- Category: HBV Treatment
- Published on Tuesday, 17 July 2012 00:00
- Written by Liz Highleyman
The European Association for the Study of the Liver (EASL) recently revised its clinical practice guidelines for the management of patients with chronic hepatitis B virus (HBV) infection. The new recommendations were announced at the International Liver Congress in April in Barcelona and published in the July 2012 Journal of Hepatology.
Approximately one third of the world’s population has evidence of past or present HBV infection and 350-400 million people have chronic hepatitis B, the guidelines authors noted.
EASL's hepatitis B clinical practice guidelines were originally released in October 2008. They are intended to assist physicians and other healthcare providers, as well as patients and interested individuals, in the clinical decision-making process by describing a range of generally accepted approaches for the diagnosis, treatment, and prevention of specific liver disease, according to a press release issued at the Congress.
The latest version includes modified indications for liver biopsy and treatment for hepatitis B "e" antigen (HBeAg) negative patients, new stopping rules for pegylated interferon alfa, amended recommendations for patients with partial virological response after 12 months on entecavir (Baraclude) or tenofovir (Viread), and recommendations for less frequent HBV DNA testing when using these 2 drugs.
The guidelines also feature a new switch strategy -- replacing the previous add-on strategy -- for people who develop drug resistance, and more detailed recommendations for specific subgroups including pregnant women and people with suppressed immunity.
The revised recommendations reflect new data that have become available since the previous guidelines were published, but the authors acknowledge that areas of uncertainty still exist and "therefore clinicians, patients, and public health authorities must continue to make choices on the basis of the evolving evidence."
- The questions the panel members addressed included:
- How should liver disease be assessed before therapy?
- What are the goals and endpoints of treatment?
- What are the definitions of response?
- What is the optimal approach to first-line treatment?
- What are the predictors of response?
- How should resistance be defined and managed?
- How should treatment be monitored?
- When can treatment be stopped?
- How should special groups be treated?
- What are the current unresolved issues?
HBV Detection and Monitoring
HBV DNA detection and viral load measurement are essential for diagnosis, deciding whether to treat, and subsequent monitoring of patients, the authors wrote. HBV DNA levels should be expressed in International Units (IU/mL) to enable accurate comparison. Clinicians should look for other causes of chronic liver disease in people with HBV, including hepatitis A virus (HAV), hepatitis C virus (HCV), hepatitis delta virus (HDV), and HIV coinfections.
The panel recommended liver biopsies for determining the degree of necro-inflammation and fibrosis, as this can inform decisions about when to start treatment. But a biopsy is usually not necessary for patients with clinical evidence of cirrhosis or those for whom treatment would be indicated regardless of biopsy findings.
The non-invasive transient elastography or FibroScan method -- which is more widely used in Europe than in the U.S. -- "offers high diagnostic accuracy for the detection of cirrhosis, although the results may be confounded by severe inflammation associated with high ALT levels and the optimal cut-off of liver stiffness measurements vary among studies," according to the authors.
The goal of hepatitis B treatment is to improve quality of life and extended survival by preventing progression to cirrhosis, hepatocellular carcinoma, decompensated or end-stage liver disease, or death, the authors wrote. Therapy that produces sustained suppression of HBV replication typically leads to reduction in histological activity (inflammation and cell turnover), which lessens the risk of negative clinical outcomes.
However, chronic HBV infection cannot be completely eradicated due to the persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. As with HIV, this may explain why HBV can reactivate if treatment is discontinued or immune function changes. Furthermore, integration of HBV genes into the host genome may contribute to development of cancer.
The ideal endpoint of treatment is hepatitis B surface antigen (HBsAg) loss, but this is usually not achievable with current therapy, according to the panel members. A more realistic endpoint is the sustained virological remission.
For both HBeAg positive and HBeAg negative patients, the ideal endpoint is sustained HBsAg loss after stopping treatment, with or without anti-HBs antibody seroconversion. For HBeAg negative patients, virological and biochemical response (ALT normalization) is a "satisfactory" endpoint associated with improved prognosis. For HBeAg positive patients who do not achieve anti-HBe seroconversion, maintained virological remission with long-term antiviral therapy is the next best endpoint.
Indications for treatment are generally the same for both HBeAg positive and negative patients, based mainly on a combination of 3 criteria: serum HBV DNA levels, serum ALT levels, and severity of liver disease. Treatment should be considered if a person has HBV DNA > 2000 IU/ml, ALT above the upper limit of normal, and biopsy evidence of moderate-to-severe necro-inflammation or at least moderate fibrosis.
Hepatitis B treatment options include the nucleoside analogs entecavir, emtricitabine (Emtriva), lamivudine (Epivir or 3TC), and telbivudine (Tyzeka) and the nucleotide analogs adefovir (Hepsera) and tenofovir (Viread); several of these agents are also used to treat HIV (for which purpose they are known as nucleoside/nucleotide reverse transcriptase inhibitors, or NRTIs).
Conventional and pegylated interferon -- the mainstay of hepatitis C treatment -- may also be used to treat chronic hepatitis B, alone or in combination with nucleoside/nucleotide analogs. Depending on patient and disease characteristics, hepatitis B treatment may entail either a finite course of therapy with nucleoside/nucleotide analogs or interferon, or else ongoing maintenance therapy with nucleoside/nucleotide analogs.
Entecavir and tenofovir are potent inhibitors of HBV with a high barrier to resistance, and therefore "can be confidently used as first-line monotherapies," the authors recommended. While lamivudine is inexpensive, resistance is common when it is used as monotherapy. Adefovir is less effective, more expensive, and more prone to resistance than tenofovir. Telbivudine is a potent inhibitor of HBV replication, but has a lower barrier to resistance.
Most people achieve sustained virological remission with either entecavir or tenofovir monotherapy. Combination nucleoside/nucleotide therapy -- which makes it harder for the virus to develop resistance -- may be used in difficult-to-treat cases (for example primary non-response or viral breakthrough), but according to the authors "there are as yet no data" to indicate whether starting with a combination regimen is more advantageous for treatment-naive patients.
The clinical practice guidelines cover treatment considerations for special patient groups including people with cirrhosis, liver transplant recipients, kidney transplant recipients and dialysis patients, HIV/HBV coinfected people (who are advised to include one or more drugs active against both viruses in their antiretroviral regimen), patients coinfected with HCV or HDV (who may experience more severe liver disease), people with acute hepatitis B, healthcare workers, children, and pregnant women (including prevention of perinatal HBV transmission).
The full EASL hepatitis B clinical practice guidelines are available for free online at www.journal-of-hepatology.eu/article/S0168-8278(12)00167-5/fulltext.
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of Chronic Hepatitis B Virus Infection. Journal of Hepatology 57(1):167-85. July 2012.
EASL. New Clinical Practice Guidelines on Alcoholic Liver Disease Published, Hepatitis B Guidelines Revised. Press release. April 19, 2012.