January 6, 2014

Clinical Gastroenterology and Hepatology
Volume 12, Issue 1 , Pages 16-26, January 2014

Suna Yapali, Nizar Talaat, Anna S. Lok

published online 08 May 2013.

Seven drugs have been approved for the treatment of chronic hepatitis B. Antiviral treatment has been shown to be effective in suppressing hepatitis B virus replication, decreasing inflammation and fibrosis in the liver, and preventing progression of liver disease. However, current medications do not eradicate hepatitis B virus; therefore, a key question is which patients need to start treatment and which patients can be monitored. Professional societies have developed guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with chronic hepatitis B. These guidelines suggest preferred approaches, and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations, and we discuss what we do in our practice to illustrate factors that may influence decisions regarding hepatitis B management.

Keywords: Chronic Hepatitis B, Management, Antiviral Therapy, Hepatitis B Guidelines

Abbreviations used in this paper: AASLD, American Association for the Study of Liver Diseases, AFP, α-fetoprotein, ALT, alanine aminotransferase, anti-HBc, hepatitis B core antibody, anti-HBe, hepatitis B e antibody, APASL, Asian Pacific Association for the Study of the Liver, CHB, chronic hepatitis B, EASL, European Association for the Study of the Liver, HBV, hepatitis B virus, HBeAg, hepatitis B e antigen, HBsAg, hepatitis B surface antigen, HCC, hepatocellular carcinoma, IFN, interferon, NUC, nucleos(t)ide analogue, PEG-IFN,pegylated-interferon, ULN, upper limit of normal

The advent of sensitive assays for the detection of hepatitis B virus (HBV) and the availability of potent antiviral agents have improved the management of patients with chronic hepatitis B (CHB); however, current treatment cannot eradicate the virus. Because of the high cost and risk of adverse events, as well as drug resistance with long-term treatment, the most important question regarding the management of hepatitis B is which patients need to be treated now and which patients can be monitored and have treatment deferred. The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), and Asian Pacific Association for the Study of the Liver (APASL) have developed clinical practice guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with CHB.1,2, 3 These guidelines suggest preferred approaches and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. Recommendations of the 3 guidelines vary slightly because of differences in timing when the guidelines were issued and also differences in available resources. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations and we discuss what we do in our practice to illustrate factors that may influence the management of CHB.

Natural History of Chronic Hepatitis B Virus Infection 

The natural course of chronic HBV infection consists of 4 phases; however, patients may not experience all phases (Figure 1).4

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Figure 1  The natural course of chronic HBV infection consists of 4 phases. The immune tolerance phase is characterized by the presence of HBeAg, high HBV DNA levels, and persistently normal ALT levels, but no evidence of active liver disease. The immune clearance phase is characterized by the presence of HBeAg and high/fluctuating HBV DNA and ALT levels. An outcome of the immune clearance phase is HBeAg seroconversion. Most patients then enter the inactive HBV carrier phase, which is characterized by the absence of HBeAg and the presence of anti-HBe, low or undetectable HBV DNA levels (<2000 IU/mL), normal ALT levels, and no/minimal inflammation on liver biopsy. The reactivation phase is characterized by the absence of HBeAg, intermittent/persistently increased ALT and HBV DNA levels, and inflammation on liver biopsy.

Reprinted with permission from Lok.4

Host, viral, and environmental factors influence progression of HBV-related liver disease. Recent studies have focused on the importance of HBV replication as an independent predictor of cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths.5, 6 However, other factors including sex, age, HBV genotype, co-infection with human immunodeficiency virus, hepatitis C virus, or hepatitis D virus, increased alanine aminotransferase (ALT) level, and alcohol and tobacco use also contribute to cirrhosis and HCC.

Indications for Treatment 

Practice guidelines recommend that the treatment decision be made based on clinical status, serum HBV DNA and ALT levels, hepatitis B e antigen (HBeAg) status, and liver histology if available.1, 2, 3

Who Should Be Treated? 

All guidelines recommend starting treatment as soon as possible in patients with life-threatening liver disease: acute liver failure, decompensated cirrhosis, or severe exacerbation of CHB regardless of HBV DNA and ALT levels. Although data from randomized controlled trials in these settings are lacking, in case series antiviral treatment has been shown to be beneficial with little or no adverse effects. In addition, for patients requiring liver transplantation, viral suppression decreases the risk of HBV recurrence after transplant.7

The AASLD and APASL guidelines recommend antiviral therapy in patients with compensated cirrhosis and serum HBV DNA level greater than 2000 IU/mL regardless of ALT level.1, 2, 3 For patients with increased ALT levels, the AASLD guidelines recommend treatment regardless of HBV DNA level.1 The EASL guideline recommends treatment of patients with any detectable level of serum HBV DNA.2 There is growing evidence that long-term treatment with nucleos(t)ide analogues (NUCs) not only prevents disease progression but also reverses fibrosis and cirrhosis. In a double-blind, randomized, placebo-controlled study of 651 patients with advanced fibrosis or cirrhosis, who were HBeAg-positive or had high levels of HBV DNA (>150,000 IU/mL), lamivudine therapy was shown to decrease progression of liver disease.8 A follow-up report of the phase 3 tenofovir vs adefovir trial including 348 patients who had paired biopsies at baseline and year 5 showed that 51% of patients had a decrease in fibrosis stage by 1 or more and 71 of 96 (74%) patients with cirrhosis on initial biopsy had regression of cirrhosis.9

All guidelines agree that treatment should be initiated in noncirrhotic patients with serum HBV DNA levels greater than 20,000 IU/mL and persistently increased ALT levels and/or histologic evidence of moderate/severe inflammation or fibrosis. However, cut-off values of HBV DNA and ALT levels and the need for liver biopsy in determining treatment indications vary slightly among the guidelines (Table 1). The AASLD guideline suggests an arbitrary HBV DNA level of 20,000 IU/mL for initiating treatment.1 The APASL guideline recommends an HBV DNA threshold of 20,000 IU/mL for HBeAg-positive patients and 2000 IU/mL for HBeAg-negative patients, whereas the EASL guideline recommends a cut-off value of 2000 IU/mL irrespective of HBeAg status.2, 3 All guidelines agree that serial HBV DNA and ALT level is more important than a single value in making treatment decisions. For patients who fulfill the criteria for HBV DNA, the EASL recommends treating patients with ALT levels greater than the upper limit of normal (ULN) if the liver biopsy (or noninvasive markers validated in HBV-infected patients) shows moderate-severe inflammation and/or at least moderate fibrosis, whereas the APASL and AASLD recommend treatment for patients with an ALT level greater than 2 times the ULN. The AASLD guideline suggested lower values be used to define the ULN for an ALT level of 30 U/L for men and 19 U/L for women, and a liver biopsy should be performed in patients with mildly increased ALT levels, particularly in patients older than age 40.1 Besides HBV replication status, ALT levels, and liver histology, all guidelines recommend that patient age, HBeAg status, family history of HCC, occupational requirements, family planning, and patient preference should be considered in making treatment decisions.

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