Discussion

Goal of Antiviral Therapy for Chronic Hepatitis B

The ultimate goal of antiviral therapy for chronic hepatitis B is to prevent the progression to cirrhosis and/or development of hepatocellular carcinoma. In a prospective study, investigators demonstrated that individuals with persistent hepatitis B e antigen (HBeAg) infection had shorter survival compared with those who exhibited spontaneous or treatment-induced HBeAg clearance[1]. Older age, the presence of cirrhosis, and persistent alanine aminotransferase (ALT) elevation are also associated with adverse sequelae in patients with HBeAg-positive and -negative infections[2]. Three large-scale prospective studies have demonstrated that high serum hepatitis B viral loads are associated with increased risk of cirrhosis or liver cancer[3,4,5]. In the REVEAL-HBV Study, 3653 HBsAg-seropositive participants from Taiwan were followed for a mean of 11.4 years; individuals with HBV DNA levels ≥2,000 IU/ml were noted to have a 3 to 15 fold greater incidence of liver cancer compared to those with viral loads lower than this benchmark (Figure 1)[3]. This study also found other independent predictors of developing hepatocellular carcinoma (HCC) or cirrhosis: genotype C, a family history, pre-core mutation G1896A and basal core promoter double mutation A1762T/G1764A, male gender and reguar alcohol intake[20]. Nevertheless, even after adjusting for these other factors, HBV DNA level remained the strongest predictor of adverse outcomes. A risk scale calculator and nomogram are available to predict an individual's risk for cirrhosis and HCC[20].

It is tempting to extrapolate from these data to conclude that antiviral treatment of chronic hepatitis B with consequent reduction of HBV DNA levels to below 2,000 IU/ml will improve clinical outcomes. It is important, however, to recognize that a beneficial effect of antiviral treatment on patient survival has only been documented in cirrhotic patients[6,7] and in patients undergoing immunosuppressive treatment[8]. Indeed, a comprehensive review for the National Institutes of Health concluded that there was insufficient evidence to assess treatment effects on clinical outcomes[21]. Nevertheless, there is a growing body of literature showing that antiviral therapy and longterm HBV suppression can result in regression of fibrosis and cirrhosis[25] and decrease the chance of liver-related mortality. For example, patients taking long-term entecavir (Baraclude) had a 63% reduction in HCC compared with untreated controls[22]. In general, the scarcity of data to support antiviral therapy may be a consequence of the long period of time required for many of these clinical events to occur.

Before initiating treatment for chronic hepatitis B, beneficial effects on clinical outcome must be balanced against the cost of therapy, medication side-effects, the risk of viral resistance, and the likelihood of response to antiviral therapy. Based on the evidence linking high HBV DNA levels to the development of hepatocellular carcinoma and death from chronic liver disease, some experts have supported maximal HBV DNA suppression as a goal of antiviral therapy[9,10,11].

Published Guidelines for the Treatment of Chronic Hepatitis B

Numerous guidelines have been published for the treatment of chronic hepatitis B[12,13,14,15]. Recommendations from the American Association for the Study of Liver Disease (AASLD) for the management of chronic hepatitis B are shown in (Figure 2) and (Figure 3). When applying such treatment guidelines to patients with chronic hepatitis B, the following three clinical data are necessary: HBeAg status, ALT level, and HBV DNA level. Once this clinical information is available, clinicians can follow the treatment algorithm shown in (Figure 2) and (Figure 3). The treatment algorithms published by Keeffe and colleagues in December 2008[14] and by Lok and McMahon (AASLD guidelines) in September 2009[15] are similar in many respects. For patients with persistently elevated ALT and high HBV DNA levels, regardless of HBeAg status, both publications recommend antiviral treatment. A high HBV DNA levels is considered to be a value ≥ 20,000 IU/ml for HBeAg-positive patients (Figure 2) and ≥2,000 IU/ml for HBeAg-negative patients (Figure 3). Both guidelines agree that patients with HBeAg-negative chronic hepatitis B, low HBV DNA levels (< 2,000 IU/ml), and normal ALT values can be considered inactive carriers and do not require antiviral therapy.

Treatment of Patients with Chronic Hepatitis B and Cirrhosis

During the early stage of cirrhosis, many patients do not have symptoms, and are considered to have compensated cirrhosis. When complications such as symptomatic ascites or hepatic encephalopathy occur, patients are considered to have decompensated cirrhosis. For compensated cirrhotics with highHBV DNA levels (>=2,000 IU/ml), treatment is recommended, while for compensated cirrhotics with low viral loads treatment should be considered, particularly for patients with elevated ALT. For decompensated cirrhotics, treatment should be considered for any patient with a detectable viral load, regardless of the level of viremia.

Defining ALT Cutoffs for Treatment Indication

Both publications draw attention to the growing body of evidence that the normal ALT range that should be used to make management decisions for patients with chronic hepatitis B may differ from normal ranges defined by local laboratories[16]. Based on a large study comparing ALT levels in patients with chronic hepatitis C with those in hepatitis C and hepatitis B uninfected blood donors, the investigators suggested using an ALT cutoff of greater than 30 U/L in men and greater than 19 U/L in women would most accurately identify those with underlying hepatitis C infection[16]. These cutoffs are lower than the upper limit of normal defined by many laboratories, which generally base normal range on results obtained from blood donors without evidence of hepatitis B or hepatitis C infection. Because of the high prevalence of fatty liver in such 'healthy' donors (thus effectively elevating the apparently 'normal' average ALT values for the population), use of the upper limit of normal obtained from such healthy donor pools may not maximize detection of individuals with underlying liver disease due to viral hepatitis[17]. Threrefore, even though a patient may have an ALT result within the normal range defined by the local laboratory, the more stringent cutoffs more accurately predict underlying liver disease. It is also important to note that a treatment decision should not be made on the basis of a single serum ALT measurement. These values often vary and a particular phase of HBV infection will need to be confirmed with multiple measurements of serum ALT over time, typically drawn every 3 to 4 months, particularly given the dynamic nature of HBV infection.

Treatment of Patients in the Immune Tolerant Phase

An important area of controversy in the treatment of chronic hepatitis B is whether to treat patients in the immune tolerant phase of chronic hepatitis B (HBeAg-positive chronic hepatitis B and normal hepatic aminotransferase levels). Treatment of HBeAg-positive patients with high HBV DNA levels but low serum ALT levels generally results in lower rates of HBeAg seroconversion than treatment of comparable patients with elevated ALT[18,19]. In addition to their history of poor response to antiviral therapy, patients in the immune tolerant phase of HBV infection tend not to experience significant liver disease progression during this phase[23,24]. Thus, initiating treatment for such patients is appropriate only if durable HBV DNA suppression is considered to be a valid treatment goal. As discussed above, current data demonstrate that HBV-infected individuals with HBV DNA levels ≥2,000 IU/ml have an increased incidence of liver cancer and death from chronic liver disease compared with individuals with lower HBV DNA levels, but data from studies exploring the potential beneficial impact of lowering HBV DNA levels with antiviral therapy in patients with high HBV DNA levels and normal ALT are not yet available. In these cases of high HBV DNA levels but normal or minimally elevated ALT levels, current guidelines recommend continued monitoring with serial ALT and consideration of a liver biopsy, especially in older patients (greater than 40 years of age), with initiation of treatment if evidence of necroinflammatory disease or fibrosis is present[15,24].

Case Summary

The patient is HBeAg-positive with a high HBV DNA load and a persistently elevated serum ALT. Thus, according to published treatment guidelines, antiviral therapy should be initiated. Choice of anti-HBV therapy will be discussed in a subsequent case.

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    Figure 1 - Cumulative incidence of Hepatocellular Carcinoma by HBV DNA Level at Baseline

    Data from Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73.

    Figure 1
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    Figure 2 - Treatment Algorithm for Patient with Chronic Hepatitis B and Positive HBeAg

    Abbreviations: ALT = alanine aminotransferase; ULN = upper limit of normal Figure Adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39.

    Figure 2
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    Figure 3 - Treatment Algorithm for Patient with Chronic Hepatitis B and Negative HBeAg

    Abbreviations: ALT = alanine aminotransferase; ULN = upper limit of normal Figure Adapted from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39.

    Figure 3