Treatment of chronic hepatitis B: Recommendations from an Italian workshop

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Digestive and Liver Disease 40 (2008) 603–617

Progress Report

Treatment of chronic hepatitis B: Recommendations from an Italian workshop夽 G. Carosi a,∗ , M. Rizzetto b a

Department of Infectious and Tropical Diseases, University of Brescia, AO Spedali Civili, Brescia, Italy b Department of Gastroenterology, University of Turin, Turin, Italy Received 13 February 2008; accepted 4 March 2008 Available online 22 May 2008

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. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Antiviral therapy; Cirrhosis; HBV; HCV; HDV; HIV; Immune suppressed

夽 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 Crax`ı, 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. ∗ Corresponding author. Tel.: +39 0303995671; fax: +39 030303061. E-mail address: [email protected] (G. Carosi).

1590-8658/$30 © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2008.03.011

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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. 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 (Societ`a Italiana per lo studio delle Malattie Infettive e Tropicali: SIMIT) and the Italian Society for the Study of Sexually Transmitted Diseases (Societ`a 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.

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?

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 [1–203]. A selection of the literature was provided to all those who attended the workshop. 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 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 A Good evidence to support a recommendation B Moderate evidence to support a recommendation C Poor evidence to support a recommendation

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

Quality of evidence I Evidence from >1 properly randomised, controlled trial II Evidence 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 III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees

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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. 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.

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 > 20,000 IU/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 > 20,000 IU/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

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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 < 20,000,000 IU/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 seroconversion could be considered in patients with less severe fibrosis (
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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 NA When a patient treated with a NA shows signs of suboptimal 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 na¨ıve 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 1 mg/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 105 IU/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 interferon There 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 NA There 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. 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 > 2000 IU/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 > 2000 IU/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 20,000 IU/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 resis-

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tant 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 (>2,000,000 IU/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 200,000 IU/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.

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 > 200 IU/mL should be considered for treatment, independently of ALT levels. Patients with HBV–DNA < 200 IU/mL should be monitored without antiHBV treatment (BIII).

Fig. 1. The “Stresa Paradigm” summarising the indications for treatment of patients with hepatitis B with or without cirrhosis.

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 < 2,000,000 IU/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-␣ should not be used in these patients. Best options are: • monotherapy with Entecavir; • monotherapy with Telbivudine or Adefovir in patients with HBV–DNA < 2,000,000 IU/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 combina-

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tion 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.

5. Immune suppressed patients 5.1. Whom to treat or protect 1. Therapy is indicated for: chronic carriers with active HBV replication (HBV–DNA > 2,000 IU/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 (>7.5 mg/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-HBcpositive 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 > 2,000 IU/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.

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 2000 IU/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 <2000 IU/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

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evaluated after 24 weeks. Response for HCV is HCV-RNA undetectable; for HBV, HBV–DNA < 20,000 IU/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).

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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

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 antiHDV 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

• Anti-HBc positive and HBsAg negative subjects No 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/␮L) or in the presence of hypertransaminasemia (BIII). • Inactive HBV carriers There 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 antiretrovirals 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 antiretroviral 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).

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• 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).

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.

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.

Research agenda • Definition of the diagnostic value of noninvasive 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 crossresistance vs. monotherapy with the most potent and effective nucleoside or nucleotide analogues with sequential early add-on in sub-optimal responders.

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 (Societ`a Italiana per lo studio delle Malattie Infettive e Tropicali: SIMIT) and the Italian Society for the Study of Sexually Transmitted Diseases (Societ`a 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 OspedalieroUniversitaria Policlinico Sant’Orsola Malpighi, Bologna; Mario Angelico, Universit`a di Roma “Tor Vergata”, Roma; Antonio Ascione, Azienda Ospedaliera “A. Cardarelli”, Napoli; Nicola Caporaso, Universit`a degli Studi di Napoli Federico II, Policlinico, Napoli; Stefano Fagiuolim, Azienda Ospedaliera Ospedali Riuniti di Bergamo; Giovanna Fattovich, Universit`a degli Studi di Verona-Policlinico G.B. Rossi, Verona; Mario Mondelli, Universit`a di Pavia-IRCCS Policlinico San Matteo, Pavia; Grazia Anna Niro, IRCCS Casa del Sollievo della Sofferenza, San Giovanni Rotondo, Foggia; Patrizia Pontisso, Universit`a degli Studi di Padova. Faculty: Ferruccio Bonino, Policlinico di Milano; Carlo Federico Perno, Universit`a 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, Universit`a 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. Fil-

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ippo 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, Universit`a 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 Universit`a 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, Universit`a 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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