The Changing Landscape in Hepatitis B
The Changing Landscape in Hepatitis B
Washington, DC; Wednesday, May 23, 2007 -- The management of chronic hepatitis B is rapidly evolving, and this is reflected in the plethora of treatment options available, including 6 US Food and Drug Administration approved therapies: standard interferon alfa-2b, lamivudine, adefovir, peginterferon alfa-2a, entecavir, and telbivudine. Clinical debate exists regarding every aspect of therapy: who, when, what, and for how long. Published guidelines are generally evidence-based. However, most clinical trails have only enrolled patients thought to be appropriate for therapy -- ie, those with elevated aminotransferases and elevated hepatitis B virus (HBV) DNA or patients who demonstrate significant disease on biopsy. This approach limits our evidence to a very specific population.
Ultimately, the goal is to initiate therapy at a time when the risk-benefit ratio is tipped in favor of therapy, before the development of significant fibrosis or malignancy. Thus, it would seem that the earlier that treatment is begun, the better. However, this decision must be weighed against issues in cost, compliance, and the potential development of drug resistance.
As we continue to gain insight into the benefits of effective treatment, a fundamental reappraisal of this disease is currently under way. This report highlights some of the key research in this area as presented during Digestive Disease Week (DDW) 2007.
Previously it was thought that disease progression in chronic hepatitis B occurred if hepatitis B e antigen (HBeAg) was positive, serum HBV DNA levels were > 10 copies/mL, and if the alanine aminotransferase (ALT) level was greater than 2 times the upper limit of normal (ULN), and that disease progression did not occur in the healthy carrier -- patients with hepatitis B surface antigen (HBsAg) positivity and HBeAg loss, normal liver enzyme levels, and with negative HBV DNA as measured by an insensitive assay (with detection only above 10 copies/mL). Although we now realize that this terminology is misleading, as "healthy carriers" can still develop disease progression, these patients continue to be viewed as relatively protected and are not traditionally offered therapy.
During this year's DDW meeting, Terrault and colleges confirmed previous findings suggesting that liver enzyme levels do not accurately reflect histology. Patients enrolled in phase 3 entecavir registration trials were categorized by ALT elevation. All had high viral load as defined by the study criteria. Among those patients with an ALT level less than 2 times ULN, more than two thirds demonstrated significant necroinflammation (Knodell necroinflammatory score: NI > 7), and a significant proportion also demonstrated advanced fibrosis. However, serum ALT level may still have some predictive value, as Chen and colleagues demonstrated a strong correlation between serum ALT elevations over the disease course, high viral load, and the risk of developing hepatocellular carcinoma (HCC). Those individuals with persistently lower (< 45 U/L) serum ALT had the lowest risk for HCC development. In this study, a single-point viral load was best at capturing the eventual risk for ALT elevation as well as predicting future HCC risk. However, Akhtar and colleagues presented a small case series of patients with significant necroinflammation and fibrosis with very low-level HBV DNA, emphasizing previous findings that suggested low viral load as a guarantee against disease progression. All of these studies serve to highlight that no patient with hepatitis B remains immune to complications, and no parameter can be used to identify a subset of patients that does not need close clinical follow-up.
Other methods may hold promise for identifying patients at increased risk for disease progression. Apoptosis, or programmed cell death, is a method that allows the body to effectively manage damaged cells. Although this may serve as a protective mechanism, for instance to prevent cancer or clear a virus, various signals can trigger a cell to die, including immune signals. Thus, markers of apoptosis may offer insight into immune activity. Papatheodoridis and colleagues found that increased serum levels of cytokeratin-18 (CK-18) fragments, a marker of apoptosis of CK-18-positive cells, was associated with liver injury, differentiating inactive HBV carriers from those with chronic active disease. Unfortunately, this marker did not correlate with severity of liver histology. Transient elastography has demonstrated clinical potential in the noninvasive evaluation of hepatic fibrosis by measurement of liver stiffness in chronic hepatitis C. Chang and colleagues verified that the application of this technology appears equally encouraging in chronic hepatitis B, demonstrating a positive predictive value of 92.3% for significant fibrosis.
One of the greatest driving forces in the evolving approach to hepatitis B therapy has been the development of several well-tolerated oral medications. However, it remains unclear how to best use these compounds, with each having attributes that may be desirable for certain patient subsets.
During DDW 2007, 2-year data were released from the telbivudine GLOBE trial, a phase 3 randomized trial in patients with chronic hepatitis B. The anti-HBV nucleoside telbivudine demonstrated significantly greater antiviral and clinical efficacy over lamivudine after 2 years. Sixty-three percent of HBeAg-positive patients treated with telbivudine vs 48% of lamivudine-treated HBeAg-positive patients achieved a therapeutic response (defined as serum HBV DNA < 10 copies/mL and serum ALT normalization or HBeAg loss). Fifty-six percent of this subset of patients also achieved HBV DNA suppression to less than 300 copies/mL while on telbivudine vs 39% of those who received lamivudine. Among the HBeAg-negative patients, 78% of those treated with telbivudine (vs 66% treated with lamivudine) achieved a therapeutic response, and 82% of those treated with telbivudine (vs 57% treated with lamivudine) suppressed serum HBV DNA to undetectable levels at 104 weeks. As previously reported, 24-week viral suppression predicted therapeutic efficacy and decreased likelihood of developing drug resistance.
The potential development of drug resistance with the use of the oral hepatitis B therapies is a growing concern because it not only decreases the therapeutic efficacy of that drug, but also reduces the efficacy of other medications in the same class. Because treatment may be used indefinitely in some patients, the concern regarding the development of resistance over time is of paramount importance. Genotypic mutations that confer drug resistance precede viral rebound (an increase in HBV DNA of 1 log or greater above nadir), which may then be followed by biochemical breakthrough (ALT elevation). All patients in the GLOBE registration trial underwent genotypic analysis at study entry and 165 of the 680 patients treated with telbivudine had HBV DNA > 1000 copies/mL at week 48 of treatment, 115 of whom were resequenced to identify genotypic mutations. The signature mutation for telbivudine resistance was reconfirmed as M204I. Forty six of these 115 patients had this "signature mutation." Thirty-two patients experienced virologic breakthrough at week 48, 28 of whom had the M204I mutation. Twenty-one patients with virologic breakthrough were then transitioned to adefovir salvage therapy (16 as follow-on monotherapy, 5 in combination with telbivudine), which generally resulted in improved liver enzyme levels and improved viral load (ie, decreased HBV DNA levels). Unfortunately, these patients were transitioned after clinical breakthrough. Data have suggested that virologic control is much easier to achieve when drug modifications are made prior to serum ALT elevation. Evaluation of the pharmacokinetic interactions between telbivudine and tenofovir, an anti-HIV nucleotide with potent anti-HBV activity, failed to reveal any significant drug-drug interaction, suggesting that tenofovir may also be an effective salvage option for patients who develop telbivudine resistance.
Preliminary cumulative resistance to telbivudine at week 92 was 21.8% in HBeAg-positive patients and 8.6% in HBeAg-negative patients. Again, resistance after 1 year was rare (1.5% in HBeAg-positive patients, and 0% in HBeAg-negative patients) if virus was suppressed to below 300 copies/mL at week 24 of therapy.
The role played by "genotype" in the management of hepatitis B remains controversial. First, this term is often used to describe both the viral subtype (A,B,C,D, etc) as well as drug resistance mutations in the HBV DNA polymerase gene. Although previous studies suggest that the viral genotype may influence treatment response and clinical course, its utility in disease management remains obscure. However, the importance of drug resistance testing is rapidly manifesting, especially when treating a patient with suboptimal response to therapy. Baseline resistance genotype in a naive patient (pre-treatment) is more contentious because wild-type virus generally predominates even if mutations exists. However, Feeney and colleagues performed baseline resistance testing in 108 treatment-naive subjects and found that 14.8% of patients had preexisting lamivudine mutations, including 2 patients with acute hepatitis B. This finding is of obvious importance, because lamivudine resistance decreases the efficacy of all the other current nucleoside agents.
Two studies presented during DDW 2007 focused on differences in drug potency. As highlighted above, early viral suppression is associated with decreased drug resistance, although the rapidity of viral suppression needed to avoid drug resistance may be different between compounds. On the basis of data presented at this meeting, treatment with the nucleoside analogs telbivudine or entecavir resulted in greater viral suppression in HBeAg-positive treatment-naive patients as compared with treatment with the nucleotide analog adefovir.
Special Populations: Chemoprophylaxis. Hepatitis B reactivation with chemotherapy is a well-recognized complication, often leading to significant morbidity and mortality. Two meta-analyses presented during this year's meeting confirmed the benefit of screening patients undergoing chemotherapy for HBV and the importance of HBV prophylaxis with lamivudine to prevent any untoward complications and to reduce overall related mortality in this setting.
HBsAg seroclearance is the goal of every antiviral therapeutic strategy; however, this endpoint does not fully eliminate the risk of developing liver disease-related complications. A retrospective literature review conducted by Retana and colleagues identified 1398 patients followed after HBsAg loss. The risk for liver complications did not decrease significantly. Predictably, those patients with cirrhosis or viral coinfection had a higher risk for hepatic complications, including liver cancer. This study emphasizes the importance of effective treatment prior to the onset of significant fibrosis.
Our approach to the management of hepatitis B continues to evolve. Although much more research is warranted, we are gaining good insight regarding who to treat, when to treat, and with what to treat. Data presented at DDW 2007 underscored the growing problem of drug resistance and further added to our basic understanding of this complicated disease.
Washington, DC; Wednesday, May 23, 2007 -- The management of chronic hepatitis B is rapidly evolving, and this is reflected in the plethora of treatment options available, including 6 US Food and Drug Administration approved therapies: standard interferon alfa-2b, lamivudine, adefovir, peginterferon alfa-2a, entecavir, and telbivudine. Clinical debate exists regarding every aspect of therapy: who, when, what, and for how long. Published guidelines are generally evidence-based. However, most clinical trails have only enrolled patients thought to be appropriate for therapy -- ie, those with elevated aminotransferases and elevated hepatitis B virus (HBV) DNA or patients who demonstrate significant disease on biopsy. This approach limits our evidence to a very specific population.
Ultimately, the goal is to initiate therapy at a time when the risk-benefit ratio is tipped in favor of therapy, before the development of significant fibrosis or malignancy. Thus, it would seem that the earlier that treatment is begun, the better. However, this decision must be weighed against issues in cost, compliance, and the potential development of drug resistance.
As we continue to gain insight into the benefits of effective treatment, a fundamental reappraisal of this disease is currently under way. This report highlights some of the key research in this area as presented during Digestive Disease Week (DDW) 2007.
Identification of Patients at Risk for Disease Progression
Previously it was thought that disease progression in chronic hepatitis B occurred if hepatitis B e antigen (HBeAg) was positive, serum HBV DNA levels were > 10 copies/mL, and if the alanine aminotransferase (ALT) level was greater than 2 times the upper limit of normal (ULN), and that disease progression did not occur in the healthy carrier -- patients with hepatitis B surface antigen (HBsAg) positivity and HBeAg loss, normal liver enzyme levels, and with negative HBV DNA as measured by an insensitive assay (with detection only above 10 copies/mL). Although we now realize that this terminology is misleading, as "healthy carriers" can still develop disease progression, these patients continue to be viewed as relatively protected and are not traditionally offered therapy.
During this year's DDW meeting, Terrault and colleges confirmed previous findings suggesting that liver enzyme levels do not accurately reflect histology. Patients enrolled in phase 3 entecavir registration trials were categorized by ALT elevation. All had high viral load as defined by the study criteria. Among those patients with an ALT level less than 2 times ULN, more than two thirds demonstrated significant necroinflammation (Knodell necroinflammatory score: NI > 7), and a significant proportion also demonstrated advanced fibrosis. However, serum ALT level may still have some predictive value, as Chen and colleagues demonstrated a strong correlation between serum ALT elevations over the disease course, high viral load, and the risk of developing hepatocellular carcinoma (HCC). Those individuals with persistently lower (< 45 U/L) serum ALT had the lowest risk for HCC development. In this study, a single-point viral load was best at capturing the eventual risk for ALT elevation as well as predicting future HCC risk. However, Akhtar and colleagues presented a small case series of patients with significant necroinflammation and fibrosis with very low-level HBV DNA, emphasizing previous findings that suggested low viral load as a guarantee against disease progression. All of these studies serve to highlight that no patient with hepatitis B remains immune to complications, and no parameter can be used to identify a subset of patients that does not need close clinical follow-up.
Other methods may hold promise for identifying patients at increased risk for disease progression. Apoptosis, or programmed cell death, is a method that allows the body to effectively manage damaged cells. Although this may serve as a protective mechanism, for instance to prevent cancer or clear a virus, various signals can trigger a cell to die, including immune signals. Thus, markers of apoptosis may offer insight into immune activity. Papatheodoridis and colleagues found that increased serum levels of cytokeratin-18 (CK-18) fragments, a marker of apoptosis of CK-18-positive cells, was associated with liver injury, differentiating inactive HBV carriers from those with chronic active disease. Unfortunately, this marker did not correlate with severity of liver histology. Transient elastography has demonstrated clinical potential in the noninvasive evaluation of hepatic fibrosis by measurement of liver stiffness in chronic hepatitis C. Chang and colleagues verified that the application of this technology appears equally encouraging in chronic hepatitis B, demonstrating a positive predictive value of 92.3% for significant fibrosis.
Issues in Treatment
One of the greatest driving forces in the evolving approach to hepatitis B therapy has been the development of several well-tolerated oral medications. However, it remains unclear how to best use these compounds, with each having attributes that may be desirable for certain patient subsets.
Telbivudine
During DDW 2007, 2-year data were released from the telbivudine GLOBE trial, a phase 3 randomized trial in patients with chronic hepatitis B. The anti-HBV nucleoside telbivudine demonstrated significantly greater antiviral and clinical efficacy over lamivudine after 2 years. Sixty-three percent of HBeAg-positive patients treated with telbivudine vs 48% of lamivudine-treated HBeAg-positive patients achieved a therapeutic response (defined as serum HBV DNA < 10 copies/mL and serum ALT normalization or HBeAg loss). Fifty-six percent of this subset of patients also achieved HBV DNA suppression to less than 300 copies/mL while on telbivudine vs 39% of those who received lamivudine. Among the HBeAg-negative patients, 78% of those treated with telbivudine (vs 66% treated with lamivudine) achieved a therapeutic response, and 82% of those treated with telbivudine (vs 57% treated with lamivudine) suppressed serum HBV DNA to undetectable levels at 104 weeks. As previously reported, 24-week viral suppression predicted therapeutic efficacy and decreased likelihood of developing drug resistance.
The potential development of drug resistance with the use of the oral hepatitis B therapies is a growing concern because it not only decreases the therapeutic efficacy of that drug, but also reduces the efficacy of other medications in the same class. Because treatment may be used indefinitely in some patients, the concern regarding the development of resistance over time is of paramount importance. Genotypic mutations that confer drug resistance precede viral rebound (an increase in HBV DNA of 1 log or greater above nadir), which may then be followed by biochemical breakthrough (ALT elevation). All patients in the GLOBE registration trial underwent genotypic analysis at study entry and 165 of the 680 patients treated with telbivudine had HBV DNA > 1000 copies/mL at week 48 of treatment, 115 of whom were resequenced to identify genotypic mutations. The signature mutation for telbivudine resistance was reconfirmed as M204I. Forty six of these 115 patients had this "signature mutation." Thirty-two patients experienced virologic breakthrough at week 48, 28 of whom had the M204I mutation. Twenty-one patients with virologic breakthrough were then transitioned to adefovir salvage therapy (16 as follow-on monotherapy, 5 in combination with telbivudine), which generally resulted in improved liver enzyme levels and improved viral load (ie, decreased HBV DNA levels). Unfortunately, these patients were transitioned after clinical breakthrough. Data have suggested that virologic control is much easier to achieve when drug modifications are made prior to serum ALT elevation. Evaluation of the pharmacokinetic interactions between telbivudine and tenofovir, an anti-HIV nucleotide with potent anti-HBV activity, failed to reveal any significant drug-drug interaction, suggesting that tenofovir may also be an effective salvage option for patients who develop telbivudine resistance.
Preliminary cumulative resistance to telbivudine at week 92 was 21.8% in HBeAg-positive patients and 8.6% in HBeAg-negative patients. Again, resistance after 1 year was rare (1.5% in HBeAg-positive patients, and 0% in HBeAg-negative patients) if virus was suppressed to below 300 copies/mL at week 24 of therapy.
Role of Genotyping
The role played by "genotype" in the management of hepatitis B remains controversial. First, this term is often used to describe both the viral subtype (A,B,C,D, etc) as well as drug resistance mutations in the HBV DNA polymerase gene. Although previous studies suggest that the viral genotype may influence treatment response and clinical course, its utility in disease management remains obscure. However, the importance of drug resistance testing is rapidly manifesting, especially when treating a patient with suboptimal response to therapy. Baseline resistance genotype in a naive patient (pre-treatment) is more contentious because wild-type virus generally predominates even if mutations exists. However, Feeney and colleagues performed baseline resistance testing in 108 treatment-naive subjects and found that 14.8% of patients had preexisting lamivudine mutations, including 2 patients with acute hepatitis B. This finding is of obvious importance, because lamivudine resistance decreases the efficacy of all the other current nucleoside agents.
Drug Potency
Two studies presented during DDW 2007 focused on differences in drug potency. As highlighted above, early viral suppression is associated with decreased drug resistance, although the rapidity of viral suppression needed to avoid drug resistance may be different between compounds. On the basis of data presented at this meeting, treatment with the nucleoside analogs telbivudine or entecavir resulted in greater viral suppression in HBeAg-positive treatment-naive patients as compared with treatment with the nucleotide analog adefovir.
Special Populations: Chemoprophylaxis. Hepatitis B reactivation with chemotherapy is a well-recognized complication, often leading to significant morbidity and mortality. Two meta-analyses presented during this year's meeting confirmed the benefit of screening patients undergoing chemotherapy for HBV and the importance of HBV prophylaxis with lamivudine to prevent any untoward complications and to reduce overall related mortality in this setting.
Treatment Endpoints
HBsAg seroclearance is the goal of every antiviral therapeutic strategy; however, this endpoint does not fully eliminate the risk of developing liver disease-related complications. A retrospective literature review conducted by Retana and colleagues identified 1398 patients followed after HBsAg loss. The risk for liver complications did not decrease significantly. Predictably, those patients with cirrhosis or viral coinfection had a higher risk for hepatic complications, including liver cancer. This study emphasizes the importance of effective treatment prior to the onset of significant fibrosis.
Concluding Remarks
Our approach to the management of hepatitis B continues to evolve. Although much more research is warranted, we are gaining good insight regarding who to treat, when to treat, and with what to treat. Data presented at DDW 2007 underscored the growing problem of drug resistance and further added to our basic understanding of this complicated disease.
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