A panel of experts in hepatitis B virus (HBV) met last year with the objective of developing guidelines for the management and treatment of HBV for physicians and other health care providers based on all available published information in the field through August 2008. This panel of experts was selected by the governing board of the European Association for the Study of the Liver (EASL). A careful process was undertaken to validate the recommendations, under which the recommendations were examined by external peer reviewers and subsequently approved by the EASL governing board. The recommendations in these guidelines were evaluated according to the Grading Recommendations Assessment Development and Evaluation (GRADE) system to specify the strength of the support evidence. These guidelines were published by the EASL in the Journal of Hepatology [1].
This review has been carried out with the objective of summarizing the new recommendations and discussing new information available since its publication. Over the last few decades, the implementations of blood screening and vaccination programs have helped to decrease the prevalence of HBV in developed countries. However, due to globalization, carriers of this infection have immigrated to developed countries where the prevalence is low, rapidly changing the mapping of this infection. Therefore, together with the prevention measures already in place in many countries, health care providers should familiarize themselves with the management and treatment of chronic hepatitis B.
The goal of therapy is to suppress HBV replication and to prevent progression of liver disease with the objective of halting progression of liver fibrosis and hence cirrhosis, liver failure, and hepatocellular carcinoma.
ASSESSMENT OF LIVER DISEASE PRIOR TO THERAPY
The first step prior to starting any therapy is to confirm the etiology of the liver disease. A careful evaluation of all possible etiologies should be carried out, including infectious, metabolic, and hereditary liver diseases. In order to maximize the utility and diminish the cost of treatment, evaluation should be patient-dependent—taking into consideration age, ethnic background, family history, and risk factors (alcohol abuse, intravenous drug use, history of blood transfusion and/or surgeries, and sexual history). It is important to point out that the mode of acquisition of HBV via the parenteral route led to the coexistence of other infections such as hepatitis D virus (HDV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Therefore, treatment evaluation should not be carried out without screening the patient for the presence of these other viruses, which could have implications for disease management.
After confirmation of the etiology or etiologies of liver disease, the severity of disease should be assessed using biochemical markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase, prothrombin time, serum albumin, blood counts, and hepatic ultrasound. In addition, HBV deoxyribonucleic acid (DNA) levels should be determined and a histological evaluation by liver biopsy should be performed in cases where there is no clear indication for treatment, but where there is an elevation in ALT and/or HBV DNA levels >2000 IU/mL and where other etiologies for the liver disease are considered.
Furthermore, during this assessment, full hepatitis B serology markers should be performed. This is because the type of treatment and duration could be affected by the presence or absence of some serological markers, specifically hepatitis B e antigen (HBeAg). Chronic hepatitis B infection may present, such as HBeAg-positive or HBeAg-negative infection. HBeAg-positive chronic hepatitis B represents the early phase of the infection and is characterized by high levels of DNA. HBeAg-negative chronic hepatitis B is due to naturally occurring variants of HBV with nucleotides substitution in the precore and/or core promoter regions of the genome. It usually represents a later phase of chronic HBV infection associated with more advanced liver disease and is usually characterized by fluctuations in HBV DNA and ALT levels. In addition, some HBeAg-negative patients have an inactive disease with normal levels of ALT and undetectable viremia. This subgroup of patients is known as chronic inactive carriers.
INDICATION FOR TREATMENT
Three parameters are taken into consideration for treatment: HBV DNA levels, serum aminotransferases, and histology. Treatment is indicated based on the presence of abnormalities in at least 2 of these parameters: HBV DNA levels in serum >2000 IU/L, elevation of serum aminotransferases, and histology showing moderate to severe active necroinflammation and/or fibrosis. These indications will be the same irrespective of HBeAg serological status (Table 1).
 | TABLE 1. Indications for treatment |
Treatment strategies
There are two types of treatment approaches based on length of therapy: finite and long-term duration strategies. Careful selection of the patients based on biochemical and histological parameters, patients’ informed personal decisions, and drug availabilities, which vary by country, should be taken into consideration before choosing one approach over the other. For the finite duration strategy, pegylated interferon alpha (PEG-IFNα) or nucleosides/ nucleotides are used. PEG-IFN treatment is more favorable for patients who have the best chance of seroconversion: HBeAg-positive and HBeAg-negative patients with baseline ALT >3 times the upper limit of normal (ULN) and HBV DNA <2x106 IU/mL (107 copies/mL) or 6.3 log10 IU/mL at baseline [2-4].
The finite nucleoside/nucleotide treatment strategy cannot be predicted prior to treatment because it can only be offered if HBeAg seroconversion or clearance is achieved during treatment. The duration of this approach also depends on when seroconversion takes place. As with the PEG-IFN approach, patients with ALT >3 times ULN and HBV DNA <2x106 IU/mL (107 copies/mL) or 6.3 log10 IU/mL at baseline are more likely to experience seroconversion [4]. Thus, if these biochemical parameters are present, it would be wise to choose potent antiviral agents with the highest barrier to resistance, such as entecavir and tenofovir. It is important to note that consolidation therapy for 6 to 12 months after seroconversion should be given to increase chances of sustained serological response.
Long-term treatment is necessary for patients who cannot achieve a sustained viral response off-treatment and who require extended therapy. It is indicated in HBeAg-negative patients and HBeAg-positive patients who do not experience seroconversion and in patients with HBV-related compensated and decompensated cirrhosis, where HBV suppression should be maintained and there is no expectation for cure. In these patients, serological parameters have not had any implications on treatment.
It is important to understand the definition of response during therapy in order to effectively monitor patients. These definitions depend on the type of therapy used (IFNα or nucleosides/nucleotides; Table 2).
 | TABLE 2. Types of response to antivirals |
Current available treatments
Seven drugs are available for treatment: IFNα or PEG-IFNα, L-nucleosides (lamivudine and telbivudine), deoxyguanosine analogues (entecavir), and acyclic nucleoside phosphonates (adefovir and tenofovir) [5-8]. There are some differences between IFN and the nucleosides/nucleotides available for treatment, and they should be taken into account by the health care provider before instituting therapy.
IFN confers some advantages over nucleosides/ nucleotides. It has not been linked to resistance; it is given for a finite term; and it has the potential to achieve a sustained viral response off-treatment and a sustained clearance of hepatitis B surface antigen (HBsAg) [7]. However, it is contraindicated in decompensated HBV-related cirrhosis, and in patients with depression, psychosis, or history of autoimmune disease. In addition, its known side effects and method of administration by subcutaneous injection are inconvenient for patients.
Nucleosides/nucleotides are administered orally, have a very high safety profile, and have minimal side effects. However, they have the disadvantage that their prolonged use selects HBV variants with amino acid substitutions, reducing susceptibility, which could be responsible for virological breakthrough during therapy.
All of these drugs have been evaluated in randomized clinical trials for at least 1 year of duration [5,9-17]. Studies with up to a 5-year duration are available for lamivudine, adefovir, entecavir, telbivudine, and tenofovir. The clinical trials were not standardized, used different HBV DNA assays, and did not use head-to-head comparisons for all the drugs. However, from the data available, entecavir, telbivudine, and tenofovir are those that achieved the highest virological response. Nevertheless, the HBeAg seroconversion rate of these drugs fell short for PEG-IFN and is similar among all the oral antivirals. Moreover, entecavir and tenofovir have a high genetic barrier and their use is associated with a low risk of HBV resistance even during long-term treatment [5,18]. The higher efficacy and the low rate of resistance make tenofovir and entecavir the drugs of choice for first-line therapy (Figures 1 and 2).
 | Figure 1. Percentage rates of hepatitis B e (HBe) seroconversion, undetectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA), and normal alanine aminotransferase (ALT) at 1
year of therapy with pegylated interferon alpha-2a (PEG-IFN), lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF) in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B in randomized clinical trials. |
 | Figure 2. Percentage rates of undetectable hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and normal alanine aminotransferase (ALT) at 1 year of therapy with pegylated
interferon alpha-2a (PEG-IFN), lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LdT), and tenofovir (TDF) in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B in randomized clinical trials. |
Approach to treatment failure
When response is suboptimal to oral antivirals, the first thing to exclude is noncompliance to the medication. If compliance is present, genotype resistance should be checked in order to “rescue” the treatment with an effective antiviral.
If primary nonresponse is present, and noncompliance is excluded, the medication should be changed to a more powerful drug such as tenofovir and entecavir. In partial virological response while on moderately potent drugs (lamivudine, adefovir, and telbivudine), the recommendation is to change to a more potent drug (entecavir or tenofovir), or to add tenofovir to lamivudine or telbivudine, or entecavir to adefovir). This is done to avoid cross-resistance. If the patient is taking a highly potent drug such as entecavir or tenofovir, some experts suggest adding the other drug, but the safety of this combination in the long term is unknown. Virological breakthrough is seen in patients with resistance caused by noncompliance, prior treatment with nucleosides/nucleotides, or in treatment-naïve patients with partial virological response during treatment. When identified, resistance mutations should be checked to adapt treatment with a similar strategy for partial virological response (Table 3).
 | TABLE 3. Management of hepatitis B virus resistance |
Treatment of special populations
Pregnant patients
When possible, treatment during pregnancy should be avoided. Among the antivirals available, lamivudine, adefovir, and entecavir are listed as category C drugs, and telbivudine and tenofovir as category B. The largest data available are for the use of tenofovir and lamivudine for pregnant women with HIV infection, and have shown these medications to be safe. Furthermore, pregnant women in the third trimester who are monoinfected with HBV have received oral antivirals with a similar safety profile [19]. Pregnant women should be treated with oral antivirals during the last trimester of pregnancy if they have high levels of HBV DNA, and the newborn should receive immunoglobulins and HBV vaccination in order to prevent perinatal transmission of HBV [20]. In this instance, the other HBV antivirals in the B and C category could be considered as well. These patients should be followed up during and after delivery in case treatment is needed for exacerbations [21].
Children
The majority of children infected with hepatitis B are in the immunotolerant phase, where treatment is not indicated. On rare occasions, treatment is needed and, so far, only conventional IFNα, lamivudine, and adefovir have been evaluated in children [22-25]. However, new studies are underway where other nucleosides/nucleotides have been tested.
Patients with acute hepatitis and fulminant hepatitis
In general, acute hepatitis by HBV does not require treatment due to its highly spontaneous recovery and seroconversion rate of HBsAg without intervention. In some cases with fulminant presentation, nucleosides/nucleotides have been reported to be of benefit [26,27]. Treatment with antivirals should be continued after HBsAg or HBeAg seroconversion for 3 and 6 months, respectively.
Patients with cirrhosis
Patients with HBV and cirrhosis should always be treated, irrespective of ALT levels, which may be normal in these patients. For compensated cirrhosis, IFN and nucleosides/nucleotides can be used [28], while in patients with decompensated cirrhosis only nucleosides/nucleotides can be used. The recommendation is to start treatment with a highly potent antiviral such as tenofovir and entecavir. For patients with decompensated cirrhosis, treatment should be instituted in connection with liver transplant centers because of the potential need for liver transplantation in these patients.
Posttransplant patients
For patients considered for liver transplantation, pretransplant therapy should be initiated with a potent nucleoside/nucleotide for all HBsAg-positive patients to achieve viral suppression before transplantation [29-31]. Studies using a combination of immunoglobulins and lamivudine or adefovir have been successful in reducing recurrence of hepatitis B in the graft.
Hepatitis C virus, hepatitis D virus, and human immunodeficiency coinfections
For patients coinfected with HCV, HDV, and HIV, it is important to understand how treatment should be approached. In patients coinfected with HCV, the HCV is usually what drives the liver disease, while HBV DNA levels are undetectable. Treatment of HCV should be given while monitoring for HBV reactivation, which could take place during treatment and HCV viral suppression. For patients with HDV coinfection, PEG-IFNα is the only drug of choice because it is the only antiviral that decreases HDV replication [32-36]. For patients with HIV and HBV, the indications of therapy are the same as they are for HIV-negative patients. However, according to HIV guidelines, treatment should target both viruses to avoid the development of resistance, because some nucleosides/nucleotides (lamivudine, entecavir, and tenofovir) affect the replication of both viruses to different degrees [37]. Tenofovir, emtricitabine, and a third agent against HIV are indicated in this case [38]. When the immune system is too depressed, sometimes HBV should be treated before HIV to avoid a flare-up of hepatitis B in the presence of advanced fibrosis due to immune restitution and in those patients in whom adefovir and telbivudine should be used.
Immunosuppressed patients
All candidates for immunosuppressive therapy should be screened for HBV with HBsAg and antibodies to HBcAg (anti-HBc) and HBsAg [39]. Vaccination should be given to patients who are seronegative. In patients who are HBsAg-positive, treatment should be given prior to chemotherapy or immunosuppression and at least for 12 months after completing chemotherapy or immunosuppressive therapy. In patients with HBsAg and anti-HBc, HBV DNA determination should be carried out and, if the level is elevated, therapy should be started. If the level is undetectable, close follow-up with transaminases and HBV DNA determination should be done at least every 4 weeks in order to start therapy as soon as reactivation is seen. The medication of choice for prophylaxis and treatment is lamivudine, but more potent drugs should be used in patients with high levels of DNA.
CONCLUSIONS
The management and treatment of HBV are complex. The new EASL guidelines should be useful not only for clinicians, but also for public health authorities, who can choose the best strategies—in terms of efficacy and costs—to implement in every country. However, we should not forget that the guidelines should be updated with new literature. Finally, education of patients and health care providers is important, together with measures for hepatitis B prevention such as HBV vaccination.
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