Digestive and Liver Disease
Volume 40, Issue 8 , Pages 603-617, August 2008

Treatment of chronic hepatitis B: Recommendations from an Italian workshop☆

  • G. Carosi

      Affiliations

    • Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 0303995671; fax: +39 030303061.
    • ,
  • M. Rizzetto

      Affiliations

    • Department of Gastroenterology, University of Turin, Turin, Italy

Received 13 February 2008; accepted 4 March 2008. published online 23 May 2008.

Article Outline

Abstract 

The changing scenario of hepatitis B virus therapy has encouraged the organisation of a workshop, endorsed by three Italian scientific societies, aimed at defining the current recommendations for hepatitis B virus treatment. Liver histology and stage of disease remain fundamental for treatment decisions; interferon and nucleoside/nucleotide analogues-based therapy represent different strategies for different phases of the hepatitis B virus disease. The recommendations defined: new and lower cut-off of hepatitis B virus–DNA for eligibility to therapy according to disease stage, how to optimise the use of nucleoside/nucleotide analogues and to individualise the monitoring of response and what to do with treatment failures. Specific recommendations have also been given for cirrhosis patients, those immune suppressed and co-infected with HIV and other hepatitis viruses.

Keywords: Antiviral therapy, Cirrhosis, HBV, HCV, HDV, HIV, Immune suppressed

 

Hepatitis B virus (HBV) infection remains a major cause of liver disease in Italy, despite the improvement in socio-economic conditions and the introduction of universal vaccination of newborn babies and young adolescents. National health bodies estimate that there might be at least one million individuals chronically infected with HBV (HBsAg carriers), and hepatitis B ranks third among the causes of liver related death occurring annually in the country. The burden of HBV infection in Italy has recently further increased by the massive influx of immigrants from regions of Europe, Africa and Asia where HBV is highly endemic. It has been estimated that during the past 10 years at least 250,000 immigrants who are carriers of HBV have entered Italy.

National guidelines and recommendations for the treatment of HBV have not been updated since 2003. Recently, however, new treatment for the disease has been developed and licensed, including pegylated interferon (PEG-IFN) alfa 2a and new nucleoside/nucleotide analogues (NAs). Six compounds are currently licensed in Italy for the treatment of chronic hepatitis B (Table 1). Tenofovir, a potent nucleotide analogue, and Emtricitabine, a nucleoside analogue, both active on HIV and HBV are licensed only for HIV treatment. Several registration trials have analysed the efficacy of new drugs against HBV. However, these studies have certain limitations due to the short duration of the trials, lack of head-to-head comparison between different compounds, and very limited information about their combined use. For these reasons, there are still open questions on the best approach to treat hepatitis B. The most recent International Guidelines and Recommendations have largely been based on expert opinion that frequently needs to be updated and also adapted to local epidemiology and resources.

Table 1. Compounds that are currently licensed in Italy for the treatment of chronic hepatitis B
Interferon (IFN) alfa 2a and alfa 2b
Lamivudine
Adefovir
Entecavir
Telbivudine
Pegylated interferon (PEG-IFN) alfa 2a

These considerations have encouraged the organisation of a workshop, endorsed by the Italian Association for the Study of the Liver (Associazione Italiana Per lo Studio del Fegato AISF), the Italian Society of Infectious and Tropical Diseases (Società Italiana per lo studio delle Malattie Infettive e Tropicali: SIMIT) and the Italian Society for the Study of Sexually Transmitted Diseases (Società Italiana per lo studio delle Malattie Sessualmente Trasmettibili: SIMAST), that was held in May 2007, in Stresa, Italy.

The aim of the workshop was to develop recommendations for the treatment of chronic HBV infection.

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1. Workshop structure and agenda 

The editors first identified five major clinical categories of patients with HBV infection and two main questions to be addressed for each category (Table 2). They also identified one expert for each category among the members of the Italian scientific community and asked each to prepare an initial statement based on an extensive literature review and expert opinion. The pertinent literature was obtained by systematic research of the Ovid databases (including MEDLINE and AIDSLINE) from 1 January 1993 to 30 April 2007, using the following keywords: hepatitis B; HCV; HIV; liver diseases; immune suppression; antiviral therapy; therapy; interferon. These medical subjects headings terms were explored and appropriate search combinations were also performed. References were manually scanned for relevant articles published before 1993. Abstracts presented at major International Congresses on viral hepatitis and HIV infection and those of International Societies of Hepatology published in the years 2005–2007 were also reviewed [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127], [128], [129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], [155], [156], [157], [158], [159], [160], [161], [162], [163], [164], [165], [166], [167], [168], [169], [170], [171], [172], [173], [174], [175], [176], [177], [178], [179], [180], [181], [182], [183], [184], [185], [186], [187], [188], [189], [190], [191], [192], [193], [194], [195], [196], [197], [198], [199], [200], [201], [202], [203]. A selection of the literature was provided to all those who attended the workshop.

Table 2. Structure of the Workshop
The five clinical categories of hepatitis B/HBV infection considered were
(1) Patients with HBeAg positive chronic hepatitis B
(2) Patients with HBeAg negative chronic hepatitis B
(3) Patients with cirrhosis
(4) Patients under immune suppression
(5) Patients with HCV and/or HDV and/or HIV co-infection(s)

The two questions posed for each clinical category were
(1) Whom and when to treat?
(2) How to treat and what strategy to take?

The initial draft statements were prepared by experts based on this review of the literature, and were formulated according to the method identified by a nominal group meeting and graded for scientific strength and quality using a modification of the scoring system proposed by the Infectious Diseases Society of America (IDSA; Table 3). Then, on the first day of the workshop meeting held in Stresa, Italy, the statements were presented by the experts and extensively discussed by the whole audience, including nine members of a scientific board. In the afternoon of the same day, five parallel smaller working groups of 10–15 participants (experts, members of the scientific board and practicing physicians) led by five “tutors” extensively discussed each of the five patients categories and reformulated the statements according to the general and small group discussions.

Table 3. System for ranking recommendations modified from Infectious Diseases Society of America–United States Public Health System Grading Service for ranking recommendations in clinical guidelines
Category, gradeDefinition
Strength of recommendation
AGood evidence to support a recommendation
BModerate evidence to support a recommendation
CPoor evidence to support a recommendation

Quality of evidence
IEvidence from >1 properly randomised, controlled trial
IIEvidence from >1 well-designed clinical trial, without randomisation; from cohort or case-controlled analytical studies; from multiple time-series, or from dramatic results from uncontrolled experiments
IIIEvidence from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees

On the second day of the workshop, the reformulated statements were presented again to the whole audience by the tutors of each group and further discussed, modified accordingly and then voted for by all participants, point by point, using a tele-voting system. Statements reaching >80% consensus were accepted while those with <80% consensus were further discussed and modified to reach >80% consensus.

Finally a jury panel of 12 experts, who had attended the whole meeting and parallel sessions, was asked to elaborate the final statement with the main recommendations of the workshop, which are summarised in this document.

The statements were prepared taking into consideration all commercially available products shown to be effective against HBV, independently and regardless of the current indications and reimbursement policies of the Italian Ministry of Health. Off-label use of drugs registered for indications other than HBV therapy was considered only when there was an important clinical need that was unmet by reimbursed drugs and use strategies.

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2. Recommendations 

2.1. Patients with HBeAg positive cronic hepatitis B 

2.1.1. Whom and when to treat 

Candidates for treatment are patients with:

(1)Active and persistent HBV replication defined by HBV–DNA>20,000IU/mL and the presence of HBeAg for more than 6 months;

(2)ALT greater than twice the upper normal limit (UNL) or abnormal ALT<2 times the ULN and at least moderate fibrosis at liver biopsy (Ishak stage S2 or more) (A1).

Patients with HBV–DNA>20,000IU/mL but with normal ALT should not be treated (BII). Liver biopsy may be considered in those with borderline ALT (abnormal ALT<2 times the UNL) when older than 40 years or with an anti-HBc IgM index value greater than 0.2. They should be considered for treatment if the biopsy displays at least moderate liver fibrosis (Isak stage≥S2) (BIII).

2.1.2. How to treat and what strategy to take 

Alfa interferon should be the first line of treatment for HBeAg positive patients without cirrhosis (BIII). Both non-pegylated alfa 2a and alfa 2b interferons, but only pegylated alfa 2a interferon are registered for this purpose, although pegylated alfa 2b interferon has shown equal efficacy in phase II studies. Response predictors to IFN therapy are baseline ALT>5 times the UNL, baseline HBV–DNA<20,000,000IU/mL, genotype A or B (AII).

Treatment with the NAs should be considered in patients with more advanced fibrosis (Ishak stage≥3) if a patient:

•is a non-responder to previous IFN therapy;

•has major contra-indications to IFN;

•is intolerant or unwilling to receive IFN.

NAs should be considered as first line of therapy when the patient has an ALT flare with jaundice (CIII). Short-term treatment with NAs aimed at obtaining anti-HBe sero-conversion could be considered in patients with less severe fibrosis (<S3) when one of the above-mentioned reasons for not using IFN is present.

Monotherapy with Entecavir (0.5mg/d) or Telbivudine (600mg/d) should be preferred to Adefovir (10mg/d) due to higher antiviral potency (CIII). Monotherapy with Lamivudine should not be used in principle due to the high risk of developing viral resistance (AI). Treatment with Entecavir should be preferred in patients with HBV–DNA≥200,000,000IU/mL (BIII). Monotherapy with NAs should be continued for 6 months after sero-conversion to anti-HBe and HBV–DNA clearance or indefinitely in patients who do not achieve anti-HBe sero-conversion but reach HBV–DNA levels <200IU/mL after 6 months (with Telbivudine) or 12 months (with Adefovir and Entecavir). Treatment should be reconsidered and adjusted in patients with sub-optimal response (see below). De novo combination regimens with two NAs (one nucleotide and one nucleoside) could be associated with a reduced risk of resistance, but there is no definitive evidence of greater antiviral efficacy compared to monotherapy (CIII). The same applies to the combination of PEG-IFN with a NA (AII).

2.1.2.1. Patients with resistance or primary non-response or sub-optimal response to NAs 


(a)Definitions
•Primary non-response to a NA is defined as a decline of HBV–DNA less than 1 log compared to the baseline after 3 months of treatment.

•Sub-optimal response to a NA is defined as an HBV–DNA level greater than 200IU/mL after 6 months of treatment with Lamivudine or Telbivudine or after 12 months of treatment with Adefovir, or Entecavir (AII).

•A breakthrough of the virologic response is defined by the occurrence of an increase of 1 log of HBV–DNA over the nadir, observed during treatment in an adherent patient and confirmed after 1 month.

Patients treated with a NA and with primary non-response, or sub-optimal response or breakthrough must be considered for treatment adjustment. Genotypic resistance testing is often useful to guide therapeutic choices (BII). Genotypic resistance testing is recommended before changing or restarting NA therapy in patients already treated with more than one antiviral drug.

(b)Adaptation of therapy in patients with sub-optimal response or resistance to NAWhen a patient treated with a NA shows signs of sub-optimal response or develops resistance, the indication of whether and how to adapt therapy should be individualised.
•A patient with resistance or sub-optimal response to Lamivudine: Add-on Adefovir (AII) or Tenofovir (when LAM resistant virus has reached very high HBV–DNA levels) is indicated (CIII).

•A patient with resistance or sub-optimal response to Adefovir: If the patient is naïve to Lamivudine adequate strategies could be: add-on Lamivudine or Telbivudine after excluding resistance to these NA by genotypic resistance testing or switch to Entecavir (BII). If the patient has been exposed to Lamivudine or Telbivudine, add-on 1mg/d of Entecavir. (CIII) or switch to Tenofovir in combination with a nucleoside analogue (based on genotypic resistance profile) should be considered.

•Patients with resistance or sub-optimal response to Entecavir: Add-on Adefovir (CIII).


2.1.2.2. Virological monitoring 

In all patients with undetectable HBV–DNA on or off therapy the HBsAg/anti-HBs status should be defined every 12 months.

(a)In patients on interferon
•HBeAg and anti-HBe should be tested at 24 and 48 weeks of treatment and 24 weeks after treatment withdrawal (AI).

•There is no way to positively predict long-term response during therapy; however, an HBV–DNA level higher than 105IU/mL after 6 months is associated with a poor chance of sustained response (CIII).

•Treatment should be planned for 12 months but can be stopped at any time after 6 months if tolerated badly.


(b)In patients on NAs
•HBeAg and anti-HBe should be determined every 3 months in order to program NA withdrawal, 6 months after sero-conversion (AII) and should be repeated after treatment withdrawal at least twice every 6 months.

•HBV–DNA should be measured with a high sensitivity quantitative method and wide linear range (real-time PCR to be preferred) every 3 months. When using Entecavir, which has a low incidence of resistance, the interval between controls could initially (first 2 years of therapy) be doubled (BII). After withdrawal of successful treatment HBV–DNA should be measured twice in 12 months.


2.1.2.3. On and off treatment non-virological monitoring 


(a)In patients treated with interferonThere should be blood counts and liver function tests every month of treatment and at 3 and 6 months after treatment withdrawal. There should be TSH every 3 months.

(b)In patients treated with NAThere should be blood counts and liver function tests (every 3 months. In patients on Adefovir treatment, creatinine should be measured at least every 3 months. In patients on Telbivudine, CPK should be measured at least every 3 months.

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3. Patients with HBeAg negative chronic hepatitis B 

3.1. Whom and when to treat 

Defining the stage of liver disease (fibrosis) plays a key role in deciding whether and how to treat (AII).

Candidates for treatment are patients with:

1.“active” HBV replication defined by serum HBV–DNA>2000IU/mL;

2.abnormal ALT (higher than UNL) and/or at least Ishak stage S2 fibrosis at liver biopsy.

Patients with active HBV replication (HBV–DNA>2000IU/mL) and normal ALT should be evaluated for evidence of liver disease using clinical and biochemical parameters, haematological parameters (platelets count, etc.) and non-invasive assessment (including ultrasound and, when available, transient elastography). Patients with normal ALT and high HBV–DNA levels should undergo sequential ALT monitoring (every 3–4 months) and evaluation of anti-HBc IgM to identify patients with liver disease. Liver biopsy should be considered when an underlying liver disease is suspected by such non-invasive evaluation. Patients with normal or borderline ALT and significant fibrosis (Ishak stage of at least S2) should be considered for treatment. Liver biopsy should also be considered in patients with high ALT and borderline HBV–DNA (between 2000 and 20,000IU/ml) to ensure that liver disease is due to HBV, and to exclude other possible cofactors of liver damage (including liver steatosis).

3.2. How to treat and what strategy to take 

Patients with Ishak stage<3 fibrosis can be monitored or treated with IFN or PEG-IFN, as outlined for HBeAg positive (AII).

In patients with Ishak stage≥3 fibrosis, IFN or PEG-IFN or NA can all be considered as first choice. Since both types of therapy have important limitations (PEG-IFN: low efficacy and significant side effects, NAs need to be taken long term, possibly life-long with a variable risk of developing resistant mutants), patients must be fully informed and should participate in the choice of therapy.

Treatment with NAs requires the protracted, possibly indefinite, administration of the NA. NAs should be selected according both to the degree of HBV inhibition (antiviral efficacy) and to the risk of developing NA resistant HBV mutants (AII). According to currently available data, monotherapy should be considered with:

(a)Entecavir

(b)Telbivudine

(c)Adefovir

“De novo” combination therapy with a nucleoside and a nucleotide seems to be a reasonable option; however evidence-based data on its use as first line treatment is lacking (CIII). Monotherapy with Lamivudine should not be used in principle due to the high risk of developing viral resistance.

In patients with high baseline viremia (>2,000,000IU/mL), Entecavir monotherapy or “de novo” combination therapy (with the limitation of the lack of evidence-based data) should be preferred (CIII).

Virological monitoring for HBV–DNA and resistance testing should be the same as that recommended in HBeAg positive patients.

In patients on interferon who maintain HBV–DNA levels greater than 200,000IU/mL after 24 weeks of treatment withdrawal should be considered because of the low probability of sustained response (CIII).

Management of resistance or sub-optimal response to NA is similar to that in HBeAg positive patients. Resistance testing should be used, as in HBe-Ag positive patients.

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4. Patients with cirrhosis (HBeAg positive and negative) 

4.1. Whom and when to treat 

Before starting treatment of a patient with cirrhosis, the following parameters should be considered:

•liver function, whether compensated or decompensated;

•age;

•HBV–DNA levels;

•viral genotype (in patients with well compensated cirrhosis who may be candidates for IFN-based therapy);

•AST/ALT levels;

•co-morbidities and co-factors potentially worsening liver disease;

•prospect of liver transplant.

Patients with compensated or decompensated cirrhosis and HBV–DNA>200IU/mL should be considered for treatment, independently of ALT levels. Patients with HBV–DNA<200IU/mL should be monitored without anti-HBV treatment (BIII).

4.2. How to treat and what strategy to take 

4.2.1. Compensated cirrhosis (HBeAg positive or negative) 

IFN and PEG-IFN or NAs can be considered as first line therapy.

PEG-IFN (or standard IFNs) should only be considered in patients without a history of decompensation and no features of portal hypertension (oesophagogastric varices), in particular those who are young, HBeAg positive and with favourable predictors of response (HBV–DNA<2,000,000IU/mL, elevated ALT, non-D HBV genotype) (BII). As in the HBeAg positive setting interferon may induce hepatic flares; this drug should be used with caution and in centres with experience in treating hepatitis B (CIII). Fig. 1 summarises treatment recommendations across the clinical spectrum of HBV diseases.

NAs should be used in patients with contraindications, intolerance, non-responders to IFN or those unwilling to receive IFN; monotherapy can be proposed with Entecavir or Telbivudine or Adefovir. Lamivudine monotherapy should not be used for the consistent risk of resistance (AI). NAs in combination should be considered when the risk of decompensation is thought to be imminent and in the presence of high HBV–DNA levels (AII); IFN and a PEG/IFN-α should not be used in these patients.

Best options are:

•monotherapy with Entecavir;

•monotherapy with Telbivudine or Adefovir in patients with HBV–DNA<2,000,000IU/mL.

Adefovir monotherapy is limited by its slow potency, in particular in patients with high baseline HBV–DNA (BIII).

4.2.2. Decompensated cirrhosis 

There are still no data on the use of Entecavir or Telbivudine monotherapy in patients with decompensated cirrhosis. All patients should be in principle treated with a combination of a nucleotide and a nucleoside analogue in order to obtain a rapid and most durable suppression of HBV–DNA. In patients eligible for liver transplant treatment should be started after consultation and in collaboration with the transplant centre of reference.

Recommended therapeutic options are:

(1)Lamivudine plus Adefovir (CIII);

(2)Telbivudine plus Adefovir or Entecavir plus Adefovir might become other options but the use of Entecavir and Telbivudine in decompensated cirrhosis has not yet been fully assessed in clinical trails (CIII).

Monitoring in cirrhotics is the same as recommended for non-cirrhotics; however liver function tests should be performed more frequently in patients on NA, in particular in those with decompensated cirrhosis.

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5. Immune suppressed patients 

5.1. Whom to treat or protect 


1.Therapy is indicated for: chronic carriers with active HBV replication (HBV–DNA>2,000IU/mL) regardless of the clinical setting (oncology, haematology, rheumatology, nephrology, gastroenterology, dermatology and solid organ transplantation) (AII).

2.Prophylaxis is indicated:
(i)In inactive HBsAg carriers undergoing anti-tumour chemotherapy or high risk immune suppressive treatment: anti-TNF, anti-CD20, anti-CD56, medium/high dose of steroids (>7.5mg/die) for prolonged periods, ciclofosphamide, metotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine and micofenolate.

(ii)In HBsAg-negative anti-HBc positive patients with an haematological disease, undergoing treatment, associated with reactivation such as: fludarabine, dose-sense regimens, autologous or allogenic bone marrow transplant, treatment with monoclonal antibodies (anti-CD-20 and anti-CD52) (BIII).


3.Anti-HBV targeted prophylaxis at disease reactivation is indicated for: the remaining inactive chronic HBsAg carriers and in HBsAg negative anti-HBc positive patients.

5.2. When to treat 


•Chronic carriers with an active HBV infection should be treated in the same way as immune-competent patients.

•Chronic inactive carrier and HBsAg-negative anti-HBc-positive patients should be given prophylaxis from the beginning of immune suppressive treatment or, if possible, 2–4 weeks before starting immunosuppressive therapies (CIII).

•Targeted prophylaxis should be started at the time of HBV disease reactivation (HBV–DNA>2,000IU/mL) in HBsAg carriers and immediately after HBsAg+ seroreversion (CIII).

5.3. How to treat 


•Chronic carriers with an active HBV infection should be treated in the same way as immune-competent patients. However, PEG-IFN is contraindicated in most of cases and NAs are the first choice of treatment (CIII). NAs with high potency and low resistance should be used, such as Entecavir; Tenofovir could be considered in selected cases. A de novo combination of a nucleotide analogue and a nucleoside analogue can be considered. The addition of a second drug is advisable in cases of sub-optimal response, or primary non-response to monotherapy (CIII).

•Prophylaxis. The limited duration of therapy diminishes the risk of resistance; low cost NA, such as Lamivudine, is recommended for Lamivudine naive patients (CIII). In patients with experience of Lamivudine, then prophylaxis with the alternative drugs indicated for Lamivudine resistant subjects is recommended (see above).

5.4. What strategy to take 


•A baseline staging of liver disease is recommended (CIII).

•HBsAg negative patients with anti-HBc reactivity should undergo HBsAg testing every 1–3 months (AIII).

Observational studies are always recommended in patients with present or past HBV infection.

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6. Co-infections 


(1)In co-infection, suppression of one or more viruses by a predominant co-infecting virus is frequent. In general, treatment should be targeted against the predominant virus.

(2)Because of possible viral interference with suppression of HBV, in the course of co-infections with HDV and/or HCV, the levels of HBV–DNA should be measured repeatedly and a cut-off level of 2000IU/ml should be used to identify active HBV infection.

For the same reason, a longitudinal and repeated evaluation of HBV–DNA is needed to identify active HBV infection or reactivation of HBV in HBsAg-positive patients on and off treatment for HCV and/or HDV co-infections (AII). In patients with HBV–DNA levels persistently <2000IU/mL there is no indication for HBV treatment (AI).

6.1. Co-infection with HCV 

6.1.1. Whom and when to treat and what strategy to take 
6.1.1.1. Patients with active HCV and HBV infections 

Treatment should be with PEG-IFN alfa+Ribavirin according to the HCV schedule (BII). Treatment response should be evaluated after 24 weeks. Response for HCV is HCV-RNA undetectable; for HBV, HBV–DNA<20,000IU/mL with a decrease of at least 1 log from baseline.

•In case of response to treatment for both viruses, treatment should be continued for 48 weeks (BIII).

•In case of response to treatment for HBV but not for HCV, PEG-IFN alfa should be continued until 48th week without Ribavirin (BIII).

•In case of response to treatment for HCV but not for HBV, PEG-IFN alfa and ribavirin should be continued as in HCV treatment; NAs should be considered to treat HBV (BIII).

•In case of lack of response for both viruses, PEG-IFN alfa and ribavirin should be stopped; NAs should be considered for treating HBV according to the above-mentioned indications (BIII).

6.1.1.2. Patients with active HCV infection and inactive HBV infection 

These patients should be treated with PEG-IFN alfa and ribavirin according to the HCV schedule (BII). HBV–DNA levels should be monitored at least bimonthly during therapy due to the possibility of HBV reactivation after HCV suppression (AI). A 48-week treatment should also be considered in treating HCV genotypes 2 and 3 (CIII). HBV reactivation during HCV therapy should be treated with NA (BIII).

Patients with active HBV infection and inactive HCV infection should be treated according to the recommendations given for HBV (AI), HCV-RNA should be monitored every 2 months during therapy due to the possibility of HCV reactivation after HBV suppression. Reactivation of HCV should be treated as indicated for chronic hepatitis C (BII).

6.2. Co-infection with HDV 

6.2.1. Whom and when to treat 

This decision should be based on:

•The HDV immuno-virologic profile, the presence of anti-HDV of IgM class and/or HDV-RNA in serum, levels of anti-HB of IgM class and HBV–DNA.

•Liver histology showing significant liver fibrosis (at least S2 by Ishak classification).

6.2.2. How to treat and what strategy to take 

In patients without anti-HD of IgM class and HDV-RNA, and with inactive HBV infection treatment is not indicated (AI). The virological evaluation for both viruses should be repeated every 4–12 months (AII).

In patients with serum HD-RNA and/or anti-HD-IgM with or without active HBV:

•There is no indication to treatment for patients with mild histological damage; follow up without treatment is recommended (BII).

•Consider PEG-IFN given for at least 48–72 weeks (BI) for treating moderately severe histological damage. If HBV infection is active after 48 therapy weeks NA should be considered (BII).

6.3. Co-infection with HDV and HCV 

6.3.1. Whom and when to treat and what strategy to take 

Patients in whom all the three infections are active should be treated with PEG-IFN for 48–72 weeks+Ribavirin for 24–48 weeks according to the HCV schedule (BIII). If there is no HBV response after 24 weeks of treatment, consider NA (BIII). In patients with one or two active infections, treatment should be targeted to the active viruses (BIII).

6.4. Co-infection with HIV 

6.4.1. Whom and when to treat 


•Anti-HBc positive and HBsAg negative subjectsNo HBV treatment is recommended (AI). Surveillance with control of HBsAg every 6–12 months is recommended after withdrawal of anti-retrovirals active on HBV, during severe immune depletion (CD4<200/μL) or in the presence of hypertransaminasemia (BIII).

•Inactive HBV carriersThere is no indication for HBV treatment (AI). Lamivudine or Emtricitabine should not be used as the only agent active on HBV (CIII). Surveillance after stopping anti-retrovirals with HBV activity is recommended, to identify early reactivation of hepatitis B (BIII).

•Active HBV carriers
o.Subjects with CD4>500 and without immediate indications for HIV treatment should be treated according to the recommendations given for HBV monoinfection (CIII), possibly in randomised controlled trials or in observational studies (CIII).

o.In subjects with CD4<500 or with indication for anti-retroviral treatment (ART) this should include two drugs active against HBV (AIII). When ART is indicated, with other drugs, knowledge of the disease stage is essential to define the treatment strategy (AIII). HBV treatment is indicated in all patients with advanced liver disease (i.e., S>3) (AII).

o.In patients with compensated or decompensated cirrhosis and severe immune depletion a pre-emptive treatment with Telbivudine could be considered before starting ART with HBV activity, in order to prevent flares of hepatitis B induced by immune restoration (CIII).


6.4.2. How to treat and what strategy to take 


•Tenofovir, Entecavir, Lamivudine and Emtricitabine, because of their anti-HIV activity, should be used only in patients assuming cART in order to avoid occurrence of HIV resistance induced by anti-HIV sub-optimal treatment (BI).

•Lamivudine and Emtricitabine should not be used as the only drug active against HBV (BII) in cART, because of the high risk of HBV resistance.

•In patients with CD4>500 and without any immediate indications for anti-HIV treatment, HBV treatment should be started as in anti-HIV negative patients (BIII), NA should be preferred to PEG-IFN in HBeAg negative patients (CIII). In patients who are candidates for NA treatment, combinations of a nucleoside analogue and a nucleotide analogue is the first choice. Adefovir and Telbivudine could be used without starting cART, Tenofovir and Lamivudine or Emtricitabine or Entecavircould be used only by anticipating cART (CIII).

•In patients with CD<500 or with indication to HIV therapy cART including Tenofovir+Entricitabine/Lamivudine should be initiated. If Tenofovir is not included as a part of cART, it should be added. In case of contra-indications, Tenofovir could be substituted by Adefovir. Entecavir and Telbivudine can substitute Emtricitabine/Lamivudine if they are not indicated as part of cART (CIII). In clinically stable HBeAg positive patients with CD4 levels greater than 350, a cycle of interferon to induce anti-HBe sero-conversion could be considered (CIII). Withdrawal of HBV drugs has been associated with a worsening prognosis in HIV co-infected patients; HBV drugs should be maintained in patients with advanced fibrosis (>S3) (BII). Costs/benefits evaluation should be pursued in before stopping all drugs active on HBV in those with milder disease (CIII).

Tests for the identification of HBV mutations associated with resistance to HBV drugs should be considered:

∘In all patients before starting any drug active against HBV, given the risk of primary infection with HBV strains resistant to HBV drugs (CIII).

∘In patients taking drugs active against HBV for more than 48 weeks, who have detectable HBV–DNA (CIII).

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7. Conclusions 

Future therapeutic needs, improvements and perspectives were debated. There is a need for further investigations to implement Tenofovir in therapeutic strategies, establish the long-term efficacy of NAs, to develop therapies for HDV disease and to minimise the risk of hepatocellular carcinoma with treatment. There was general agreement that in the future the most efficacious therapeutic strategies will be a combination of drugs rather than a therapy with a single drug, however potent. It was nevertheless admitted that current attempts to combine PEG-IFN and Lamivudine or Adefovir do not seem to be any more rewarding. The problem of drug-resistant mutants under therapy created a lot of interest and the risk of the ultimate emergence of mutants resistant to all antivirals raised concern. It was recommended that NA-therapies should be guided by knowledge of the genotypic asset of HBV rather than by empirical treatment/adaptation; genotype-guided therapy was regarded as mandatory in patients to be re-treated after a viral breakthrough.

The issue of the cost of therapy and the burden to the public or private economy was considered; the prohibitive impact on public health budgets of the current costs of combination therapies was recognised as a major non-medical obstacle to combination therapy.

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Practice points 

Prevention of HBV drugs resistance

•Avoid unnecessary treatment and think twice before treating very high viraemia, normal ALT, immunotolerant.

•Start with a potent drug with high genetic barrier, target lower genetic barrier drugs to patients with low HBV–DNA with close monitoring of the early response and use “de novo” combination in patients with advanced/decompensated liver disease.

•Adapt therapy in sub-optimal responders and immediately after the emergence of genotypic resistance by choosing the appropriate second/third drug based on treatment history, no cross-resistance and sequencing data.

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Research agenda 


•Definition of the diagnostic value of non-invasive markers of progressive disease in assessing liver disease stage.

•Implementation of Tenofovir in treatment strategies.

•Studies aimed at comparing efficacy, safety and durability of de novo combination with complementary drugs with no cross-resistance vs. monotherapy with the most potent and effective nucleoside or nucleotide analogues with sequential early add-on in sub-optimal responders.

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Conflict of interest statement 

None declared.

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Acknowledgments 

The workshop was endorsed by Italian Association for the Study of the Liver (Associazione Italiana Per lo Studio del Fegato AISF), the Italian Society of Infectious and Tropical Diseases (Società Italiana per lo studio delle Malattie Infettive e Tropicali: SIMIT) and the Italian Society for the Study of Sexually Transmitted Diseases (Società Italiana per lo studio delle Malattie Sessualmente Trasmettibili: SIMAST).

The following persons took part to this event and to the elaboration process of these recommendations.

Scientific board: Pietro Andreone, Azienda Ospedaliero-Universitaria Policlinico Sant’Orsola Malpighi, Bologna; Mario Angelico, Università di Roma “Tor Vergata”, Roma; Antonio Ascione, Azienda Ospedaliera “A. Cardarelli”, Napoli; Nicola Caporaso, Università degli Studi di Napoli Federico II, Policlinico, Napoli; Stefano Fagiuolim, Azienda Ospedaliera Ospedali Riuniti di Bergamo; Giovanna Fattovich, Università degli Studi di Verona-Policlinico G.B. Rossi, Verona; Mario Mondelli, Università di Pavia-IRCCS Policlinico San Matteo, Pavia; Grazia Anna Niro, IRCCS Casa del Sollievo della Sofferenza, San Giovanni Rotondo, Foggia; Patrizia Pontisso, Università degli Studi di Padova.

Faculty: Ferruccio Bonino, Policlinico di Milano; Carlo Federico Perno, Università degli Studi di Roma, Tor Vergata; Daniele Prati, Ospedale A Manzoni Lecco.

Other invited participants: Massimo Andreoni, Ospedale Civile degli Infermi, Biella; Gioacchino Angarano, Ospedali Riuniti di Foggia; Eleonora Annicchiarico, Università Cattoloca Sacro Cuore-Policlinico Gemelli, Roma; Rosa Boncoraglio, Ospedale Maggiore di Modica; Diego Brustia, Azienda Ospedaliera Maggiore, Novara; Nino Calabrese, Azienda Ospedaliera Benfratelli, Palermo; Antonio Carlotto, Ospedale San Camillo De Lellis, Schio; Luisa Cavalletto, Azienda Ospedaliera di Padova, Padova; Maurizio Cavina, Azienda Ospedaliera Policlinico Modena; Luchino Chessa, Policlinico Universitario di Cagliari Monserrato; Guido Croce, Ospedale San Carlo Borromeo, Milano; Giuseppe De Sanctis, Policlinico Umberto I, Roma; Francesco Di Candilo, Policlinico Silvestrini S.M. della Misericordia, Perugia; Paolo Fabris, Ospedale Civile S. Bortolo, Vicenza; Osvaldo Fracassetti, Ospedali Riuniti di Bergamo; Alfonso Galeota Lanza, A.O.R.N. Cardarelli, Napoli; Tiziana Giuberti, Azienda Ospedaliera di Parma; Giuseppe Guazzotti, Azienda Ospedaliera San Pietro e Paolo, Borgosesia; Tiziana Iacovazzi, Ospedale Fallacara, Bari; Vincenzo Iovinella, ASL NA 1 Ospedale San Paolo, Napoli; Antonio Izzi, Azienda Ospedaliera D. Cotugno, Napoli; Pietro Loperfido, Ospedale Santissima Annunziata, Taranto; Carlo Fedrico Magni, Ospedale Luigi Sacco, Milano; Nicoletta Marino, Ospedale S.M.Annunziata Azienda Sanitaria di Firenze; Vincenzo Messina, Azienda Ospedaliera Sant’Anna e San Sebastiano di Caserta; Giuseppe Michelone, IRCCS Policlinico San Matteo, Pavia; Roberto Morante, Policlinica Federico II, Napoli; Alessandra Moretti, Ospedale S. Filippo Neri, Roma; Paola Nasta Spedali Civili di Brescia; Leone Nauri, San Camillo, Roma; Amerigo Paffetti, Policlinico Umberto I, Roma; Michela Pasino, Azienda Ospedaliera Borgo Roma Policlinica Rossi, Verona; Giorgio Perboni, Ospedale Carlo Poma, Mantova; Enzo Petrelli, Azienda Ospedaliera “Ospedale San Salvatore”, Pesaro; Antonio Picciotto, Università di Genova; Massimo Pozzi, Ospedale San Gerardo, Monza; Francesco Purificato, Presidio Ospedaliero Sud Formia e Gaeta; Tiziana Re, Azienda Ospedaliera Legnano Cuggiono; Roberto Rinaldi, Azienda Ospedaliera di Padova; Spartaco Sani, Ospedale Livorno; Renato Santoro, Azienda Ospedaliera Ospedali Riuniti, Salerno; Ornella Schioppa, CRO Istituto Nazionale Tumori, Aviano; Gaetano Scotto, Ospedali Riuniti di Foggia; Massimo Siciliano Università Cattolica S. Cuore, Roma; Orazio Sorbello, Policlinico Universitario, Monserrato; Giovanni Squadrito, Azienda Ospedaliera Universitaria Policlinico G. Martino, Messina; Maria Teresa Taddei, Azienda Ospedaliera S. Carlo Borromeo, Milano; Antonio Traversa, Azienda Ospedaliera di Aosta; Paolo Tundo, Ospedale Santa Caterina Novella, Galatina; Giovanna Venezia, Università degli Studi di Palermo; Luigi Vilardo, Azienda Ospedaliera di Cosenza; Anna Linda Zignego, Azienda Ospedaliero-Universitaria Careggi, Firenze; Alessia Zoncada, Azienda Ospedaliera Maggiore di Cremona; Massimo Zuin, Azienda Ospedaliera San Paolo, Milano.

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References 

  1. Alberti A. Can serum HBV-DNA be used as a primary end point to assess efficacy of new treatments for chronic hepatitis B?. Hepatology. 2003;38:18–20
  2. Alberti A, Brunetto MR, Colombo M, Craxì A. Recent progress and new trends in the treatment of hepatitis B. J Med Virol. 2002;67:458–462
  3. Alberti A, Clumeck N, Collins S, Gerlich W, Lundgren J, Palù G, et al. 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
  4. Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology. 1998;27:1670–1677
  5. Andreone P, Spertini F, Negro F. Lamivudine-associated remission of chronic hepatitis delta. Ann Intern Med. 2000;132:598
  6. Angus P, Vaughan R, Xiong S, Yang H, Delaney W, Gibbs C, et al. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology. 2003;125:292–297
  7. Aroldi A, Lampertico P, Montagnino G, Passerini P, Villa M, Campise MR, et al. Natural history of hepatitis B and C in renal allograft recipients. Transplantation. 2005;79:1132–1136
  8. Bani-Sadr F, Palmer P, Scieux C, Molina JM. Ninety-six-week efficacy of combination therapy with lamivudine and tenofovir in patients coinfected with HIV-1 and wild- type hepatitis B virus. Clin Infect Dis. 2004;39:1062–1064
  9. Barbon V, Gaia S, Marzano A, Lagget M, Rizzetto M. Prompt relapse of viremia after lamivudine discontinuation in e-minus chronic hepatitis B patients completely responders during 5 years of therapy. J Hepatol. 2004;41:500–501
  10. Bartholomeusz A, Locarnini SA. Antiviral drug resistance: clinical consequences and molecular aspects. Semin Liver Dis. 2006;26:162–170
  11. Bartholomew MM, Jansen RW, Jeffers LJ, Reddy KR, Johnson LC, Bunzendahl H, et al. Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet. 1997;349:20–22
  12. Beckebaum S, Malagó M, Dirsch O, Cicinnati VR, Trippler M, Lampertico P, et al. Efficacy of combined lamivudine and adefovir dipivoxil treatment for severe HBV graft reinfection after living donor liver transplantation. Clin Transplant. 2003;17:554–559
  13. Benhamou Y, Thibault V, Vig P, Calvez V, Marcelin AG, Fievet MH, et al. Safety and efficacy of adefovir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol. 2006;44:62–67
  14. Benhamou Y, Fleury H, Trimoulet P, Pellegrin I, Urbinelli R, Katlama C, et al. Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology. 2006;43:548–555
  15. Benhamou Y, Bochet M, Thibault V, Di Martino V, Caumes E, Bricaire F, et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patitents. Hepatology. 2000;31:1030–1031
  16. Benvegnù L, Gios M, Boccato S, Alberti A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut. 2004;53:744–749
  17. Boni C, Bertoletti A, Penna A, Cavalli A, Pilli M, Urbani S, et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest. 1998;102:968–975
  18. Boni C, Penna A, Bertoletti A, Lamonaca V, Rapti I, Missale G, et al. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol. 2003;39:595–605
  19. Boni C, Penna A, Ogg GS, Bertoletti A, Pilli M, Cavallo C, et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology. 2001;33:963–971
  20. Bonino F, Marcellin P, Lau GK, Hadziyannis S, Jin R, Piratvisuth T, et al. Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group Predicting response to peginterferon alpha-2a, lamivudine and the two combinedfor HBeAg-negative chronic hepatitis B. Gut. 2007;56:699–705
  21. Bonino F, Oliveri F, Colombatto P, Brunetto MR. Impact of interferon-alpha therapy on the development of hepatocellular carcinoma in patients with liver cirrhosis: results of an international survey. J Viral Hepat. 1997;4(Suppl. 2):79–82
  22. Borghesio E, Rosina F, Smedile A, Lagget M, Niro MG, Marinucci G, et al. Serum immunoglobulin M antibody to hepatitis D as a surrogate marker of hepatitis D in interferon-treated patients and in patients who underwent liver transplantation. Hepatology. 1998;27:873–876
  23. Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors [see comments]. Hepatology. 1989;10:761–763
  24. Brunetto MR, Oliveri F, Colombatto P, Coco B, Ciccorossi P, Bonino F. Treatment of HBeAg-negative chronic hepatitis B with interferon or pegylated interferon. J Hepatol. 2003;39(Suppl. 1):S164–S167
  25. Brunetto MR. Tailoring antiviral therapy in chronic hepatitis B patients with lamivudine resistance. J Hepatol. 2007;46:756–758
  26. Brunetto MR, Oliveri F, Coco B, Leandro G, Colombatto P, Gorin JM, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol. 2002;36:263–270
  27. Bruno R, Sacchi P, Zocchetti C, Ciappina V, Puoti M, Filice G. Rapid hepatitis B virus-DNA decay in co-infected HIV-hepatitis B virus ‘e-minus’ patients with YMDD mutations after 4 weeks of tenofovir therapy. AIDS. 2003;17:783–784
  28. Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Villari D, de Franchis R, et al. Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with chronic HBV infection. Hepatology. 2000;31:507–512
  29. Chan HL, Leung NW, Hui AY, Wong VW, Liew CT, Chim AM, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med. 2005;142:240–250
  30. Chan TM, Fang GX, Tang CS, Cheng IK, Lai KN, Ho SK. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology. 2002;36:1246–1252
  31. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010
  32. Chang TT, Gish RG, Hadziyannis SJ, Cianciara J, Rizzetto M, Schiff ER, et al. A dose-ranging study of the efficacy and tolerability of entecavir in Lamivudine-refractory chronic hepatitis B patients. Gastroenterology. 2005;129:1198–1209
  33. Chang TT, Lai CL, Chien RN, Guan R, Lim SG, Lee CM, et al. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B. J Gastroenterol Hepatol. 2004;19:1276–1282
  34. Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology. 2003;37:1320–1328
  35. Chien RN, Liaw YF, Atkins M. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B Asian Hepatitis Lamivudine Trial Group. Hepatology. 1999;30:770–774
  36. Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology. 2003;38:1267–1273
  37. Ciancio A, Smedile A, Rizzetto M, Lagget M, Gerin J, Korba B. Identification of HBV DNA sequences that are predictive of response to lamivudine therapy. Hepatology. 2004;39:64–73
  38. Ciccorossi P, Filipponi F, Oliveri F, Coco B, Colombatto P, Giannotti A, et al. Impact of antiviral treatment on recurrence of hepatitis B virus infection and disease. Transplant Proc. 2003;35:1028–1029
  39. Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminases. J Viral Hepat. 2007;14:360–369
  40. Colloredo G, Bellati G, Leandro G, Colombatto P, Rho A, Bissoli F, et al. Quantitative analysis of IgM anti-HBc in chronic hepatitis B patients using a new “gray-zone” for the evaluation of “borderline” values. J Hepatol. 1996;25:644–648
  41. Colombatto P, Civitano L, Bizzarri R, Oliveri F, Choudhury S, Gieschke R, et al. Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group A multiphase model of the dynamics of HBV infection in HBeAg-negative patients during pegylated interferon-alpha2a, lamivudine and combination therapy. Antivir Ther. 2006;11:197–212
  42. Colombatto P, Oliveri F, Leandro G, Baldi M, Capalbo M, Rocca G, et al. Platelet and white blood cell counts during therapy with different types of alpha interferon in patients with chronic viral hepatitis. Investigators of the Alpha Interferon Study Group of Piemonte, Italy. Ital J Gastroenterol Hepatol. 1997;29:441–447
  43. Colonno R, Rose R, Baldick C, Levine S, Pokornowski K, Yu C, et al. Resistance after two years of entecavir treatment in nucleoside-naive patients is rare. Hepatology. 2006;45:1656–1665
  44. Cortelezzi A, Viganò M, Zilioli VR, Fantini NN, Pasquini MC, Deliliers GL, et al. Adefovir added to lamivudine for hepatitis B recurrent infection in refractory B-cell chronic lymphocytic leukemia on prolonged therapy with Campath-1H. J Clin Virol. 2006;35:467–469
  45. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003;
  46. Craxì A, Antonucci G, Cammà C. Treatment options in HBV. J Hepatol. 2006;44(1 Suppl.):S77–S83
  47. Craxi A, Cooksley WG. Pegylated interferons for chronic hepatitis B. Antiviral Res. 2003;60:87–89
  48. Craxì A, Di Bona D, Cammà C. Interferon-alpha for HBeAg-positive chronic hepatitis B. J Hepatol. 2003;39(Suppl. 1):S99–S105
  49. Craxì A, Yurdaydin C. From viral pathobiology to the treatment of hepatitis B virus infection EASL Monothematic Conference (Istanbul, Turkey, October 6-82005). J Hepatol. 2006;44:1186–1195
  50. De Filippi F, Lampertico P, Soffredini R, Rumi MG, Lunghi G, Aroldi A, et al. High prevalence, low pathogenicity of hepatitis G virus in kidney transplant recipients. Dig Liver Dis. 2001;33:477–479
  51. Di Bisceglie AM, Lai CL, Gane E, Chen Y-C, Thongsawat S, Wang Y, et al. Telbivudine globe trial: maximal early HBV suppression is predictive of optimal two-year efficacy in nucleoside-treated hepatitis B patients. Hepatology. 2006;44(Suppl.):230A–231A
  52. Di Marco V, Craxì A. Adefovir for lamivudine resistant HBV: more than meets the eye. J Hepatol. 2007;47:618–619
  53. Di Marco V, Lo Iacono O, Cammà C, Vaccaro A, Giunta M, Martorana G, et al. The long-term course of chronic hepatitis B. Hepatology. 1999;30:257–264
  54. Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al. Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004;40:883–891
  55. Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. New Engl J Med. 1999;341:1256–1263
  56. Dienstag JL, Cianciara J, Karayalcin S, Kowdley KV, Willems B, Plisek S, et al. Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology. 2003;37:748–755
  57. Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124:105–117
  58. Di Martino V, Thevenot T, Colin JF, Boyer N, Martinot M, Degos F, et al. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B. Gastroenterology. 2002;123:1812–1822
  59. Dore GJ, Cooper DA, Pozniak AL, DeJesus E, Zhong L, Miller MD, et al. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapynaive and -experienced patients coinfected with HIV-1 and hepatitis B virus. J Infect Dis. 2004;189:1185–1192
  60. EASL International Consensus Conference on Hepatitis B, September 13–14, 2002, Geneva, Switzerland. Consensus Statement (short version). J Hepatol 2003;38:533–40.
  61. El-Sayed MH, Mohamed MM, Karim A, Maina AM, Oliveri F, Brunetto MR, et al. Severe liver disease is caused by HBV rather than HCV in children with hematological malignancies. Hematol J. 2003;4:321–327
  62. Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Forne M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis. Gut. 2004;53:1363–1365
  63. Filippini P, Coppola N, Pisapia R, Martini S, Marrocco C, Di Martino F, et al. Virological and clinical aspects of HBV-HCV coinfection in HIV positive patients. J Med Virol. 2007;79:1679–1685
  64. Fontana RJ, Hann HW, Perrillo RP, Vierling JM, Wright T, Rakela J, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123:719–727
  65. Franchello A, Ghisetti V, Marzano A, Romagnoli R, Salizzoni M. Transplantation of hepatitis B surface antigen-positive livers into hepatitis B virus-positive recipients and the role of hepatitis delta coinfection. Liver Transpl. 2005;11:922–928
  66. Fung SK, Chae HB, Fontana RJ, Conjeevaram H, Marrero J, Oberhelman K, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006;44:283–290
  67. Fung SK, Andreone P, Han SH, Reddy KR, Regev A, Keeffe EB, et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol. 2005;43:937–943
  68. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat. 2004;11:432–438
  69. Gaeta GB, Precone DF, Cozzi-Lepri A, Cicconi P, D’Arminio Monforte A. Multiple viral infections. J Hepatol. 2006;44(1 Suppl.):S108–S113
  70. Gaia S, Marzano A, Smedile A, Barbon V, Abate ML, Olivero A, et al. Four years of treatment with lamivudine: clinical and virological evaluations in HBe antigen-negative chronic hepatitis B. Aliment Pharmacol Ther. 2004;20:281–287
  71. Gerken G, Gomes J, Lampertico P, Colombo M, Rothaar T, Trippler M, et al. Clinical evaluation and applications of the Amplicor HBV Monitor test, a quantitative HBV DNA PCR assay. J Virol Methods. 1998;74:155–165
  72. Ghisetti V, Marzano A, Zamboni F, Barbui A, Franchello A, Gaia S, et al. Occult hepatitis B virus infection in HBsAg negative patients undergoing liver transplantation: clinical significance. Liver Transpl. 2004;10:356–362
  73. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg negative chronic hepatitis B. N Engl J Med. 2005;352:2673–2681
  74. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003;348:800–807
  75. Hadziyannis SJ, Papatheodoridis GV, Dimou E, Laras A, Papaioannou C. Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2000;32:847–851
  76. Hadziyannis S, Tassopoulos N, Chang TT, Heathcote J, Kitis G, Rizzetto M, et al. Long-term adefovir dipivoxil treatment induces regression of liver fibrosis in patients with HBeAg-negative chronic hepatitis B: results after 5 years of therapy [Abstract]. Hepatology. 2005;42(Suppl.):754A
  77. Hoff J, Bani-Sadr F, Gassin M, Raffi F. Evaluation of chronic hepatitis B virus (HBV) infection in coinfected patients receiving lamivudine as a componet of anti-human immunodeficiency virus regimens. Clin Infect Dis. 2001;32:963–969
  78. Honkoop P, de Man RA, Niesters HG, Zondervan PE, Schalm SW. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy. Hepatology. 2000;32:635–639
  79. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok ASF. Management of hepatitis b: summary of a clinical research workshop. Hepatology. 2007;45:1056–1075
  80. Hui CK, Cheung WW, Au WY, Lie AK, Zhang HY, Yueng YH, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut. 2005;54:1597–1603
  81. Hung CH, Lee CM, Lu SN, Wang JH, Tung HD, Chen CH, et al. Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection. J Gastroenterol Hepatol. 2005;20:727–732
  82. Iannitto E, Minardi V, Calvaruso G, Mulè A, Ammatuna E, Di Trapani R, et al. Hepatitis B virus reactivation and alemtuzumab therapy. Eur J Haematol. 2005;74:254–258
  83. Janssen HL, Gerken G, Carreño V, Marcellin P, Naoumov NV, Craxi A, et al. Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology. 1999;30:238–243
  84. Jonas MM, Kelley DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706–1713
  85. Kuo A, Dienstag JL, Chung RT. Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol. 2004;2:266–272
  86. Krogsgaard K, Bindslev N, Christensen E, Craxi A, Schlichting P, Schalm S, et al. The treatment effect of alpha interferon in chronic hepatitis B is independent of pre-treatment variables. Results based on individual patient data from 10 clinical controlled trials. European Concerted Action on Viral Hepatitis (Eurohep). J Hepatol. 1994;21:646–655
  87. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. New Engl J Med. 1998;339:61–68
  88. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020
  89. Lai CL, Leung N, Teo EK, Tong M, Wong F, Hann HW, et al. A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology. 2005;129:528–536
  90. Lai CL, Gane E, Liaw YF, Thongsawat S, Wang Y, Chen Y, et al. Telbivudine (LDT) vs. Lamivudine for Chronic hepatitis B: first-year results from the international phase III globe trial [abstract]. Hepatology. 2005;42(Suppl.):748A
  91. Lai CL, Gane E, Chao-Wei H, Thongsawat S, Wang Y, Chen Y, et al. Two-year results from the globe trial in patients with hepatitis b: greater clinical and antiviral efficacy for telbivudine (LDT) vs. lamivudine [abstract]. Hepatology. 2006;44(Suppl.):222A
  92. Lampertico P, Viganò M, Manenti E, Iavarone M, Sablon E, Colombo M. Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology. 2007;133:1445–1451
  93. Lampertico P, Del Ninno E, Manzin A, Donato MF, Rumi MG, Lunghi G, et al. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology. 1997;26:1621–1625
  94. Lampertico P, Del Ninno E, Viganò M, Romeo R, Donato MF, Sablon E, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology. 2003;37:756–763
  95. Lampertico P, Manzin A, Rumi MG, Paolucci S, Del Ninno E, Clementi M, et al. Hepatitis B virus precore mutants in HBeAg carriers with chronic hepatitis treated with interferon. J Viral Hepat. 1995;2:251–256
  96. Lampertico P, Viganò M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005;42:1414–1419
  97. Lau DT, Khokhar MF, Doo E, Ghany MG, Herion D, Park Y, et al. Long-term therapy of chronic hepatitis B with lamivudine. Hepatology. 2000;32:828–834
  98. Lau DT, Doo E, Park Y, Kleiner DE, Schmid P, Kuhns MC, et al. Lamivudine for chronic delta hepatitis. Hepatology. 1999;30:546–549
  99. Lau GK, He ML, Fong DY, Bartholomeusz A, Au WY, Lie AK, et al. Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation. Hepatology. 2002;36:702–709
  100. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742–1749
  101. Lee KM, Cho SW, Kim SW, Kim HJ, Hahm KB, Kim JH. Effect of virological response on post-treatment durability of lamivudine-induced HBeAg seroconversion. J Viral Hepat. 2002;9:208–212
  102. Lee HC, Suh DJ, Ryu SH, Kim H, Shin JW, Lim YS, et al. Quantitative polymerase chain reaction assay for serum hepatitis B virus DNA as a predictive factor for post-treatment relapse after lamivudine induced hepatitis B e antigen loss or seroconversion. Gut. 2003;52:1779–1783
  103. Lee YS, Suh DJ, Lim YS, Jung SW, Kim KM, Lee HC, et al. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology. 2006;43:1385–1391
  104. Leung NW, Lai CL, Chang TT, Guan R, Lee CM, Ng KY, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33:1527–1532
  105. Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al. Asian-pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int. 2005;25:472–489
  106. Liaw YF, Chien RN, Yeh CT. No benefit to continue lamivudine therapy after emergence of YMDD mutations. Antivir Ther. 2004;9:257–262
  107. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172–180
  108. Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence ofYMDD motif mutation during lamivudine therapy. Hepatology. 1999;30:567–572
  109. Lim SG, Ng TM, Kung N, Krastev Z, Volfova M, Husa P, et al. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med. 2006;166:49–56
  110. Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM, Chen DS. Ribavirin and interferon is effective for hepatitis C virus clearance in hepatis B and C dually infected patients. Hepatology. 2003;37:568–576
  111. Lobello S, Lorenzoni U, Vian A, Floreani A, Brunetto MR, Chiaramonte M. Interferon treatment in hepatitis B surface antigen-positive hepatitis B e antibody-positive chronic hepatitis B: role of hepatitis B core antibody IgM titre in patient selection and treatment monitoring. J Viral Hepat. 1998;5:61–66
  112. Locasciulli A, Bruno B, Alessandrino EP, Meloni G, Arcese W, Bandini G, et al. Italian Cooperative Group for Blood and Marrow Transplantation. Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation. Bone Marrow Transplant. 2003;31:295–300
  113. Locasciulli A, Testa M, Valsecchi MG, Bacigalupo A, Solinas S, Tomas JF, et al. The role of hepatitis C and B virus infections as risk factors for severe liver complications following allogeneic BMT: a prospective study by the Infectious Disease Working Party of the European Blood and Marrow Transplantation Group. Transplantation. 1999;68:1486–1491
  114. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182–188
  115. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–1722
  116. Lok AS, Lai CL, Wu PC, Leung EK. Long-term follow-up in a randomised controlled trial of recombinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection. Lancet. 1988;2:298–302
  117. Lok AS, Hussain M, Cursano C, Margotti M, Gramenzi A, Grazi GL, et al. Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy. Hepatology. 2000;32:1145–1153
  118. Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology. 2001;121:101–109
  119. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. 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
  120. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808–816
  121. Marzano A, Angelucci E, Andreone P, Brunetto M, Bruno R, Burra P, et al. Prophylaxis and treatment of hepatitis B in immunocompromised patients. Dig Liver Dis. 2007;39397–39408
  122. Marzano A, Debernardi-Venon W, Condreay L, Rizzetto M. Efficacy of lamivudine re-treatment in a patient with hepatitis B virus (HBV) recurrence after liver transplantation and HBV-DNA breakthrough during the first treatment. Transplantation. 1998;65:1499–1500
  123. Marzano A, Debernardi-Venon W, Smedile A, Brunetto MR, Torrani Cerenzia MR, Actis GC, et al. Recurrence of hepatitis B in liver transplants treated with antiviral therapy. Ital J Gastroenterol Hepatol. 1998;30:77–81
  124. Marzano A, Gaia S, Ciardo V, Premoli A, Ghisetti V, Salizzoni M, et al. Prophylaxis of hepatitis B virus infection before liver transplantation, 1990–2001: a single-center experience. Transplant Proc. 2003;35:1020–1021
  125. Marzano A, Gaia S, Ghisetti V, Carenzi S, Premoli A, Debernardi-Venon W, et al. Viral load at the time of liver transplantation and risk of hepatitis B virus recurrence. Liver Transpl. 2005;11:402–409
  126. Marzano A, Lampertico P, Mazzaferro V, Carenzi S, Vigano M, Romito R, et al. Prophylaxis of hepatitis B virus recurrence after liver transplantation in carriers of lamivudine-resistant mutants. Liver Transpl. 2005;11:532–538
  127. Marzano A, Salizzoni M, Debernardi-Venon W, Smedile A, Franchello A, Ciancio A, et al. Prevention of hepatitis B virus recurrence after liver transplantation in cirrhotic patients treated with lamivudine and passive immunoprophylaxis. J Hepatol. 2001;34:903–910
  128. Mazzaferro V, Regalia E, Montalto F, Pulvirenti A, Brunetto MR, Bonino F, et al. Risk of HBV reinfection after liver transplantation in HBsAg-positive cirrhosis. Primary hepatocellular carcinoma is not a predictor for HBV recurrence. The European Cooperative Study Group on Liver Cancer and Transplantation. Liver. 1996;16:117–122
  129. Melegari M, Scaglioni PP, Wands JR. Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. Hepatology. 1998;27:628–633
  130. Moriconi F, Colombatto P, Coco B, Ciccorossi P, Oliveri F, Flichman D, et al. Emergence of hepatitis B virus quasispecies with lower susceptibility to nucleos(t)ide analogues during lamivudine treatment. J Antimicrob Chemother. 2007;60:341–349
  131. Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006;44:713–720
  132. Niro GA, Ciancio A, Tillman HL, Lagget M, Olivero A, Perri F, et al. Lamivudine therapy in chronic delta hepatitis: a multicentre randomized-controlled pilot study. Aliment Pharmacol Ther. 2005;22:227–232
  133. Niro GA, Rosina F, Rizzetto M. Treatment of hepatitis D. J Viral Hepat. 2005;12:2–9
  134. Niro GA, Santantonio T, Fontana R, Insalata M, Facciorusso D, Signorile F, et al. Re-treatment of patients with anti-HBe-positive chronic hepatitis B who relapsed after an initial course of lamivudine. Aliment Pharmacol Ther. 2003;18:933–940
  135. Núñez M, Puoti M, Camino N, Soriano V. Treatment of chronic hepatitis B in the human immunodeficiency virus-infected patient: present and future. Clin Infect Dis. 2003;37:1678–1685
  136. Oliveri F, Santantonio T, Bellati G, Colombatto P, Mels GC, Carriero L, et al. Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon. Am J Gastroenterol. 1999;94:1366–1372
  137. Ono SK, Kato N, Shiratori Y, Kato J, Goto T, Schinazi RF, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Invest. 2001;107:449–455
  138. Ono-Nita SK, Kato N, Shiratori Y, Masaki T, Lan KH, Carrilho FJ, et al. YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: a study by in vitro full-length viral DNA transfection. Hepatology. 1999;29:939–945
  139. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003;62:686–687
  140. Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36:186–194
  141. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg negative chronic hepatitis B. J Hepatol. 2001;34:306–313
  142. Papatheodoridis GV, Dimou E, Dimakopoulos K, Manolakopoulos S, Rapti I, Kitis G, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology. 2005;42:121–129
  143. Papatheodoridis GV, Dimou E, Laras A, Papadimitropoulos V, Hadziyannis SJ. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology. 2002;36:219–226
  144. Perrillo RP, Wright T, Rakela J, Levy G, Schiff E, Gish R, et al. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B. Hepatology. 2001;33:424–432
  145. Peters MG, Anderson J, Lynch P, Tun L, Alston-Smith B, Carol L, et al. Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology. 2006;44:1110–1116
  146. Peters MG, Hann H, Martin P, Heathcote EJ, Buggisch P, Rubin R, et al. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology. 2004;126:91–101
  147. Pontisso P, Gerotto M, Benvegnù L, Chemello L, Alberti A. Coinfection by hepatitis B virus and hepatitis C virus. Antivir Ther. 1998;3(Suppl. 3):137–142
  148. Puoti M, Airoldi M, Bruno R, Zanini B, Spinetti A, Pezzoli C, et al. Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects. AIDS Rev. 2002;4:27–35
  149. Puoti M, Cozzi-Lepri A, Ancarani F, Bruno R, Ambu S, Ferraro T, et al. HepaI CoNA Study Group; ICoNA Study Group The management of hepatitis B virus/HIV-1 co-infected patients starting their first HAART regimen. Treating two infections for the price of one drug?. Antivir Ther. 2004;9:811–817
  150. Puoti M, Cozzi-Lepri A, Arici C, Paraninfo G, Moller NF, Lundgren JD HBV-HIV International Intercohort Study Group. Impact of lamivudine on the risk of liver-related death in 2041 HBsAg- and HIV-positive individuals: results from an inter-cohort analysis. Antivir Ther. 2006;11:567–574
  151. Puoti M, Rossi S, Forleo MA, Zaltron S, Spinetti A, Putzolu V, et al. Treatment of chronic hepatitis D with interferon alpha-2b in patients with human immunodeficiency virus infection. J Hepatol. 1998;29:45–52
  152. Puoti M, Torti C, Bruno R, Filice G, Carosi G. Natural history of chronic hepatitis B in co-infected patients. J Hepatol. 2006;44(1 Suppl.):S65–S70
  153. Raimondo G, Brunetto MR, Pontisso P, Smedile A, Maina AM, Saitta C, et al. Associazione Italiana Studio Fegato Cooperative Group Longitudinal evaluation reveals a complex spectrum of virological profiles in hepatitis B virus/hepatitis C virus-coinfected patients. Hepatology. 2006;43:100–107
  154. Raimondo G, Cacciamo G, Saitta C. Hepatitis B virus and hepatitis C virus co-infection: additive players in chronic liver disease?. Ann Hepatol. 2005;4:100–106
  155. Ristig MB, Crippin J, Aberg JA, Powderly WG, Lisker-Melman M, Kessels L, et al. Tenofovir disoproxil fumarate therapy for chronic hepatitis B in human immunodeficiency virus/hepatitis B virus-coinfected individuals for whom interferon-alpha and lamivudine therapy have failed. J Infect Dis. 2002;186:1844–1847
  156. Raimondo G, Pollicino T, Squadrito G. What is the clinical impact of occult hepatitis B virus infection?. Lancet. 2005;365:638–640
  157. Rizzetto M, Marzano A, Lagget M. Treatment of hepatitis B e antigen-negative chronic hepatitis B with lamivudine. J Hepatol. 2003;39(Suppl. 1):S168–S171
  158. Rizzetto M, Tassopoulos NC, Goldin RD, Esteban R, Santantonio T, Heathcote EJ, et al. Extended lamivudine treatment in patients with HBeAg-negative chronic hepatitis B. J Hepatol. 2005;42:173–179
  159. Rosina F, Conoscitore P, Cuppone R, Rocca G, Giuliani A, Cozzolongo R, et al. Changing pattern of chronic hepatitis D in Southern Europe. Gastroenterology. 1999;117:161–166
  160. Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol. 2001;115:58–62
  161. Ryu SH, Chung YH, Choi MH, Kim JA, Shin JW, Jang MK, et al. Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study. J Hepatol. 2003;39:614–619
  162. Saitta C, Pontisso P, Brunetto MR, Fargion S, Gaeta GB, Niro GA, et al. Virological profiles in hepatitis B virus/hepatitis C virus coinfected patients under interferon plus ribavirin therapy. Antivir Ther. 2006;11:931–934
  163. Samuel D, Forns X, Berenguer M, Trautwein C, Burroughs A, Rizzetto M, et al. Report of the monothematic EASL conference on liver transplantation for viral hepatitis (Paris, France, January 12–14, 2006). J Hepatol. 2006;45:127–143
  164. Santantonio T, Gunther S, Sterneck M, Rendina M, Messner M, Launois B, et al. Liver graft infection by HBV S-gene mutants in transplant patients receiving long-term HBIg prophylaxis. Hepatogastroenterology. 1999;46:1848–1854
  165. Santantonio T, Mazzola M, Iacovazzi T, Miglietta A, Guastadisegni A, Pastore G. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine. J Hepatol. 2000;32:300–306
  166. Santantonio T, Mazzola M, Pastore G. Lamivudine is safe and effective in fulminant hepatitis B. J Hepatol. 1999;30:551
  167. Santantonio T, Niro GA, Sinisi E, Leandro G, Insalata M, Guastadisegni A, et al. Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients: a controlled pilot study. J Hepatol. 2006;36:799–804
  168. Schalm SW, Heathcote J, Cianciara J, Farrell G, Sherman M, Willems B, et al. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial [see comments]. Gut. 2000;46:562–568
  169. Schiff ER, Dienstag JL, Karayalcin S, Grimm IS, Perrillo RP, Husa P, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol. 2003;38:818–826
  170. Schiff E, Lai CL, Neuhaus P, Tillmann HL, Samuel D, Villeneuve JP. Adefovir dipivoxil (ADV) provides significant clinical benefit, reduces meld score and prevents transplantation in chronic hepatitis B patients wait-listed for liver transplantation (OLT) with Lamivudine-resistance (LAM-R) [abstract]. J Hepatol. 2005;42(Suppl. 2):5
  171. Schiff ER, Lai CL, Hadziyannis S, Neuhaus P, Terrault N, Colombo M, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419–1427
  172. Sheldon JA, Corral A, Rodes B, Mauss S, Rockstroh J, Berger F, et al. Risk of selecting K65R in antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir. AIDS. 2005;19:2036–2038
  173. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory. HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039–2049
  174. Smedile A, Mangia A, Brunetto MR, Giarin M, Marzano A, Ottobrelli A, et al. Different aspects of HDV and HBV reinfections and liver disease in orthotopic liver transplant (OLT). Prog Clin Biol Res. 1993;382:393–402
  175. Sokal EM, Kelly DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:225–232
  176. Song BC, Suh DJ, Lee HC, Chung YH, Lee YS. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology. 2000;32:803–806
  177. Soriano V, Puoti M, Bonacini M, Brook G, Cargnel A, Rockstroh J, et al. Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel. AIDS. 2005;19:221–240
  178. Stornaiuolo G, Amato A, Gaeta GB. Adefovir dipivoxil-associated thrombocytopenia in a patient with chronic hepatitis B. Dig Liver Dis. 2006;38:211–212
  179. Stornaiuolo G, Stanzione M, Brancaccio G, Cuomo G, Precone V, Di Biase S, et al. Viral blips during long-term treatment with standard or double dose lamivudine in HBe antigen negative chronic hepatitis B. World J Gastroenterol. 2007;13:5642–5647
  180. Stuyver LJ, Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, et al. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology. 2001;33:751–757
  181. Sung JJYLJ, Zeuzem S, Chow WC, Heathcote E, Perrillo R, Brosgart C, et al. A randomized double-blind phase II study of lamivudine compared to lamivudine plus adefovir dipivoxil for treatment naïve patients with chronic hepatitis B: week 52 analysis. J Hepatol. 2003;25
  182. Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, et al. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology. 1999;29:889–896
  183. Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine. Antimicrob Agents Chemother. 2004;48:3498–3507
  184. Terrault N, Roche B, Samuel D. Management of the hepatitis B virus in the liver transplantation setting: a European and an American perspective. Liver Transpl. 2005;11:716–732
  185. van Bommel F, Wunsche T, Mauss S, Reinke P, Bergk A, Schurmann D, et al. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology. 2004;40:1421–1425
  186. van Bommel F, Berg T. Reactivation of viral replication after replacement of tenofovir by adefovir. Hepatology. 2005;42:239–240
  187. van Nunen AB, Hansen BE, Suh DJ, Lohr HF, Chemello L, Fontaine H, et al. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut. 2003;52:420–424
  188. van Zonneveld M, Honkoop P, Hansen BE, Niesters HG, Murad SD, de Man RA, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology. 2004;39:804–810
  189. Verhelst D, Monge M, Meynard JL, Fouqueray B, Mougenot B, Girard PM, et al. Fanconi syndrome and renal failure induced by tenofovir: a first case report. Am J Kidney Dis. 2002;40:1331–1333
  190. Viganò M, Colombo M, Aroldi A, Lunghi G, Manenti E, Ponticelli C, et al. Long-term lamivudine monotherapy in renal-transplant recipients with hepatitis-B-related cirrhosis. Antivir Ther. 2005;10:709–713
  191. Villa E, Grottola A, Buttafoco P, Colantoni A, Bagni A, Ferretti I, et al. High doses of alpha-interferon are required in chronic hepatitis due to coinfection with hepatitis B virus and hepatitis C virus: long term results of a prospective randomized trial. Am J Gastroenterol. 2001;96:2973–2977
  192. Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G, Fenyves D, Bilodeau M, et al. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B. Hepatology. 2000;31:207–210
  193. Villeneuve JP, Durantel D, Durantel S, Westland C, Xiong S, Brosgart CL, et al. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient. J Hepatol. 2003;39:1085–1089
  194. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol. 2000;33:301–307
  195. Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000;62:299–307
  196. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–220
  197. Yim HJ, Hussain M, Liu Y, Wong SN, Fung S, Lok A. Evolution of multi-drug resistant hepatits B viurs during sequential therapy: implications on rescue therapy. Hepatology. 2006;44:703–712
  198. Yuen MF, Hui CK, Cheng CC, Wu CH, Lai YP, Lai CL. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications. Hepatology. 2001;34:139–145
  199. Yuen MF, Sablon E, Hui CK, Yuan HJ, Decraemer H, Lai CL. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785–791
  200. Westland CE, Yang H, Delaney WE, Gibbs CS, Miller MD, Wulfsohn M, et al. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology. 2003;38:96–103
  201. Westland C, Delaney Wt, Yang H, Chen SS, Marcellin P, Hadziyannis S, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil1. Gastroenterology. 2003;125:107–116
  202. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J. 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
  203. Wong VW, Chan HL, Wong ML, Tam JS, Leung NW. Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants. Aliment Pharmacol Ther. 2004;19:323–329

☆ Jury: Alfredo Alberti, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy; Giuseppe Cariti, Department of Infectious Diseases, University of Turin, Turin, Italy; Massimo Colombo, Department of Gastroenterology, University of Milan, Milan, Italy; Antonio Craxì, Department of Gastroenterology, University of Palermo, Palermo, Italy; Gaetano Filice, Department of Infectious Diseases, University of Pavia, Pavia, Italy; Massimo Levrero, Department of Internal Medicine, University of Rome La Sapienza, Rome, Italy; Francesco Mazzotta, Department of Infectious Diseases, S.S. Annunziata Hospital, Antella, Firenze, Italy; Giuseppe Pastore, Department of Infectious Diseases, University of Bari, Italy; Felice Piccinino, Department of Infectious Diseases SUN, Napoli, Italy; Giovanni Raimondo, Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy; Evangelista Sagnelli, Department of Infectious Diseases SUN, Napoli, Italy; Mario Toti, Department of Infectious Diseases, Grosseto Hospital, Grosseto, Italy. Expert Panel and Working Groups’ Tutors: Maurizia Brunetto, Gastroenterology and Hepatology Unit, University Hospital of Pisa, Pisa, Italy; Raffaele Bruno, Department of Infectious Diseases, University of Pavia, Pavia, Italy; Vito Di Marco, Department of Gastroenterology, University of Palermo, Palermo, Italy; Carlo Ferrari, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Giovanni B. Gaeta, Department of Infectious Diseases SUN, Napoli, Italy; Pietro Lampertico, Department of Gastroenterology, University of Milan, Milan, Italy; Alfredo Marzano, Department of Gastroenterology, University of Turin, Turin, Italy; Teresa Pollicino, Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy; Massimo Puoti, Department of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; Teresa Santantonio, Department of Infectious Diseases, University of Bari, Italy; Antonina Smedile, Department of Gastroenterology, University of Turin, Turin, Italy.

PII: S1590-8658(08)00112-6

doi:10.1016/j.dld.2008.03.011

Digestive and Liver Disease
Volume 40, Issue 8 , Pages 603-617, August 2008

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