Discussion

Question | Discussion | References | CME Credit | CNE Credit

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. Unfortunately, data to define factors associated with the adverse outcomes of chronic hepatitis B infection are limited. More than 10 years ago, Niederau et al. demonstrated that individuals who did not clear hepatitis B e antigen (HBeAg) had decreased 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 were also associated with adverse sequelae in patients with HBeAg-positive and –negative infections [2]. More recently, three large scale prospective studies have demonstrated that high serum hepatitis B viral loads are associated with increased risk of cirrhosis or liver cancer [3-5]. In the REVEAL-HBV Study, 3653 HBsAg- seropositive participants from Taiwan were followed for a mean of 11.4 years; individuals with HBV viral loads ≥ 104 copies/ml (≥ 2,000 IU/ml) were noted to have a 3-15 fold greater incidence of liver cancer compared to those with viral loads lower than this benchmark (Figure 1) [3].

It is tempting to extrapolate from these recent data to conclude that antiviral treatment of chronic hepatitis B with consequent reduction of HBV DNA levels to below 104 copies/ml (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]. Data demonstrating a similar beneficial effect of HBV DNA suppression for non-cirrhotic patients with chronic hepatitis B are not yet available.

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 [8]. Nevertheless, the only treatment endpoint that has been linked to improved survival in non-cirrhotic hepatitis B-infected patients is interferon-induced HBeAg loss [1].

Published Guidelines for the Treatment of Chronic Hepatitis B

Numerous guidelines have been published for the treatment of chronic hepatitis B [9-12]. Recommendations 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 August 2006 [11] and by Lok and McMahon in February 2007 [12] are similar in many respects. For patients with persistently elevated ALT and high viral load, regardless of HBeAg status, both publications recommend antiviral treatment. A high viral load is considered to be a value ≥ 20,000 IU/ml and ≥ 2,000 IU/ml for patients with HBeAg positive (Figure 2) and HBeAg-negative (Figure 3) chronic hepatitis B, respectively.

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 high viral loads (≥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. Finally, both guidelines agree that patients with HBeAg-negative chronic hepatitis B and low viral loads (< 2,000 IU/ml) do not require antiviral therapy.

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 [13]. 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, it was suggested that an ALT cutoff of greater than 30 U/L in men and greater than 19 U/L in women most accurately identifies those with underlying hepatitis C infection [13]. 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. Nevertheless, because the prevalence of hepatic steatosis in such ‘healthy’ donors may be quite high (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. Thus, even though a patient may have an ALT result within the normal range defined by the local laboratory, the above lower, more stringent cutoffs more accurately predict underlying liver disease.

Treatment of Patients in the Immune Tolerant Phase

An important area of controversy in the treatment of chronic hepatitis B is whether patients in the Immune Tolerant Phase of chronic hepatitis B (HBeAg-positive chronic hepatitis B and normal hepatic aminotransferase levels) should be treated. Treatment of HBeAg-positive patients with high HBV DNA levels but low serum ALT levels generally results in lower rates of HBeAg seroconversion than those for patients who are similar except for elevated ALT [14,15]. Thus, 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 viral loads ≥2,000 IU/ml have an increased incidence of liver cancer and death from chronic liver disease compared to individuals with lower viral loads, but data from studies exploring the potential beneficial impact of lowering HBV DNA with anti-viral therapy in patients with high viral loads are not yet available. In these cases of high viral loads but normal or minimally elevated ALT levels, current guidelines recommend a liver biopsy, with initiation of treatment if evidence of necroinflammatory disease or fibrosis is present.

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.

[Back to Question | See References]

CME Credit | CNE Credit | Back to Top

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
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
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


CASE BASED MODULES Hepatitis A Hepatitis B Hepatitis C Other Hepatitis Viruses Common Management Issues Home About This Site Free CE High Risk Populations Resources Site Map Contact Us Editors and Authors	Hepatitis B
	Question \| Discussion \| References \| CME Credit \| CNE Credit 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. Unfortunately, data to define factors associated with the adverse outcomes of chronic hepatitis B infection are limited. More than 10 years ago, Niederau et al. demonstrated that individuals who did not clear hepatitis B e antigen (HBeAg) had decreased 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 were also associated with adverse sequelae in patients with HBeAg-positive and –negative infections [2]. More recently, three large scale prospective studies have demonstrated that high serum hepatitis B viral loads are associated with increased risk of cirrhosis or liver cancer [3-5]. In the REVEAL-HBV Study, 3653 HBsAg- seropositive participants from Taiwan were followed for a mean of 11.4 years; individuals with HBV viral loads ≥ 104 copies/ml (≥ 2,000 IU/ml) were noted to have a 3-15 fold greater incidence of liver cancer compared to those with viral loads lower than this benchmark (Figure 1) [3]. It is tempting to extrapolate from these recent data to conclude that antiviral treatment of chronic hepatitis B with consequent reduction of HBV DNA levels to below 104 copies/ml (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]. Data demonstrating a similar beneficial effect of HBV DNA suppression for non-cirrhotic patients with chronic hepatitis B are not yet available. 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 [8]. Nevertheless, the only treatment endpoint that has been linked to improved survival in non-cirrhotic hepatitis B-infected patients is interferon-induced HBeAg loss [1]. Published Guidelines for the Treatment of Chronic Hepatitis B Numerous guidelines have been published for the treatment of chronic hepatitis B [9-12]. Recommendations 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 August 2006 [11] and by Lok and McMahon in February 2007 [12] are similar in many respects. For patients with persistently elevated ALT and high viral load, regardless of HBeAg status, both publications recommend antiviral treatment. A high viral load is considered to be a value ≥ 20,000 IU/ml and ≥ 2,000 IU/ml for patients with HBeAg positive (Figure 2) and HBeAg-negative (Figure 3) chronic hepatitis B, respectively. 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 high viral loads (≥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. Finally, both guidelines agree that patients with HBeAg-negative chronic hepatitis B and low viral loads (< 2,000 IU/ml) do not require antiviral therapy. 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 [13]. 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, it was suggested that an ALT cutoff of greater than 30 U/L in men and greater than 19 U/L in women most accurately identifies those with underlying hepatitis C infection [13]. 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. Nevertheless, because the prevalence of hepatic steatosis in such ‘healthy’ donors may be quite high (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. Thus, even though a patient may have an ALT result within the normal range defined by the local laboratory, the above lower, more stringent cutoffs more accurately predict underlying liver disease. Treatment of Patients in the Immune Tolerant Phase An important area of controversy in the treatment of chronic hepatitis B is whether patients in the Immune Tolerant Phase of chronic hepatitis B (HBeAg-positive chronic hepatitis B and normal hepatic aminotransferase levels) should be treated. Treatment of HBeAg-positive patients with high HBV DNA levels but low serum ALT levels generally results in lower rates of HBeAg seroconversion than those for patients who are similar except for elevated ALT [14,15]. Thus, 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 viral loads ≥2,000 IU/ml have an increased incidence of liver cancer and death from chronic liver disease compared to individuals with lower viral loads, but data from studies exploring the potential beneficial impact of lowering HBV DNA with anti-viral therapy in patients with high viral loads are not yet available. In these cases of high viral loads but normal or minimally elevated ALT levels, current guidelines recommend a liver biopsy, with initiation of treatment if evidence of necroinflammatory disease or fibrosis is present. 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. [Back to Question \| See References] CME Credit \| CNE Credit \| Back to Top	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 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 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
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