World Gastroenterology Organisation Global Guideline Hepatitis B
2016; Lippincott Williams & Wilkins; Volume: 50; Issue: 9 Linguagem: Inglês
10.1097/mcg.0000000000000647
ISSN1539-2031
AutoresJordan J. Feld, Harry L.A. Janssen, Zaigham Abbas, A Elewaut, Péter Ferenci, Isakov Va, Aamir Ghafoor Khan, Seng Gee Lim, Stephen Locarnini, Ono S, Jose D. Sollano, C. Wendy Spearman, Chau‐Ting Yeh, Man‐Fung Yuen, Anton LeMair,
Tópico(s)Hepatitis C virus research
ResumoINTRODUCTION The hepatitis B virus (HBV) causes acute and chronic liver disease and is endemic in many areas of the world. The virus is transmitted through contact with blood or other body fluids from an infected person. Every individual with chronic HBV (CHB) infection represents an opportunity for further cases to be prevented. It is important to take the time needed to educate patients and to explain the risks that the infection poses to the patients themselves and to others. Although most patients with CHB do not develop hepatic complications, all infected individuals are at increased risk of progressive liver fibrosis, leading to cirrhosis and ultimately to hepatic decompensation and/or hepatocellular carcinoma (HCC). Fortunately, effective treatment can reduce the risk of HBV-related complications. Of the many viral causes of human disease, few are of greater global importance than HBV1: More than 2 billion people alive today have serologic evidence of past or present HBV infection. About 250 million are chronically infected and are at risk of developing HBV-related liver disease.2 Some 15% to 40% of chronically infected patients will develop cirrhosis, progressing to liver failure and/or HCC during their lifetime. Every year, there are over 4 million acute clinical cases of HBV. An estimated 1 million people die each year from CHB infection and its complications: cirrhosis or primary liver cancer.3 HBV-related liver deaths (2010) are estimated at 786,000 annually.4 The prevalence of HBV varies markedly between different regions of the world. In the literature, a distinction is usually made between areas of high, medium, low, and very low endemicity. The wide range of prevalence figures for CHB infection is largely related to differences in age at infection. Increasing numbers of patients with chronic infection are developing HBV variants that express little or no hepatitis B e antigen (HBeAg); this HBeAg-negative form of hepatitis B may require long-term therapy to reduce the likelihood that liver disease will progress, with relapse occurring when the patient is off treatment. This Global WGO Guideline includes a set of cascades to provide resource-sensitive options for the diagnosis and management of hepatitis B. These WGO Cascades are intended to serve as a "global" complement to, rather than a replacement for, the "gold standard" guidelines from the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), the Asian-Pacific Association for the Study of the Liver (APASL), and the National Institute for Care and Health Excellence (NICE).5–8 CLINICAL COURSE OF HBV INFECTION The outcome of HBV infection largely depends on the host-virus interaction, mediated by the adaptive immune response. The clinical course of HBV infection is variable and includes acute (self-limiting) infection, fulminant hepatic failure, inactive carrier state, and chronic hepatitis with chances of progression to cirrhosis and HCC.9,10 CHB Infection The risk of chronicity in acute HBV infection is related to age at primary infection. Adults who become chronically infected during childhood have a 15% to 25% lifetime risk of dying from HBV-related cirrhosis or liver cancer, with a significantly increased risk in men in comparison with women11 (Table 1).TABLE 1: Risk of Chronicity and Age at Primary InfectionCHB is a dynamic disease that fluctuates over time, likely relating to interactions between the virus and the host immune system. The following 5—not necessarily sequential—phases can be identified in CHB infection. Immune-tolerant phase: Characterized by high levels of serum HBV DNA, HBeAg positivity, normal alanine aminotransferase (ALT) levels, and absent liver necroinflammation. Disease progression is minimal in patients who remain in this phase.12 Patients are highly contagious in this phase. Immune-reactive phase (HBeAg-positive CHB): Patients enter this phase after a variable time, linked to the age when HBV infection occurred. The immune system becomes more active and the infected hepatocytes are attacked. Characterized by highly fluctuating, but progressively decreasing, HBV DNA levels, elevated ALT, and hepatic necroinflammation (HBeAg-positive CHB). A prolonged immune-active phase with multiple ALT flares may result in progressive liver fibrosis, leading to cirrhosis. Immune-control phase (and inactive carrier state): Transition into this phase as an outcome of the immune-active phase is marked by seroconversion from HBeAg to anti-HBe positivity. Characterized by low (<2000 IU/mL) or undetectable serum HBV DNA, normal ALT levels, and disappearance of liver necroinflammation (inactive carrier state). Reactivation phase (HBeAg-negative CHB): Despite HBe seroconversion, reactivation of HBV replication may occur due to the selection of HBeAg-defective HBV mutants. Characterized by positive anti-HBe antibody levels, fluctuating HBV DNA and ALT levels, and a high risk of progression to severe hepatic fibrosis (HBeAg-negative CHB). Periodic ALT flares with intervening normalization may make it difficult to distinguish between HBeAg-negative CHB and inactive disease, and thus continued follow-up is required before patients with normal ALT and low HBV DNA levels are designated as inactive carriers. Emerging evidence suggests that a low HBV DNA titer (<2000 IU/mL) combined with a low hepatitis B surface antigen (HBsAg) titer ( 6 months. Cascade 1.CASCADE 1: Diagnostic Tests for Acute Hepatitis BThe differential diagnosis of HBsAg-positive acute hepatitis includes exacerbations of CHB, which may occur at any time in any individual who is chronically infected (at these times, reversion back to anti-HBc IgM may occur). Acute hepatitis may occur following withdrawal from immunosuppressive therapy or through superinfection of a person chronically infected with hepatitis B with hepatitis C and/or D virus, or hepatitis A virus. Superimposed acute hepatitis due to drugs and other toxins administered to someone who has "silent" CHB infection may also present as acute hepatitis. A precipitating factor is sometimes not identified. Resolved HBV Infection Previous HBV infection is characterized by the presence of anti-HBs and IgG anti-HBc. Anti-HBs sometimes becomes undetectable after many years. (Anti-HBs is frequently undetectable if HBV infection occurred during childhood, as is seen in sub-Saharan Africa.) Notably, although these individuals are referred to as having "resolved HBV" infection, trace amounts of HBV DNA remain in their livers for years and possibly even lifelong. Immune control prevents viral expansion, but means that with severe immunosuppression [eg, with advanced human immunodeficiency virus (HIV) coinfection, bone marrow transplantation, rituximab use, etc.], HBsAg may reappear (reverse seroconversion) or viral replication may be detectable in the liver even without the reappearance of serum HBV DNA. Immunity to HBV infection after vaccination is characterized by the presence of only anti-HBs. CHB Infection Diagnosis of CHB infection is defined as the persistence of HBsAg for >6 months. It must first be established whether the individual is in the HBeAg-positive or HBeAg-negative phase of the infection (Table 3). Additional tests for markers of HBV replication—namely, HBeAg and serial measurements of serum HBV DNA, in addition to ALT—should be carried out. This will in part determine whether the patient should be considered for HBV therapy. Both HBeAg-positive and HBeAg-negative patients, even if they have normal serum ALT (women <20 IU/L and men <30 IU/L) and/or undetectable HBV DNA, still need to be monitored lifelong, as the condition may change over time even if they remain asymptomatic. Among individuals with chronic persistence of HBsAg, those with elevated serum ALT concentrations should be followed more closely, preferably with serial HBV DNA measurements. It is important to know the lower limit of detection of the method used to measure HBV DNA, as values that are persistently ≥2000 IU/mL will prompt consideration of antiviral therapy. The decision on whether to initiate therapy depends on multiple factors (ie, not just the level of HBV DNA and/or ALT). If the liver disease appears to be progressing (as judged by liver biopsy and noninvasive markers of inflammation and fibrosis such as transient elastography), treatment should be considered. Additional tests for hepatitis C and hepatitis D should also be conducted to rule out superinfection with other hepatitis virus(es), particularly in patients with elevated ALT but low or undetectable HBV DNA. Other things to consider include drug-induced liver injury (due to supplements), nonalcoholic steatohepatitis, and iron overload. TABLE 3: Differentiation of Phases of CHB InfectionDifferent levels of HBV DNA are used for initiating treatment for HBeAg-positive and HBeAg-negative disease, depending on the genotype prevalent in different regions. As a general rule (and because genotyping all patients is not feasible), the EASL level can be used for white patients: 2×103 IU/mL level (and age above 30 y), and the APASL/AASLD level can be used for Asian patients: 2×104 IU/mL (and age above 40 y). Initial Evaluation of Patients With CHB Infection Individuals with newly detected CHB need to understand that long-term monitoring for the development of chronic hepatitis, cirrhosis, and HCC through a series of clinical examinations and laboratory tests is required even if they are asymptomatic. It is important to verify the stage of CHB and decide the frequency of follow-up examinations needed. CHB infection is not necessarily accompanied by progressive liver disease requiring antiviral therapy. Accurate evaluation of all HBsAg-positive carriers is required to identify17: Phase of infection. Grade of liver inflammation. Stage of liver fibrosis. Concurrent causes of liver disease. Need for treatment. Presence of cofactors increasing the risk of progression to cirrhosis or HCC: coinfections with hepatitis D virus (HDV), hepatitis C virus (HCV), and HIV; comorbidities including alcoholism, autoimmune disease, or metabolic liver disease. The initial examination should include: History and physical examination, including skin and abdominal examination. Markers of HBV infection, including HBeAg/anti-HBe and HBV DNA to classify the phase of CHB, as well as the HBV genotype if antiviral therapy with interferon is contemplated. Markers of other viral infections, including HCV and HDV, particularly if ALT is elevated but HBV DNA is low or undetectable. Before oral antiviral therapy is introduced, all patients should be screened for HIV. Complete liver panel (ALT/AST to identify active inflammation, and bilirubin, prothrombin time, and albumin to check liver synthetic function). Complete blood count, particularly platelets, which serve as a surrogate marker for portal hypertension. Abdominal ultrasonography for baseline screening for HCC—α-fetoprotein (AFP) may be used in areas with high HBV endemicity and poorly differentiated HCC, as well as in areas without easy access to high-quality ultrasound. Measurement of liver fibrosis by serological testing, FibroScan (transient elastography), or liver biopsy. Table 4.TABLE 4: Host and Viral Risk Factors Associated With Progression of Chronic Hepatitis BOccult HBV Occult HBV infection refers to the persistence of HBV DNA in liver tissue (and in some cases in serum) in individuals in whom HBsAg is not detectable in the blood, usually with positive anti-HBc. Occult HBV infection is prevalent worldwide, but its frequency is related to the prevalence of overt HBV infection in a specific geographic area. Occult HBV is transmissible through blood transfusions and organ transplantation. Blood products should be screened for HBsAg, anti-HBc, and ideally HBV DNA. Organs from donors with anti-HBc and/or anti-HBs should preferably be used only for recipients who test positive for anti-HBs or HBsAg. Although the true relevance of occult HBV infection is unknown, it may be an additional risk factor for HCC in anti-HCV-positive patients and in HIV-infected individuals. It may also be associated with progression of chronic liver disease due to causes other than HBV. HBV Reactivation HBV replication is controlled by the host immune system. Immune suppression of any kind can lead to a loss of immune control and subsequent HBV reactivation, which can result in a range of consequences, from a subclinical increase in HBV DNA to icteric and even fulminant and/or fatal liver failure. Reactivation occurs most frequently with cancer chemotherapy, but may occur with other immunosuppressive or immunomodulator therapy (eg, targeted immunotherapy). The addition of systemic corticosteroids to inhaled corticosteroids increases the risk of HBV reactivation, especially when systemic corticosteroids are administered chronically or at high doses.19 Screening for HBsAg and anti-HBc is necessary before chemotherapy or immunosuppressive/immunomodulator therapy is started. Patients who are HBsAg positive should receive preemptive antiviral therapy during and for 6 to 12 months after chemotherapy. The benefits of preemptive treatment for occult HBV reactivation remain unclear at present. For patients with evidence of previous HBV infection, as confirmed by positive anti-HBc with or without anti-HBs, serial monitoring of HBV-related markers is recommended during and after immunosuppressive therapy. Patients receiving chemotherapy or immunosuppression should follow the AASLD and APASL guidelines (Fig. 2). FIGURE 2: APASL algorithm for all candidates for chemotherapy. HBsAg indicates hepatitis B surface antigen; NA, nucleoside analogue. Source: Asian-Pacific Association for the Study of the Liver.HCC Screening The aim is to detect tumors smaller than 3 cm in diameter, and preferably <2 cm, to offer a potential for curative treatment. Screening for HCC is advocated in all cirrhotic patients, as they are at the highest risk of developing HCC. However, in Africa and South-East Asia, where HBV infection is acquired early in life, HCC may develop in a noncirrhotic liver. The AASLD recommends HCC surveillance in the following types of patients with CHB: Asian men over the age of 40 and Asian women over the age of 50. All patients with cirrhosis, regardless of age. Patients with a family history of HCC; any age. Africans over the age of 20. Any individuals with HBV/HIV coinfection. Singal and colleagues showed that in a "real-world" clinical setting, a combination of ultrasound and AFP is the most effective strategy for detecting HCC at an early stage. The sensitivity significantly improved to 90%, with a minimal loss of specificity (83%). AFP alone may be better than ultrasound alone, as the reliability of ultrasound is very dependent on the skill and experience of the ultrasonographer.20 For hepatitis B carriers not included in this list, the risk of HCC varies depending on the severity of the underlying liver disease and current and past hepatic inflammatory activity. Those with high HBV DNA concentrations and ongoing hepatic inflammatory activity (evidenced by elevated ALT values) are at increased risk for HCC, and surveillance should be considered. Genotype C infection and the presence of BCP and pre-S1 mutations are also associated with an increased risk of HCC. TREATMENT FOR CHB Before any form of HBV therapy is started, and optimally at the time of first presentation, the patient needs to be provided with information about CHB and its treatment. Important information includes: The dynamic clinical course of CHB. Most infections remain initially entirely asymptomatic, even in the case of severe disease. The need for regular lifelong monitoring. Possible transmission to contacts—family and contacts need HBV screening and vaccination of those who are not immune to HBV, and referral for clinical evaluation of those who are HBsAg positive. Timing of the start of treatment. The need for absolute compliance with potentially long-term therapy. The need for absolute compliance with follow-up examinations both when the patient is on treatment and when he/she is off treatment. The importance of alcohol abstinence and attention to the use of medications that may be hepatotoxic or dangerous in patients with advanced liver disease (eg, NSAIDs) should be emphasized. Those who are not immune to hepatitis A should receive 2 doses of hepatitis A vaccine 6 to 18 months apart. This information should be explained and discussed with the patient. In women of childbearing potential, drugs that are considered safe in pregnancy are preferred, because once a nucleoside or nucleotide has been prescribed it cannot be stopped in those who remain HBeAg positive. The patient needs to understand that cessation of treatment may precipitate severe hepatitis, which can, rarely, lead to fulminant acute liver failure, even in the absence of cirrhosis. The phase of CHB can be determined on the basis of the serological and virological profile—each type is characterized by a distinct natural course, prognosis, and treatment indications.5,6,21 Immune-tolerant carrier: Treatment not indicated. Appropriate longitudinal follow-up is crucial. Measure ALT every 3 to 6 months. Inactive carrier: Treatment not indicated. Appropriate longitudinal follow-up is crucial. Assess ALT and HBV DNA levels every 3 months during the first year, then every 6 months. If the serum HBV DNA is <2000 IU/mL and the HBsAg level is 1 log10 IU/mL in comparison with the nadir (lowest value) HBV DNA level during treatment with confirmed compliance, then another agent with the optimal resistance profile—that is, tenofovir or entecavir—should be substituted or added. The following strategies can be used to prevent resistance: For the first-line therapy, choose a potent antiviral drug and/or one with a low incidence of resistance (high genetic barrier) over time (entecavir/tenofovir). Emphasize to the patient once again the importance of absolute compliance with therapy. The HBV DNA level should be monitored frequently when using drugs with a low barrier to resistance (every 3 to 6 mo) during treatment, and resistance testing (genotyping) should be carried out in case of viral breakthrough or suboptimal viral suppression, to allow genotypic resistance to be detected before clinical consequences develop. No drug resistance to interferon has been described, although some individuals do not respond to therapy, in which case it should be stopped. If available, the HBsAg titer can be used to guide interferon therapy (see below). HBeAg-positive Hepatitis Recommendations: HBeAg-positive patients with persistent ALT ≥2× the upper limit of normal, and with HBV DNA≥2000 IU/mL, should be considered for treatment. It is imperative to check for HIV coinfection before treatment, because all approved nucleoside/nucleotide analogues (NAs) have activity against HIV and will rapidly lead to drug-resistant HIV if used as monotherapy. HDV testing should be mandatory in countries with a high prevalence of hepatitis D infection (Romania, Moldavia, former Soviet Central Asian Republics, Russia). In patients who have had a liver biopsy, treatment should be started for those with moderate to severe inflammation or significant fibrosis (≥F2). Treatment should be initiated in those who have cirrhosis with detectable HBV DNA, even those with a low HBV DNA level, irrespective of the ALT level. Any of the approved therapies can be chosen, and the decision regarding the selection of therapy should include an assessment of efficacy, safety, and genetic barriers to resistance. To avoid resistance, entecavir and tenofovir are the preferred choices for NA therapy. It is important to ensure that patients have a secure source of support to pay for medications over the longer term before starting therapy, to avoid abrupt cessations of treatment, which can be dangerous. Patients should be monitored regularly during therapy at 3 to 6 monthly intervals, or more frequently if they are receiving interferon-based therapy, to monitor for efficacy, safety, and early evidence of resistance (for NAs). Ideally, patients should be monitored with ALT, HBeAg, anti-HBe, and HBV DNA, but this may not be possible in countries in which these tests are not available or are prohibitively expensive, in which case ALT will have to suffice. Virologic breakthrough: an increase in HBV DNA >1 log above the nadir after a virologic response has been achieved during continued treatment (for NAs). Before assuming this is resistance, adherence should be discussed with the patient. A continued increase in the HBV DNA titer over time is suggestive of resistance in a patient who is complying with the treatment. Patients with resistance should be considered for rescue therapy with nucleosides/nucleotides that do not have a cross-resistant profile (lamivudine, telbivudine, and entecavir have an overlapping resistance profile, so that tenofovir substitution would be preferable—or if unavailable, adefovir add-on therapy). Oral agents should be continued until at least 12 months after the end point of HBeAg seroconversion occurs in HBeAg-positive hepatitis, and it may be preferable to continue until HBsAg loss occurs because of the high risk of reactivation after cessation of therapy. Close monitoring is recommended after oral therapy has been stopped or withdrawn, because of the risk of a treatment withdrawal flare. Peginterferon-based therapies have the advantage of a fixed duration of therapy. HBeAg seroconversion may take place up to 6 months after discontinuation of interferon. HBeAg loss and seroconversion seem to be much more durable when induced with interferon in comparison with a NA. Interferon is most effective in patients with genotype A infection and least effective in those with genotypes D and C. If HBsAg titers are available, they can be used to guide interferon-based therapy. Discontinuation of interferon therapy is indicated in all patients with HBsAg>20,000 IU/mL at week 24, irrespective of the HBV genotype.25 Alternatively, those with no decline in the HBsAg titer at 12 weeks should also stop therapy. Stopping rules improve the cost-effectiveness of peginterferon therapy.26 HBeAg-negative Hepatitis HBeAg-negative CHB represents a late phase in the course of CHB infection. The patient should be considered for treatment if: HBV DNA ≥20,000 IU/mL and serum ALT >2×ULN. Liver biopsy or other forms of fibrosis assessment should be considered in patients with: HBV DNA ≥20,000 IU/mL and serum ALT ULN. Treatment should be administered if the liver biopsy shows moderate/severe necroinflammation or significant fibrosis (≥F2). Treat any patient with cirrhosis who has detectable HBV DNA. Recommendations for treatment: It is imperative to check for HIV coinfection before treatment, as all approved NAs have activity
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