive of HBe seroconversion are low viral load (HBV DNA below 107 IU/ml or 7 log10 IU/ml), high serum ALT levels (above 3 times ULN), high activity scores on liver biopsy (at least A2) [].
- •During treatment with lamivudine, adefovir or telbivudine, a virological response at 24 or 48 weeks (undetectable HBV DNA in a real-time PCR assay) is associated with a lower incidence of resistance, i.e. an improved chance of maintained virological response, and HBe seroconversion in HBeAg-positive patients [41,46,57] (B1).
- •HBV genotype does not influence the response to any NUC.
4.8 Treatment strategies: how-to-treat
- (1)Treatment of finite duration with pegylated interferon alpha or NUCs. This strategy is intended to achieve a sustained virological response off-treatment (A1).
- •Finite-duration treatment with pegylated interferon alpha: a 48-week course of pegylated interferon alpha is mainly recommended for HBeAg-positive patients with the best chance of HBe seroconversion. It can also be used for HBeAg-negative patients who have the best chance of a sustained response off-treatment. In both groups, these are patients with high baseline ALT (>3 times ULN) and HBV DNA less than 2 × 106 IU/ml (approximately 107 copies/ml) or 6.3 log10 IU/ml at baseline. Full information about the advantages, adverse events and inconveniences of pegylated interferon alpha versus NUCs (Table 2) should be provided so the patient can participate in the decision. (B2)Table 2Main respective advantages and disadvantages of pegylated interferon alpha and NUCs in the treatment of CHB
Pegylated interferon alpha NUCs Advantages Finite duration Potent antiviral effect Absence of resistance Good tolerance Higher rates of HBe and HBs seroconversion Oral administration Disadvantages Moderate antiviral effect Indefinite duration Poor tolerance Risk of resistance Subcutaneous injections Lower rates of HBe and HBs seroconversionThe combination of pegylated interferon alpha with lamivudine showed a higher on-treatment response but did not show a higher rate of sustained response. There is limited information on the efficacy and safety of combination of pegylated interferon alpha with other NUCs and presently this type of combination is not recommended.
- •Finite-duration treatment with NUCs is achievable for HBeAg-positive patients who develop HBe seroconversion on treatment. However, duration is unpredictable prior to therapy as it depends on when HBe seroconversion occurs. HBe seroconversion is more frequent in patients with high baseline ALT (>3 times ULN) and HBV DNA less than 2 × 106 IU/ml (approximately 107 copies/ml) or 6.3 log10 IU/ml at baseline (A1). An attempt at finite treatment should use the most potent agents with the highest barrier to resistance (entecavir or tenofovir) to rapidly reduce levels of viremia to undetectable levels and avoid rebounds due to HBV resistance (A1). Telbivudine might be used in patients with good predictors of response (HBV DNA <2 × 106 IU/ml, i.e. approximately 107 copies/ml, or 6.3 log10 IU/ml at baseline) with verification of HBV DNA suppression below detection in real-time PCR assay at 24 weeks. Once HBe seroconversion occurs on NUC, treatment should be prolonged for an additional 6 to (preferentially) 12 months; a durable response (persistence of anti-HBe antibodies off-treatment) can be expected in 80% of these patients (B1).
- (2)Long-term treatment with NUCs. This strategy is necessary for patients who cannot achieve a sustained virological response off-treatment and require extended therapy, i.e. for HBeAg-positive patients who do not develop HBe seroconversion and in HBeAg-negative patients. This strategy is also recommended in patients with cirrhosis irrespective of HBeAg status or HBe seroconversion on treatment (A1).
4.9 Treatment failure
- (1)Primary non-response. Primary non-response seems to be more frequent with adefovir (approximately 10–20%) than with other NUCs because of suboptimal dosing. A rapid switch to tenofovir or entecavir is recommended (B1). Primary non-response is rarely observed with lamivudine, telbivudine, entecavir or tenofovir. In patients with primary non-response, it is important to check for compliance. In a compliant patient with a primary non-response, identification of possible HBV resistance mutations can formulate a rescue strategy that must reasonably be based on an early change to a more potent drug that is active against the resistant HBV variant (B1).
- (2)Partial virological response. Partial virological response may be encountered with all available NUCs. It is important to check for compliance. In patients receiving lamivudine, adefovir or telbivudine with a partial virological response at week 24, two strategies can be used: change to a more potent drug (entecavir or tenofovir) or addition of a more potent drug that does not share cross-resistance (add tenofovir to lamivudine or telbivudine, or add entecavir to adefovir) (A1). In patients receiving entecavir or tenofovir with a partial virological response at week 48, some experts would suggest adding the other drug in order to prevent resistance in the long term (C1). The long-term safety of tenofovir and entecavir in combination is however unknown.
- (3)Virological breakthrough. Virological breakthrough in compliant patients is related to viral resistance. Rates of resistance at up to 5 years of administration are shown for the different NUCs in Fig. 3. Resistance is associated with prior treatment with NUCs (i.e., lamuvidine, adefovir, telbivudine, emtricitabine) or, in treatment-naive patients, with high baseline HBV DNA levels, a slow decline in HBV DNA and partial virological response during treatment. Resistance should be identified as early as possible before clinical breakthrough (increased ALT) by means of HBV DNA monitoring, and if possible identification of the pattern of resistance mutations should be used to adapt therapeutic strategies. Indeed, clinical and virological studies have demonstrated the benefit of an early treatment adaptation, as soon as viral load increases [52,63] (A1).
- •Lamivudine resistance: add tenofovir (add adefovir if tenofovir not yet available) (B1).
- •Adefovir resistance: it is recommended to switch to tenofovir if available and add a second drug without cross-resistance. If an N236T substitution is present, add lamivudine, entecavir or telbivudine or switch to tenofovir plus emtricitabine (in one tablet) (C1). If an A181T/V substitution is present, add entecavir (the safety of the tenofovir–entecavir combination is unknown) or switch to tenofovir plus emtricitabine (B1).
- •Telbivudine resistance: add tenofovir (add adefovir if tenofovir not yet available). The long-term safety of these combinations is unknown (C1).
- •Entecavir resistance: Add tenofovir (the safety of this combination is unknown) (C1).
- •Tenofovir resistance: resistance to tenofovir has not been described so far. It is recommended that genotyping and phenotyping be done by an expert laboratory to determine the cross-resistance profile. Entecavir, telbivudine, lamivudine or emtricitabine could be added (the safety of these combinations is unknown) (B1).
|HBV variant||Level of susceptibility|
|L180M + M204V||R||R||I||S||S|
|L180M + M204V/I ± I169T ± V173L ± M250V||R||R||R||S||S|
|L180M + M204V/I ± T184G ± S202I/G||R||R||R||S||S|
4.10 How to monitor treatment and stopping points
4.10.1 Finite therapy with pegylated interferon alpha
- •In HBeAg-positive patients, HBeAg and anti-HBe antibodies should be checked at weeks 24 and 48 and 24 weeks post-treatment. HBe seroconversion together with ALT normalisation and serum HBV DNA below 2000 IU/ml (approximately 10,000 copies/ml), i.e. 3.3 log10 IU/ml, is the desired outcome (A1). Undetectable serum HBV DNA by real-time PCR during follow-up is the optimal outcome since it is associated with a high chance of HBsAg loss. HBeAg-positive patients who develop HBe seroconversion with pegylated interferon or NUCs require long follow-up because of the possibility of HBe seroreversion or HBeAg-negative chronic hepatitis B. HBsAg should be checked at 6-month intervals after HBe seroconversion if HBV DNA is undetectable. Quantitative HBsAg assay is still a research tool. In case of a primary non-response, i.e. failure to achieve a 1 log10 reduction from baseline at 12 weeks, interferon treatment should be stopped and replaced by a NUC (B1).
- •HBeAg-negative patients should be similarly monitored for efficacy and safety through 48 weeks of treatment. A virological response with HBV DNA <2000 IU/ml (approximately 10,000 copies/ml), i.e. 3.3 log10 IU/ml, is generally associated with remission of the liver disease. Undetectable HBV DNA in real-time PCR is the ideal desired off-treatment sustained response with a high probability of HBsAg loss in the longer term. HBsAg should be checked at 6-month intervals if HBV DNA is undetectable (B1).
4.10.2 Finite treatment with NUCs in HBeAg-positive patients
4.10.3 Long-term therapy with NUCs
4.11 Treatment of patients with severe liver disease
4.11.1 Treatment of patients with cirrhosis
4.11.2 Treatment of patients with decompensated cirrhosis
4.12 Prevention of recurrent hepatitis B after liver transplantation
4.13 Treatment in special patient groups
4.13.1 HIV co-infected patients
4.13.2 HDV co-infected patients
4.13.3 HCV co-infected patients
4.13.4 Acute severe hepatitis
4.13.6 Healthcare workers
4.13.7 Pregnant women
4.13.8 Pre-emptive therapy before immunosuppressive therapy or chemotherapy
4.13.9 Dialysis and renal transplant patients
4.13.10 Extrahepatic disease
5. Unresolved issues and unmet needs
- (1)Improve knowledge of the natural history, in particular of immunotolerant patients, with long-term follow-up of cohorts: experimental studies to provide more definite prognostic information, and biomarkers to determine prognosis and indications for treatment.
- (2)Develop and assess new therapeutic approaches, particularly immunomodulatory therapies to enhance loss of HBeAg and HBsAg and subsequent seroconversion.
- (3)Assess the role of indirect markers (serum and biophysical) to assess the severity of liver disease and for the follow-up of treated and untreated patients.
- (4)Assess the role of HBV genotype to determine prognosis and response to therapy and the risk of resistance.
- (5)Assess the efficacy of different durations (24 weeks to 2 years) and lower doses of pegylated interferon alpha.
- (6)Assess long-term efficacy and safety and resistance to new analogues (entecavir, telbivudine and tenofovir).
- (7)Better define monitoring algorithms: timing of HBV DNA measurement with the new generation of NUCs with a high genetic barrier to resistance; role of genotypic resistance assays in adapting therapy.
- (8)Assess the role of combination therapy with two NUCs to reduce resistance.
- (9)Assess the efficacy of the combination of pegylated interferon alpha with potent NUCs (entecavir or tenofovir) to increase HBe and HBs seroconversion rates.
- (10)Develop new drugs to manage multidrug resistant HBV resistant to both lineages of current NUCs.
- (11)Assess long-term impact of therapy on the prevention of cirrhosis and its complications and HCC.
- (12)Develop effective and optimum treatment for HDV coinfection.
Conflicts of interest disclosure
- –Patrick Marcellin has received research support from Hofmann-La Roche, Schering-Plough and Gilead Sciences and has acted as an advisor and lecturer for Hofmann-La Roche, Schering-Plough, Gilead Sciences, Novartis/Idenix and Bristol-Myers Squibb.
- –Geoffrey Dusheiko has received research support and has acted as an advisor to Hofmann-La Roche, Gilead Sciences, Novartis/Idenix, GlaxoSmithKline and Bristol-Myers Squibb.
- –Fabien Zoulim has received research support from Gilead Sciences and BioMérieux and has acted as an advisor and/or lecturer for Gilead Sciences, Novartis/Idenix, Bristol-Myers Squibb, Transgene, Siemens Medical Solutions Diagnostics and Abbott Molecular.
- –Rafael Esteban has acted as an advisor and lecturer for Schering-Plough, Gilead Sciences, Novartis/Idenix, Bristol-Myers Squibb and GlaxoSmithKline.
- –Stefanos Hadziyannis has received research support from Hofmann-La Roche and Gilead Sciences, and has acted as an advisor or a lecturer to Hofmann-La Roche, Gilead Sciences, Novartis/Idenix, Bristol-Myers Squibb and GlaxoSmithKline.
- –Pietro Lampertico has acted as an advisor to Hofmann-La Roche, Gilead Sciences, and is a lecturer for Hofmann-La Roche, GlaxoSmithKline, Gilead Sciences, Novartis/Idenix and Bristol-Myers Squibb.
- –Michael Manns has received grant support, honoraria and/or has served as an advisor for Hofmann-La Roche, Gilead Sciences, GlaxoSmithKline, Bristol-Myers Squibb and Novartis/Idenix.
- –Daniel Shouval has received research support from Hofmann-La Roche, GlaxoSmithKline and Bristol-Myers Squibb and has been a lecturer for Gilead Sciences.
- –Cihan Yurdaydin has acted as an advisor and lecturer for Gilead Sciences, Novartis/Idenix, Bristol-Myers Squibb and Hofmann-La Roche.
- –Antonio Craxi has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche, Gilead Sciences, Novartis/Idenix and Bristol-Myers Squibb.
- –Xavier Forns has received research support from Hofmann-La Roche and has served as an advisor to Hofmann-La Roche and Novartis/Idenix.
- –Darius Moradpour has received research support and has acted as an advisor for Hofmann-La Roche and Novartis/Idenix.
- –Jean-Michel Pawlotsky has received research support from Gilead Sciences and has acted as an advisor for Hofmann-La Roche, Gilead Sciences, Novartis/Idenix, Bristol-Myers Squibb, Siemens Medical Solutions Diagnostics and Abbott Molecular.
- –Joerg Petersen has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche, Gilead Sciences, Novartis/Idenix and Bristol-Myers Squibb.
- –Heiner Wedemeyer has received research support and has acted as an advisor and a lecturer for Hofmann-La Roche, Gilead Sciences, Novartis/Idenix and Bristol-Myers Squibb.
EASL International Consensus Conference on Hepatitis B. 13–14 September, 2002: Geneva, Switzerland. Consensus statement (short version). J Hepatol 2003;38:533–540.
- Hepatitis B virus infection – natural history and clinical consequences.N Engl J Med. 2004; 350: 1118-1129
- Management of hepatitis B: summary of a clinical research workshop.Hepatology. 2007; 45: 1056-1075
- Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma.Semin Liver Dis. 2005; 25: 40-47
- Chronic hepatitis B.Hepatology. 2007; 45: 507-539
- Viral hepatitis in the third millennium.Res Virol. 1998; 149: 251-256
- Chronic HBV-related liver disease.Mol Aspects Med. 2008; 29: 72-84
- Characteristics of patients with chronic hepatitis B in France: predominant frequency of HBe antigen negative cases.J Hepatol. 2006; 45: 355-360
- Hepatitis B virus-related cirrhosis: natural history and treatment.Semin Liver Dis. 2006; 26: 142-152
- Natural history and prognosis of hepatitis B.Semin Liver Dis. 2003; 23: 47-58
- Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.J Hepatol. 2008; 48: 335-352
- Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.Gut. 2008; 57: 84-90
- Hepatocellular carcinoma in cirrhosis: incidence and risk factors.Gastroenterology. 2004; 127: S35-S50
- Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.J Hepatol. 2002; 36: 543-546
- Hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2001; 34: 617-624
- Statements from the Taormina expert meeting on occult hepatitis B virus infection.J Hepatol. 2008; 49: 652-657
- Solid-organ transplantation in HBsAg-negative patients with antibodies to HBV core antigen: low risk of HBV reactivation.Transplantation. 2005; 79: 1631-1633
- Redevelopment of hepatitis-B surface antigen after renal transplantation.Gastroenterology. 1991; 100: 1432-1434
Guyatt GH, Cook DJ, Jaeschke R, Pauker SG, Schunemann HJ. Grades of recommendation for antithrombotic agents: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:123S–131S.
- Going from evidence to recommendations.Br Med J. 2008; 336: 1049-1051
- Incorporating considerations of resources use into grading recommendations.Br Med J. 2008; 336: 1170-1173
- What is “quality of evidence” and why is it important to clinicians?.Br Med J. 2008; 336: 995-998
- GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.Br Med J. 2008; 336: 924-926
- Use of GRADE grid to reach decisions on clinical practice guidelines when consensus is elusive.Br Med J. 2008; 337: 744
- Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.Br Med J. 2008; 336: 1106-1110
- Performance of the Cobas AmpliPrep/Cobas TaqMan real-time PCR assay for hepatitis B virus DNA quantification.J Clin Microbiol. 2008; 46: 1716-1723
- Characterization of a new sensitive PCR assay for quantification of viral DNA isolated from patients with hepatitis B virus infections.J Clin Microbiol. 2007; 45: 3948-3953
- Rapid quantification of hepatitis B virus DNA by automated sample preparation and real-time PCR.J Clin Microbiol. 2004; 42: 2445-2449
- Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: recommendations for a standardized approach.Gastroenterology. 2008; 134: 405-415
- An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques.Vox Sang. 2001; 80: 63-71
- Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1449-1457
- Meta-analyses of FibroTest diagnostic value in chronic liver disease.BMC Gastroenterol. 2007; 7: 40
Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Lédinghen V, et al. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int; in press.
- Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B.J Hepatol. 2003; 39: 222-230
- Transient elastography for patients with chronic hepatitis B and C virus infection: non-invasive, quantitative assessment of liver fibrosis.Hepatol Res. 2007; 37: 1002-1010
- An accurate definition of the status of inactive hepatitis B virus carrier by a combination of biomarkers (FibroTest–ActiTest) and viral load.PLoS ONE. 2008; 3: e2573
- Lamivudine for patients with chronic hepatitis B and advanced liver disease.N Engl J Med. 2004; 351: 1521-1531
- A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.N Engl J Med. 2006; 354: 1001-1010
- Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet. 2005; 365: 123-129
- A one-year trial of lamivudine for chronic hepatitis B.N Engl J Med. 1998; 339: 61-68
- Telbivudine versus lamivudine in patients with chronic hepatitis B.N Engl J Med. 2007; 357: 2576-2588
- Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med. 2005; 352: 2682-2695
- Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.N Engl J Med. 2003; 348: 808-816
- A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAG positive chronic hepatitis B (CHB): Study GS-US-174-0103.Hepatology. 2007; 46: 861A
- Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217
- Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.Gastroenterology. 2006; 131: 1743-1751
- A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAG-negative chronic hepatitis B (CHB): Study GS-US-174-0102.Hepatology. 2007; 46: 290A-291A
- Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2006; 354: 1011-1020
- Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.Hepatology. 1999; 29: 889-896
- A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.N Engl J Med. 1990; 323: 295-301
- Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.Ann Intern Med. 1993; 119: 312-323
- Hepatitis B: reflections on the current approach to antiviral therapy.J Hepatol. 2008; 48: S2-S19
- Predicting response to peginterferon alpha-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B.Gut. 2007; 56: 699-705
- HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B.Hepatology. 2008; 47: 428-434
- Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.Hepatology. 2002; 36: 186-194
Flink HJ, van Zonneveld M, Hansen BE, de Man RA, Schalm SW, Janssen HL. HBV 99-01 Study Group. Treatment with Peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 2006;101:297–303.
- Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response.Hepatology. 2007; 46: 1695-1703
- Tenofovir disoproxil fumarate (TDF) for the treatment of HBeAg-positive chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 103).J Hepatol. 2008; 48: S32
- Tenofovir disoproxil fumarate (TDF) for the treatment of HBeAg-negative chronic hepatitis B: week 72 TDF data and week 24 adefovir dipivoxil switch data (study 102).J Hepatol. 2008; 48: S26
- Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.Hepatology. 2000; 32: 847-851
- Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy.Hepatology. 2000; 32: 1145-1153
- Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management.Hepatology. 2007; 46: 254-265
- Add-on adefovir prevents the emergence of adefovir resistance in lamivudine-resistant patients: A 4-year study.J Hepatol. 2008; 48: S259
- Antiviral therapy of chronic hepatitis B: prevention of drug resistance.Clin Liver Dis. 2007; 11: 869-892
- Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis.Hepatology. 2007; 46: 388-394
- Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus.Gastroenterology. 2004; 126: 81-90
- Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.Gastroenterology. 2002; 123: 719-727
- Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis.Lancet. 1996; 348: 1212-1215
- Management of hepatitis B in liver transplantation patients.Semin Liver Dis. 2004; 24: 55-62
- Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results.Liver Transplant. 2007; 13: 349-360
- Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B.Gastroenterology. 2002; 123: 1812-1822
- Clinical implications of HIV and hepatitis B co-infection in Asia and Africa.Lancet Infect Dis. 2007; 7: 402-409
- Natural history of chronic hepatitis B in co-infected patients.J Hepatol. 2006; 44: S65-S70
- Influence of viral hepatitis on HIV infection.J Hepatol. 2006; 44: S25-S27
- Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV–HBV International Panel.AIDS. 2005; 19: 221-240
- Viral hepatitis and HIV coinfection.J Hepatol. 2008; 48: 353-367
- Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients.J Hepatol. 2005; 42: 615-624
- European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults.HIV Med. 2008; 9: 82-88
- Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.Hepatology. 2006; 43: 548-555
- Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up.Hepatology. 2006; 44: 728-735
- Treatment of chronic hepatitis D: new advances, old challenges.Hepatology. 2006; 44: 536-539
- Treatment of chronic hepatitis D.J Viral Hepat. 2007; 14: 58-63
- Treatment of chronic hepatitis D with interferon alfa-2a.N Engl J Med. 1994; 330: 88-94
- Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta.Hepatology. 2006; 44: 713-720
- 72 week data of the HIDIT-1 trial: a multicenter randomised study comparing peginterferon alpha-2a plus adefovir vs peginterferon alpha-2a plus placebo vs adefovir in chronic delta hepatitis.J Hepatol. 2007; 46: S4
- A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis.J Viral Hepat. 2007; 14: 812-816
- The HEP-NET B/C co-infection trial: a prospective multicenter study to investigate the efficacy of pegylated interferon-alpha2b and ribavirin in patients with HBV/HCV co-infection.J Hepatol. 2008; 48: S320
- Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment.J Gastroenterol Hepatol. 2008; 23: 512-520
- Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients.Hepatology. 2003; 37: 568-576
- Chronic hepatitis C responds poorly to combination therapy in chronic hepatitis B carriers.Neth J Med. 2008; 66: 191-195
- Hepatitis B and C virus coinfection in the TREAT Asia HIV observational database.J Gastroenterol Hepatol. 2007; 22: 1510-1518
- Acute liver failure: summary of a workshop.Hepatology. 2008; 47: 1401-1415
- Lamivudine treatment for acute severe hepatitis B: report of a case and review of the literature.Acta Gastroenterol Belg. 2008; 71: 30-32
- Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience.J Viral Hepat. 2006; 13: 256-263
- Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.Hepatology. 2008; 47: 1863-1871
- Long-term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety.J Viral Hepat. 2008; 15: 20-27
- Virological response during treatment of chronic hepatitis B with pegylated interferon alfa-2a in children.Gastroenterology. 2008; 134: A811
- The pharmacokinetics and safety of adefovir dipivoxil in children and adolescents with chronic hepatitis B virus infection.J Clin Pharmacol. 2008; 48: 512-517
- Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients.J Clin Virol. 2003; 27: 213-230
- Treating chronic hepatitis B infection in patients who are pregnant or are undergoing immunosuppressive chemotherapy.Semin Liver Dis. 2007; 27: 18-24
- Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection.J Viral Hepat. 2003; 10: 294-297
- Exacerbation of chronic hepatitis B infection after delivery.J Viral Hepat. 2008; 15: 37-41
- Rituximab increases the risk of de novo hepatitis B infection in hepatitis B surface antigen negative patients undergoing cytotoxic chemotherapy.J Gastroenterol Hepatol. 2006; 21: A73-A74
- Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies.Br J Hematol. 2007; 136: 699-712
- Hepatitis B virus reactivation after cytotoxic chemotherapy: the disease and its prevention.Clin Gastroenterol Hepatol. 2006; 4: 1076-1081
- A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial.Hepatology. 2008; 47: 844-853
- Kinetics of hepatitis B virus reactivation after chemotherapy: more questions than answers.Gastroenterology. 2006; 131: 1656-1657
- Hepatitis B reactivation after chemotherapy: two decades of clinical research.Hepatol Int. 2008; 2: 152-162
- Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation.Transplantation. 1997; 64: 1624-1627
Contributors: Clinical Practice Guidelines Panel: Patrick Marcellin, Geoffrey Dusheiko, Fabien Zoulim, Rafael Esteban, Stefanos Hadziyannis, Pietro Lampertico, Michael Manns, Daniel Shouval, Cihan Yurdaydin; Reviewers: Antonio Craxi, Xavier Forns, Darius Moradpour, Jean-Michel Pawlotsky, Joerg Petersen, Heiner Wedemeyer.