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HepB Forum : Unofficial Research Thread (URT) Tx info
I am reposting articles / summaries on the treatment management of chronic HepB. "cajim" located these articles which are quite informative. I thought about putting them on a seaprate Health Page but didn't think it was appropriate since we didn't write them.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Let's make this a sort of "Unofficial Research Thread" or "URT" for this type of information. Let's keep this URT free of comments. For comments, start a new thread indicating that it's in reference to URT.
We'll see how it goes.
Resistance Through 6 Years of Entecavir Treatment
Anna S. F. Lok, MD: To start our discussion, several studies presented at the 2009 European Association for the Study of the Liver (EASL) meeting focused on patients who had received multiple years of nucleos(t)ide analogue therapy, one of which provided an update on long-term resistance data for patients treated with entecavir. ETV-901 is a nonrandomized rollover followup study designed to evaluate long-term entecavir treatment of patients from 6 phase II and III clinical studies. Nucleos(t)ide-naive and lamivudine-refractory patients (those with continued viremia or confirmed resistance while on lamivudine) with chronic hepatitis B virus (HBV) infection who received > 12 weeks of continuous entecavir therapy in the previous trials were eligible for inclusion in ETV-901. Tenney and colleagues[1] reported on the cumulative probability of entecavir resistance through Year 6, identified by sequencing annually or at withdrawal from study or at any time if the patient had HBV DNA ≥ 300 copies/mL (~ 59 IU/mL) or virologic breakthrough (≥ 1 log10 IU/mL increase in HBV DNA from nadir) (Entecavir Resistance Rare in Nucleoside-Naive HBV Patients Through 6 Years). During the first year of ETV-901, 663 nucleoside-naive patients and 187 lamivudine-refractory patients were evaluable, but during the course of the follow-up, as with any long-term study of this kind, many patients discontinued treatment after achieving hepatitis B e antigen (HBeAg) seroconversion or failing to achieve a study-defined treatment response, in which case they were eligible to receive alternative therapies. As a result, only 99 patients who were nucleoside naive and 29 who were lamivudine refractory at initial enrollment were still being monitored on entecavir therapy in the ETV-901 study 6 years later. The cumulative rate of genotypic resistance to entecavir remained very low at 1.2% among nucleoside-naive patients by Year 6 of treatment. These results are extremely encouraging; this study represents the longest follow-up data available on nucleos(t)ide analogue therapy, and the initial very low rate of resistance has been maintained during a long-term treatment course.
Patrick Marcellin, MD: Results at 4 and 5 years have been presented previously and are now confirmed at 6 years. However, the number of patients is becoming ever smaller, so there is some limitation to the conclusions that can be drawn.
Anna S. F. Lok, MD: Indeed, one shortcoming of this study is the fact that only 99 of the
original 663 patients were still in the study at the time of the Year 6 analysis. The patients who withdrew because of failure to achieve an adequate response may have been those at the greatest risk of developing drug resistance, so the rate of resistance reported here may underestimate the rate that would be seen on an intent-to-treat basis. Moreover, a higher resistance rate could be seen in clinical practice than was reported in this study because patients are typically not monitored as closely in the clinic as in a clinical trial such as this, and some patients may be less motivated to adhere to treatment, resulting in higher resistance rates. Nonetheless, these data are very encouraging compared with the resistance data that have been reported for some of the other oral agents, such as lamivudine, adefovir, and telbivudine.
Maria Buti, MD: When assessing the extrapolation of these data to clinical practice, it is also important to note that the study population only includes patients who achieved undetectable HBV DNA (< 0.7 mEq/mL [~ 1.2 x 105 IU/mL]) at Year 2 but did not achieve HBeAg loss (for HBeAg-positive patients) or normalized alanine aminotransferase (ALT) (for HBeAg-negative patients). Patients who achieved HBV DNA suppression < 1.2 x 105 IU/mL and HBeAg loss (or ALT normalization) at Year 1 were allowed to discontinue therapy and were not included in this analysis. In addition, patients who were rolled over could have had up to a 35-day gap in treatment when transitioning to ETV-901. Because the ETV-901 study was blinded and included patients rolling over from both the entecavir and the lamivudine arms of the previous studies in treatment-naive and lamivudine-refractory patients, all patients initially received a combination of 100-mg lamivudine and 1-mg entecavir for up to 18-20 weeks before the protocol was amended and lamivudine was discontinued while entecavir was continued at 1 mg/day. In clinical practice, the approved dose for treatment-naive patients is 0.5 mg/day. It is not clear whether these factors might have influenced the resistance rates seen in the study population.
Anna S. F. Lok, MD: I agree that this study presents a best-case scenario and in clinical
practice it may be less likely that such a low resistance rate will be achieved. Nonetheless, the results are still very encouraging. Nearly all clinical studies have provided patients the option to modify therapy after some point, so unfortunately only some of the original lamivudine studies are providing a pure perspective on long-term outcomes with monotherapy in every single patient. For example, the ongoing long-term tenofovir trials Study 102 [2] and Study 103[3] permit the addition of emtricitabine at Week 72 for patients with detectable viremia, so the long-term results will not reflect strict
monotherapy.
Maria Buti, MD: Although these aspects of study design may hamper the generation of pure data sets, they also reflect the reality that optimal management of patients at high risk of resistance may require special approaches such as combination therapy, rather than continued treatment with a single agent that is not achieving optimal suppression.
Patrick Marcellin, MD: In summary, although it is important to note the limitations of this study, the key conclusion remains that entecavir is a highly effective drug with a very low resistance rate in treatment-naive patients.
Anna S. F. Lok, MD: Turning to the patients who were lamivudine refractory when they started entecavir, the resistance rate in these patients rose from 6% at the end of Year 1 to 57% at the end of Year 6. We should note that there was a much smaller number of lamivudine-refractory patients and of the 187 patients at Year 1, only 29 remained on study at the end of Year 6, so these resistance data are based on a very small number of patients. Nonetheless, the data are strong enough to indicate that entecavir monotherapy is not an optimal option for patients who failed to respond to previous lamivudine treatment. The investigators also reported on the patterns of entecavir-associated resistance mutations found over time in ETV-901. In previous studies, the mutations associated with entecavir resistance were located at amino acid positions 184, 202, and 250. No new mutations were identified at any other amino acid positions during 6 years. As a reminder, mutations at those 3 positions only confer entecavir resistance in the presence of the M204I/V ± L180M mutations.
Anna S. F. Lok, MD: To start our discussion, several studies presented at the 2009 European Association for the Study of the Liver (EASL) meeting focused on patients who had received multiple years of nucleos(t)ide analogue therapy, one of which provided an update on long-term resistance data for patients treated with entecavir. ETV-901 is a nonrandomized rollover followup study designed to evaluate long-term entecavir treatment of patients from 6 phase II and III clinical studies. Nucleos(t)ide-naive and lamivudine-refractory patients (those with continued viremia or confirmed resistance while on lamivudine) with chronic hepatitis B virus (HBV) infection who received > 12 weeks of continuous entecavir therapy in the previous trials were eligible for inclusion in ETV-901. Tenney and colleagues[1] reported on the cumulative probability of entecavir resistance through Year 6, identified by sequencing annually or at withdrawal from study or at any time if the patient had HBV DNA ≥ 300 copies/mL (~ 59 IU/mL) or virologic breakthrough (≥ 1 log10 IU/mL increase in HBV DNA from nadir) (Entecavir Resistance Rare in Nucleoside-Naive HBV Patients Through 6 Years). During the first year of ETV-901, 663 nucleoside-naive patients and 187 lamivudine-refractory patients were evaluable, but during the course of the follow-up, as with any long-term study of this kind, many patients discontinued treatment after achieving hepatitis B e antigen (HBeAg) seroconversion or failing to achieve a study-defined treatment response, in which case they were eligible to receive alternative therapies. As a result, only 99 patients who were nucleoside naive and 29 who were lamivudine refractory at initial enrollment were still being monitored on entecavir therapy in the ETV-901 study 6 years later. The cumulative rate of genotypic resistance to entecavir remained very low at 1.2% among nucleoside-naive patients by Year 6 of treatment. These results are extremely encouraging; this study represents the longest follow-up data available on nucleos(t)ide analogue therapy, and the initial very low rate of resistance has been maintained during a long-term treatment course.
Patrick Marcellin, MD: Results at 4 and 5 years have been presented previously and are now confirmed at 6 years. However, the number of patients is becoming ever smaller, so there is some limitation to the conclusions that can be drawn.
Anna S. F. Lok, MD: Indeed, one shortcoming of this study is the fact that only 99 of the
original 663 patients were still in the study at the time of the Year 6 analysis. The patients who withdrew because of failure to achieve an adequate response may have been those at the greatest risk of developing drug resistance, so the rate of resistance reported here may underestimate the rate that would be seen on an intent-to-treat basis. Moreover, a higher resistance rate could be seen in clinical practice than was reported in this study because patients are typically not monitored as closely in the clinic as in a clinical trial such as this, and some patients may be less motivated to adhere to treatment, resulting in higher resistance rates. Nonetheless, these data are very encouraging compared with the resistance data that have been reported for some of the other oral agents, such as lamivudine, adefovir, and telbivudine.
Maria Buti, MD: When assessing the extrapolation of these data to clinical practice, it is also important to note that the study population only includes patients who achieved undetectable HBV DNA (< 0.7 mEq/mL [~ 1.2 x 105 IU/mL]) at Year 2 but did not achieve HBeAg loss (for HBeAg-positive patients) or normalized alanine aminotransferase (ALT) (for HBeAg-negative patients). Patients who achieved HBV DNA suppression < 1.2 x 105 IU/mL and HBeAg loss (or ALT normalization) at Year 1 were allowed to discontinue therapy and were not included in this analysis. In addition, patients who were rolled over could have had up to a 35-day gap in treatment when transitioning to ETV-901. Because the ETV-901 study was blinded and included patients rolling over from both the entecavir and the lamivudine arms of the previous studies in treatment-naive and lamivudine-refractory patients, all patients initially received a combination of 100-mg lamivudine and 1-mg entecavir for up to 18-20 weeks before the protocol was amended and lamivudine was discontinued while entecavir was continued at 1 mg/day. In clinical practice, the approved dose for treatment-naive patients is 0.5 mg/day. It is not clear whether these factors might have influenced the resistance rates seen in the study population.
Anna S. F. Lok, MD: I agree that this study presents a best-case scenario and in clinical
practice it may be less likely that such a low resistance rate will be achieved. Nonetheless, the results are still very encouraging. Nearly all clinical studies have provided patients the option to modify therapy after some point, so unfortunately only some of the original lamivudine studies are providing a pure perspective on long-term outcomes with monotherapy in every single patient. For example, the ongoing long-term tenofovir trials Study 102 [2] and Study 103[3] permit the addition of emtricitabine at Week 72 for patients with detectable viremia, so the long-term results will not reflect strict
monotherapy.
Maria Buti, MD: Although these aspects of study design may hamper the generation of pure data sets, they also reflect the reality that optimal management of patients at high risk of resistance may require special approaches such as combination therapy, rather than continued treatment with a single agent that is not achieving optimal suppression.
Patrick Marcellin, MD: In summary, although it is important to note the limitations of this study, the key conclusion remains that entecavir is a highly effective drug with a very low resistance rate in treatment-naive patients.
Anna S. F. Lok, MD: Turning to the patients who were lamivudine refractory when they started entecavir, the resistance rate in these patients rose from 6% at the end of Year 1 to 57% at the end of Year 6. We should note that there was a much smaller number of lamivudine-refractory patients and of the 187 patients at Year 1, only 29 remained on study at the end of Year 6, so these resistance data are based on a very small number of patients. Nonetheless, the data are strong enough to indicate that entecavir monotherapy is not an optimal option for patients who failed to respond to previous lamivudine treatment. The investigators also reported on the patterns of entecavir-associated resistance mutations found over time in ETV-901. In previous studies, the mutations associated with entecavir resistance were located at amino acid positions 184, 202, and 250. No new mutations were identified at any other amino acid positions during 6 years. As a reminder, mutations at those 3 positions only confer entecavir resistance in the presence of the M204I/V ± L180M mutations.
Patients in the Immune-Tolerance Phase Who Are Younger Than 30 Years Case 7
A 27-year-old Chinese woman was found to be HBsAg positive during a checkup. Subsequent tests showed ALT 18 IU/L, HBeAg-positive disease, and HBV DNA 5.6 x 109 IU/mL. Her mother and 1 brother also tested positive for HBsAg.
Discussion
This patient fits the profile of a patient in the immune-tolerance phase of HBV infection, and treatment is not recommended by the AASLD Practice Guidelines at this time because the likelihood of significant liver injury at this stage is low.[1] An additional reason for not recommending treatment is the low rate of treatment-related HBeAg seroconversion among patients with normal pretreatment ALT.[27] Recent studies showed that up to 50% of HBV carriers with normal ALT had significant liver disease on biopsies and HBV carriers with ALT 0.5-1.0 x ULN had higher rates of liver-related deaths than those with ALT 40 years.[30,31] Similarly, studies reporting abnormal liver histology in patients with normal ALT found that moderate to severe inflammation or fibrosis was mainly observed in patients older than 40 years of age.[33] Studies that focused on patients in the immune-tolerance phase showed that 33% to 49% had stage 0 fibrosis whereas the remainder had stage I fibrosis.[34,35] In one study, follow-up biopsies after a mean of 5 years revealed no change in fibrosis score in 41 out of 48 patients who remained in the immune-tolerance phase.[35] Another study found that only 5% of patients progressed to cirrhosis and none to HCC during a follow-up period of 10.5 years.[36] Finally, available treatments have not been shown to increase the rate of HBeAg seroconversion in patients with normal ALT, based on cutoffs established by diagnostic laboratories.[27] Given the need for long durations of therapy, the benign outcome in the shortterm future for the vast majority of patients in the immune-tolerance phase, and the possibility of a benign long-term outcome in those patients who achieve HBeAg seroconversion early in life, treatment is not recommended for young patients (younger than 35 years of age) in the immune-tolerance phase.
Cases Where The Treatment Decision Must Be Individualized
Patients in the Immune-Tolerance Phase Who Are Older Than 40 Years
Case 8
A 45-year-old Korean man was found to be HBsAg positive. Blood test results revealed ALT 29 IU/L at initial testing, and he was HBeAg positive with an HBV DNA level of 5.4 x 107 IU/mL. Subsequent testing revealed ALT 24 IU/L 6 months later
Discussion
This patient fits the profile of a patient in the immune-tolerance phase as defined by the AASLD Practice Guidelines.[1] Although this patient had a lower serum HBV DNA level than the patient in Case 7, treatment should be considered because of this patient’s older age. Recent studies showed that although significant liver disease is rarely found among young patients in the immune-tolerance phase, delayed HBeAg seroconversion after the age of 40 years and persistently high serum HBV DNA levels after 4 decades of infection are Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 12 associated with increased risks of adverse outcomes.[37] A liver biopsy may help in determining the urgency of treatment.
Patients With a Strong Family History of HCC
Case 9
A 30-year-old Korean woman was found to be HBsAg positive after her 37-year-old brother was recently diagnosed with HCC. Her mother and all her siblings were HBV carriers and 1 of her maternal uncles also had HCC that was diagnosed when he was 58 years of age. Blood test results showed the patient to be HBeAg positive with serum ALT IU/L and HBV DNA 7.4 x 107 IU/mL. Repeat tests after 4 and 12 months showed ALT 15 IU/L and 20 IU/L, respectively.
Discussion
Based on AASLD Practice Guideline definitions, this patient is in the immune-tolerance phase.[1] As a result and given her young age, treatment is not indicated at this time. There have been several reports of familial clustering of HCC, but it is unclear whether this is related to genetic or environmental factors or a more virulent strain of HBV.[38] It is understandable that this patient would be very concerned about her risk of HCC. Some experts advocate treating all chronic hepatitis B patients with a strong family history of HCC, regardless of their clinical and virological profile. However, it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent HCC and there is no model to predict the risk of HCC in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future.
Patients With Borderline High or Fluctuating Serum HBV DNA and/or ALT
Case 10
A 45-year-old black man was found to have mildly elevated ALT. Serial test results showed ALT 25 IU/L, 64 IU/L, and 43 IU/L. Other test results showed HBeAg-negative, HBV DNA 4500 IU/mL in an initial test, and HBV DNA 31,000 IU/mL in a repeat test.
Discussion
This patient appeared to be in the inactive carrier state at initial presentation, but subsequent tests showed continued mildly elevated ALT and increasing serum HBV DNA. Because of the need for many years—if not lifelong—treatment, the AASLD Practice Guidelines recommend liver biopsy to ascertain the presence of histologic damage, with treatment recommended for those with moderate to severe inflammation and/or significant fibrosis.[1] A longer period of observation before biopsy might be appropriate if the patient was younger (younger than 30 years of age) with similar characteristics and history, particularly if the patient is reluctant to undergo liver biopsy.
Summary: Implications for Clinical Practice
• Currently available HBV treatments suppress but do not eradicate HBV.
• Most patients require long durations of treatment to derive continued clinical benefit.
• Treatment may be required for years, decades, or the duration of the patient’s life. Therefore, the decision to initiate treatment must balance the long-term benefits vs the long-term risks.
• Treatment is indicated if the risk of liver-related morbidity and mortality in the near future (within 5-10 years) and the likelihood of achieving maintained viral suppression during continued treatment are both high.
• Treatment is also indicated if the risk of liver-related morbidity and mortality in the foreseeable future of 10-20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are both high (Table).
• Treatment is not indicated if the risk of liver-related morbidity and mortality in the next 20 years and/or the likelihood of achieving sustained viral suppression after a defined course of treatment are low.
A 27-year-old Chinese woman was found to be HBsAg positive during a checkup. Subsequent tests showed ALT 18 IU/L, HBeAg-positive disease, and HBV DNA 5.6 x 109 IU/mL. Her mother and 1 brother also tested positive for HBsAg.
Discussion
This patient fits the profile of a patient in the immune-tolerance phase of HBV infection, and treatment is not recommended by the AASLD Practice Guidelines at this time because the likelihood of significant liver injury at this stage is low.[1] An additional reason for not recommending treatment is the low rate of treatment-related HBeAg seroconversion among patients with normal pretreatment ALT.[27] Recent studies showed that up to 50% of HBV carriers with normal ALT had significant liver disease on biopsies and HBV carriers with ALT 0.5-1.0 x ULN had higher rates of liver-related deaths than those with ALT 40 years.[30,31] Similarly, studies reporting abnormal liver histology in patients with normal ALT found that moderate to severe inflammation or fibrosis was mainly observed in patients older than 40 years of age.[33] Studies that focused on patients in the immune-tolerance phase showed that 33% to 49% had stage 0 fibrosis whereas the remainder had stage I fibrosis.[34,35] In one study, follow-up biopsies after a mean of 5 years revealed no change in fibrosis score in 41 out of 48 patients who remained in the immune-tolerance phase.[35] Another study found that only 5% of patients progressed to cirrhosis and none to HCC during a follow-up period of 10.5 years.[36] Finally, available treatments have not been shown to increase the rate of HBeAg seroconversion in patients with normal ALT, based on cutoffs established by diagnostic laboratories.[27] Given the need for long durations of therapy, the benign outcome in the shortterm future for the vast majority of patients in the immune-tolerance phase, and the possibility of a benign long-term outcome in those patients who achieve HBeAg seroconversion early in life, treatment is not recommended for young patients (younger than 35 years of age) in the immune-tolerance phase.
Cases Where The Treatment Decision Must Be Individualized
Patients in the Immune-Tolerance Phase Who Are Older Than 40 Years
Case 8
A 45-year-old Korean man was found to be HBsAg positive. Blood test results revealed ALT 29 IU/L at initial testing, and he was HBeAg positive with an HBV DNA level of 5.4 x 107 IU/mL. Subsequent testing revealed ALT 24 IU/L 6 months later
Discussion
This patient fits the profile of a patient in the immune-tolerance phase as defined by the AASLD Practice Guidelines.[1] Although this patient had a lower serum HBV DNA level than the patient in Case 7, treatment should be considered because of this patient’s older age. Recent studies showed that although significant liver disease is rarely found among young patients in the immune-tolerance phase, delayed HBeAg seroconversion after the age of 40 years and persistently high serum HBV DNA levels after 4 decades of infection are Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 12 associated with increased risks of adverse outcomes.[37] A liver biopsy may help in determining the urgency of treatment.
Patients With a Strong Family History of HCC
Case 9
A 30-year-old Korean woman was found to be HBsAg positive after her 37-year-old brother was recently diagnosed with HCC. Her mother and all her siblings were HBV carriers and 1 of her maternal uncles also had HCC that was diagnosed when he was 58 years of age. Blood test results showed the patient to be HBeAg positive with serum ALT IU/L and HBV DNA 7.4 x 107 IU/mL. Repeat tests after 4 and 12 months showed ALT 15 IU/L and 20 IU/L, respectively.
Discussion
Based on AASLD Practice Guideline definitions, this patient is in the immune-tolerance phase.[1] As a result and given her young age, treatment is not indicated at this time. There have been several reports of familial clustering of HCC, but it is unclear whether this is related to genetic or environmental factors or a more virulent strain of HBV.[38] It is understandable that this patient would be very concerned about her risk of HCC. Some experts advocate treating all chronic hepatitis B patients with a strong family history of HCC, regardless of their clinical and virological profile. However, it must be emphasized that there are no data to support the hypothesis that antiviral therapy can completely prevent HCC and there is no model to predict the risk of HCC in this patient. The potential benefits of antiviral therapy must be balanced against the risks of years of antiviral therapy that may indeed be lifelong, and those potential risks must be weighed particularly carefully for a young woman who might be planning to start a family in the near future.
Patients With Borderline High or Fluctuating Serum HBV DNA and/or ALT
Case 10
A 45-year-old black man was found to have mildly elevated ALT. Serial test results showed ALT 25 IU/L, 64 IU/L, and 43 IU/L. Other test results showed HBeAg-negative, HBV DNA 4500 IU/mL in an initial test, and HBV DNA 31,000 IU/mL in a repeat test.
Discussion
This patient appeared to be in the inactive carrier state at initial presentation, but subsequent tests showed continued mildly elevated ALT and increasing serum HBV DNA. Because of the need for many years—if not lifelong—treatment, the AASLD Practice Guidelines recommend liver biopsy to ascertain the presence of histologic damage, with treatment recommended for those with moderate to severe inflammation and/or significant fibrosis.[1] A longer period of observation before biopsy might be appropriate if the patient was younger (younger than 30 years of age) with similar characteristics and history, particularly if the patient is reluctant to undergo liver biopsy.
Summary: Implications for Clinical Practice
• Currently available HBV treatments suppress but do not eradicate HBV.
• Most patients require long durations of treatment to derive continued clinical benefit.
• Treatment may be required for years, decades, or the duration of the patient’s life. Therefore, the decision to initiate treatment must balance the long-term benefits vs the long-term risks.
• Treatment is indicated if the risk of liver-related morbidity and mortality in the near future (within 5-10 years) and the likelihood of achieving maintained viral suppression during continued treatment are both high.
• Treatment is also indicated if the risk of liver-related morbidity and mortality in the foreseeable future of 10-20 years and the likelihood of achieving sustained viral suppression after a defined course of treatment are both high (Table).
• Treatment is not indicated if the risk of liver-related morbidity and mortality in the next 20 years and/or the likelihood of achieving sustained viral suppression after a defined course of treatment are low.
Discussion
It is important to determine if this patient is experiencing acute hepatitis B or an exacerbation of chronic hepatitis B. Antiviral treatment is not necessary and provides no clinical benefit in the vast majority of patients with acute hepatitis B infection; > 95% of immunocompetent adults with acute hepatitis B recover spontaneously.[1,16] Differentiating severe exacerbation of chronic hepatitis B from acute hepatitis B can be difficult in persons who are not known to be carriers because IgM anti-HBc can be positive during severe exacerbations. Although ALT flares are frequently observed in patients with chronic HBV infection and may be a sign of a vigorous host immune response that may result in successful HBeAg seroconversion, ALT flares associated with an increase in bilirubin or INR are ominous. Serum HBV DNA levels are often low and may at times be undetectable in patients presenting with ALT flares, particularly in patients who present after the peak of the ALT flare. Several case series have Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 9 found that antiviral therapy in patients with severe exacerbation of chronic hepatitis B improves survival compared with untreated historical controls.[17,18] Although data from randomized controlled trials are not available, antiviral therapy should be instituted for patients with icteric ALT flares or those resulting in derangements in liver synthetic function to prevent progression to hepatic failure and to minimize irreversible liver damage.[1] Patients with mild exacerbations—defined as normal bilirubin and INR, ALT 700,000 Eq/mL.[14] In this trial, the impact of antiviral therapy on HCC alone was only marginally significant (hazard ratio: 0.49; P = .047). Whether antiviral therapy will prevent disease progression in patients with advanced fibrosis or cirrhosis and lower serum HBV DNA levels is unclear. The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines recommended an HBV DNA cutoff of > 2000 IU/mL for initiating treatment in patients with compensated cirrhosis and close monitoring of those with HBV DNA levels 20,000 IU/mL and ALT > 2 x ULN followed by treatment if no spontaneous HBeAg loss occurs.[1] The guidelines also suggest that a pretreatment liver biopsy in compensated patients is useful in assessing the degree of inflammation and the extent of fibrosis but is not a prerequisite for initiating treatment.
Patients With HBeAg-Negative Chronic Hepatitis
Case 5
A 62-year-old Greek woman presented during routine examination with abnormal liver enzymes. Blood test results showed ALT 83 IU/L, and upon further testing, the patient was found to be HBeAg negative with HBV DNA 69,000 IU/mL. Liver biopsy showed mild inflammation with a histologic activity index of 5 and early bridging indicated by an Ishak fibrosis score of 3.
Discussion
This patient meets AASLD Practice Guidelines criteria for initiation of treatment for HBeAgnegative chronic hepatitis.[1] Contrary to HBeAg-positive patients, spontaneous sustained remission is extremely rare among HBeAg-negative patients; therefore, a short period of observation before initiating treatment is not required when there is biochemical and histologic evidence of significant liver injury.[1]
Clear-cut Cases in Which Treatment Can Be Deferred
Inactive HBV Carriers
Case 6
A 38-year-old Vietnamese woman was found to be hepatitis B surface antigen (HBsAg) positive during routine checkup. She has no previous history of hepatitis or jaundice. Blood test results showed serum ALT 20 IU/L, HBeAg-negative disease, and HBV DNA 50 IU/mL.
Discussion
After spontaneous HBeAg seroconversion, 67% to 80% of patients become inactive carriers.[20-22] This patient meets the criteria of an inactive carrier; therefore, treatment is not indicated at this time.[1] However, given the fluctuating nature of HBeAg-negative chronic hepatitis, follow-up testing of ALT and HBV DNA levels at 1- to 3-month intervals during the first year and at 6-month intervals thereafter is needed to ascertain that this patient is indeed in the inactive carrier state.[23,24] Most inactive carriers have persistent or intermittent detection of serum HBV DNA, albeit at low levels.[25] Nonetheless, studies are lacking to show that antiviral treatment during this period will improve outcome or prevent subsequent HBV reactivation. Several long-term follow-up studies showed that the prognosis of inactive carriers is favorable, especially if the inactive carrier state is reached early. One study of 296 Italian HBsAg-positive blood donors reported no increase in mortality and no hepatic decompensation after 23 years.[26] All inactive carriers should continue to be monitored because reactivation of HBV replication can occur after varying durations in the inactive carrier state. Longitudinal studies of adult inactive carriers reported that 15% to 24% developed HBeAg-negative chronic hepatitis and 1% to 17% had sustained reversion back to HBeAg positivity.[21]
It is important to determine if this patient is experiencing acute hepatitis B or an exacerbation of chronic hepatitis B. Antiviral treatment is not necessary and provides no clinical benefit in the vast majority of patients with acute hepatitis B infection; > 95% of immunocompetent adults with acute hepatitis B recover spontaneously.[1,16] Differentiating severe exacerbation of chronic hepatitis B from acute hepatitis B can be difficult in persons who are not known to be carriers because IgM anti-HBc can be positive during severe exacerbations. Although ALT flares are frequently observed in patients with chronic HBV infection and may be a sign of a vigorous host immune response that may result in successful HBeAg seroconversion, ALT flares associated with an increase in bilirubin or INR are ominous. Serum HBV DNA levels are often low and may at times be undetectable in patients presenting with ALT flares, particularly in patients who present after the peak of the ALT flare. Several case series have Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 9 found that antiviral therapy in patients with severe exacerbation of chronic hepatitis B improves survival compared with untreated historical controls.[17,18] Although data from randomized controlled trials are not available, antiviral therapy should be instituted for patients with icteric ALT flares or those resulting in derangements in liver synthetic function to prevent progression to hepatic failure and to minimize irreversible liver damage.[1] Patients with mild exacerbations—defined as normal bilirubin and INR, ALT 700,000 Eq/mL.[14] In this trial, the impact of antiviral therapy on HCC alone was only marginally significant (hazard ratio: 0.49; P = .047). Whether antiviral therapy will prevent disease progression in patients with advanced fibrosis or cirrhosis and lower serum HBV DNA levels is unclear. The American Association for the Study of Liver Diseases (AASLD) Practice Guidelines recommended an HBV DNA cutoff of > 2000 IU/mL for initiating treatment in patients with compensated cirrhosis and close monitoring of those with HBV DNA levels 20,000 IU/mL and ALT > 2 x ULN followed by treatment if no spontaneous HBeAg loss occurs.[1] The guidelines also suggest that a pretreatment liver biopsy in compensated patients is useful in assessing the degree of inflammation and the extent of fibrosis but is not a prerequisite for initiating treatment.
Patients With HBeAg-Negative Chronic Hepatitis
Case 5
A 62-year-old Greek woman presented during routine examination with abnormal liver enzymes. Blood test results showed ALT 83 IU/L, and upon further testing, the patient was found to be HBeAg negative with HBV DNA 69,000 IU/mL. Liver biopsy showed mild inflammation with a histologic activity index of 5 and early bridging indicated by an Ishak fibrosis score of 3.
Discussion
This patient meets AASLD Practice Guidelines criteria for initiation of treatment for HBeAgnegative chronic hepatitis.[1] Contrary to HBeAg-positive patients, spontaneous sustained remission is extremely rare among HBeAg-negative patients; therefore, a short period of observation before initiating treatment is not required when there is biochemical and histologic evidence of significant liver injury.[1]
Clear-cut Cases in Which Treatment Can Be Deferred
Inactive HBV Carriers
Case 6
A 38-year-old Vietnamese woman was found to be hepatitis B surface antigen (HBsAg) positive during routine checkup. She has no previous history of hepatitis or jaundice. Blood test results showed serum ALT 20 IU/L, HBeAg-negative disease, and HBV DNA 50 IU/mL.
Discussion
After spontaneous HBeAg seroconversion, 67% to 80% of patients become inactive carriers.[20-22] This patient meets the criteria of an inactive carrier; therefore, treatment is not indicated at this time.[1] However, given the fluctuating nature of HBeAg-negative chronic hepatitis, follow-up testing of ALT and HBV DNA levels at 1- to 3-month intervals during the first year and at 6-month intervals thereafter is needed to ascertain that this patient is indeed in the inactive carrier state.[23,24] Most inactive carriers have persistent or intermittent detection of serum HBV DNA, albeit at low levels.[25] Nonetheless, studies are lacking to show that antiviral treatment during this period will improve outcome or prevent subsequent HBV reactivation. Several long-term follow-up studies showed that the prognosis of inactive carriers is favorable, especially if the inactive carrier state is reached early. One study of 296 Italian HBsAg-positive blood donors reported no increase in mortality and no hepatic decompensation after 23 years.[26] All inactive carriers should continue to be monitored because reactivation of HBV replication can occur after varying durations in the inactive carrier state. Longitudinal studies of adult inactive carriers reported that 15% to 24% developed HBeAg-negative chronic hepatitis and 1% to 17% had sustained reversion back to HBeAg positivity.[21]
Therapy of Chronic Hepatitis B: Who to Treat and When to Treat? A Case-Based Discussion , 2008
Introduction
Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 6 approved therapies, including 2 formulations of interferon alfa (standard interferon alfa and peginterferon alfa) and 4 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, and telbivudine). It is anticipated that another nucleotide analogue, tenofovir, may be approved in the near future. Therefore, many treatment options are available that are effective in suppressing hepatitis B virus (HBV) replication, can be administered orally, and have excellent safety profiles. This has prompted some experts to recommend that all HBV carriers should receive treatment because chronic HBV infection can progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, current treatments do not eradicate HBV (see “Can Hepatitis B Be Cured?” by Marc G. Ghany, MD). Therefore, most patients require long durations of treatment, and in many instances, life-long treatment is required to maintain viral suppression. Sustained viral suppression, in turn, is required to achieve continued clinical benefit and to prevent hepatitis flares resulting from virologic relapse associated with the withdrawal of treatment. Not all HBV carriers will experience adverse consequences of chronic HBV infection, and for those individuals who do experience such complications, they may not occur until years or decades later. Furthermore, host immune response can result in spontaneous remission in some patients, which can at times be long lasting. Therefore, until a safe and affordable “cure” for hepatitis B is available, it is prudent to assess the long-term benefits vs long-term risks before recommending treatment (Figure 1).
When evaluating the benefits associated with treatment, one must take into consideration not only on-treatment viral suppression but also the durability of viral suppression after treatment is discontinued, the ability to maintain viral suppression during continued treatment, and most importantly, the impact on liver disease progression and HCC development. Risks associated with treatment include adverse effects, potential development of drug resistance, and costs. Interferon alfa is associated with a wide spectrum of adverse events.[1] Nucleos(t)ide analogues are generally well tolerated. However, adefovir has been associated with a low rate of nephrotoxicity,[2,3] and telbivudine has been reported to be associated with rare cases of myopathy and peripheral neuropathy.[4] Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 7 Recognition that the natural course of chronic HBV infection involves different phases with marked variations in HBV replication and activity of liver disease over time has shifted the paradigm in hepatitis B treatment from “who to treat” to “when to treat” (Figure 2). Therefore, all persons with chronic hepatitis B are potential treatment candidates. A patient who is not a treatment candidate at the time of presentation may become a treatment candidate during the course of follow-up if serum HBV DNA or alanine aminotransferase (ALT) levels increase or if there is clinical evidence of hepatic decompensation. For this reason, all patients who are not considered treatment candidates at presentation should be monitored and treatment initiated later if indications arise.
The decision of whether to treat now or to defer treatment hinges on 3 key questions: 1) How active or advanced is the liver disease now? 2) What is the risk of progression to cirrhosis, hepatic decompensation, or HCC in the next 10-20 years? 3) What is the likelihood that clinical benefit can be maintained after a finite course of treatment, for example, 3-5 years? In this review, examples are presented of clear-cut scenarios in which treatment should be initiated, clear-cut scenarios in which treatment can be deferred, and debatable scenarios in which the decision to treat should be individualized. Moreover, the rationale for recommending immediate treatment vs deferral of treatment is discussed for each case. The choice of treatment and the endpoints of therapy are covered in “Therapy of Chronic Hepatitis B: What to Choose, When to Stop, and When to Change” by Ira M. Jacobson, MD.
Clear-cut Cases in Which Treatment Should Be Initiated
Patients With Detectable Serum HBV DNA and Hepatic Decompensation
Case 1
A 58-year-old white man presented with jaundice and ascites for 2 weeks. Blood test results showed HBV DNA 7000 IU/mL, ALT 38 IU/L (normal < 40 IU/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) of prothrombin time of 1.6.
Discussion
Although the serum HBV DNA level is not very high in this patient, nucleos(t)ide therapy should be initiated in this case. Interferon alfa–based treatment is contraindicated in patients with decompensated cirrhosis because of high rates of treatment-associated adverse events.[5,6] However, several studies have shown that lamivudine is effective in stabilizing the liver disease in these patients.[7-9] This may allow patients to undergo liver transplantation,[10,11] or in some cases reversal of liver failure may allow patients to be removed from the transplant waiting list.[12,13] It should be emphasized that although viral suppression can be evident within 4 weeks of antiviral therapy, clinical benefit takes 3-6 months to be apparent. Therefore, all patients who present with hepatic decompensation should be evaluated for liver transplantation.[11] Furthermore, HCC surveillance should be continued as HCC has been reported even in patients in whom HBV DNA had been suppressed.[8,14] For patients who proceed to transplantation, viral suppression before transplantation can decrease the risk of HBV reinfection after transplantation. In addition, antiviral therapy should be continued posttransplantation, and the combination of hepatitis B immune globulin and nucleos(t)ide analogues such as lamivudine and adefovir have significantly improved patient outcomes.[15] Although most of these data are based on studies of lamivudine therapy, it is reasonable to assume that other nucleos(t)ide analogues will provide the same benefits.
Patients With Severe Hepatitis Flare
Case 2
A 41-year-old Chinese man presented with a 3-week history of fatigue. Blood test results showed ALT 725 IU/L, total bilirubin 1.7 mg/dL, INR 1.2, platelet count 145,000/mm3, HBeAgpositive, and HBV DNA 64,000 IU/mL. Repeat blood tests 1 week later showed ALT 650 IU/L, total bilirubin 2.1 mg/dL, INR 1.3, and IgM antibodies to hepatitis B core antigen (anti-HBc) positive.
Introduction
Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Currently, there are 6 approved therapies, including 2 formulations of interferon alfa (standard interferon alfa and peginterferon alfa) and 4 nucleos(t)ide analogues (lamivudine, adefovir, entecavir, and telbivudine). It is anticipated that another nucleotide analogue, tenofovir, may be approved in the near future. Therefore, many treatment options are available that are effective in suppressing hepatitis B virus (HBV) replication, can be administered orally, and have excellent safety profiles. This has prompted some experts to recommend that all HBV carriers should receive treatment because chronic HBV infection can progress to cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC). However, current treatments do not eradicate HBV (see “Can Hepatitis B Be Cured?” by Marc G. Ghany, MD). Therefore, most patients require long durations of treatment, and in many instances, life-long treatment is required to maintain viral suppression. Sustained viral suppression, in turn, is required to achieve continued clinical benefit and to prevent hepatitis flares resulting from virologic relapse associated with the withdrawal of treatment. Not all HBV carriers will experience adverse consequences of chronic HBV infection, and for those individuals who do experience such complications, they may not occur until years or decades later. Furthermore, host immune response can result in spontaneous remission in some patients, which can at times be long lasting. Therefore, until a safe and affordable “cure” for hepatitis B is available, it is prudent to assess the long-term benefits vs long-term risks before recommending treatment (Figure 1).
When evaluating the benefits associated with treatment, one must take into consideration not only on-treatment viral suppression but also the durability of viral suppression after treatment is discontinued, the ability to maintain viral suppression during continued treatment, and most importantly, the impact on liver disease progression and HCC development. Risks associated with treatment include adverse effects, potential development of drug resistance, and costs. Interferon alfa is associated with a wide spectrum of adverse events.[1] Nucleos(t)ide analogues are generally well tolerated. However, adefovir has been associated with a low rate of nephrotoxicity,[2,3] and telbivudine has been reported to be associated with rare cases of myopathy and peripheral neuropathy.[4] Copyright © 2008 Clinical Care Options, LLC. All rights reserved. 7 Recognition that the natural course of chronic HBV infection involves different phases with marked variations in HBV replication and activity of liver disease over time has shifted the paradigm in hepatitis B treatment from “who to treat” to “when to treat” (Figure 2). Therefore, all persons with chronic hepatitis B are potential treatment candidates. A patient who is not a treatment candidate at the time of presentation may become a treatment candidate during the course of follow-up if serum HBV DNA or alanine aminotransferase (ALT) levels increase or if there is clinical evidence of hepatic decompensation. For this reason, all patients who are not considered treatment candidates at presentation should be monitored and treatment initiated later if indications arise.
The decision of whether to treat now or to defer treatment hinges on 3 key questions: 1) How active or advanced is the liver disease now? 2) What is the risk of progression to cirrhosis, hepatic decompensation, or HCC in the next 10-20 years? 3) What is the likelihood that clinical benefit can be maintained after a finite course of treatment, for example, 3-5 years? In this review, examples are presented of clear-cut scenarios in which treatment should be initiated, clear-cut scenarios in which treatment can be deferred, and debatable scenarios in which the decision to treat should be individualized. Moreover, the rationale for recommending immediate treatment vs deferral of treatment is discussed for each case. The choice of treatment and the endpoints of therapy are covered in “Therapy of Chronic Hepatitis B: What to Choose, When to Stop, and When to Change” by Ira M. Jacobson, MD.
Clear-cut Cases in Which Treatment Should Be Initiated
Patients With Detectable Serum HBV DNA and Hepatic Decompensation
Case 1
A 58-year-old white man presented with jaundice and ascites for 2 weeks. Blood test results showed HBV DNA 7000 IU/mL, ALT 38 IU/L (normal < 40 IU/L), total bilirubin 3.1 mg/dL, and international normalized ratio (INR) of prothrombin time of 1.6.
Discussion
Although the serum HBV DNA level is not very high in this patient, nucleos(t)ide therapy should be initiated in this case. Interferon alfa–based treatment is contraindicated in patients with decompensated cirrhosis because of high rates of treatment-associated adverse events.[5,6] However, several studies have shown that lamivudine is effective in stabilizing the liver disease in these patients.[7-9] This may allow patients to undergo liver transplantation,[10,11] or in some cases reversal of liver failure may allow patients to be removed from the transplant waiting list.[12,13] It should be emphasized that although viral suppression can be evident within 4 weeks of antiviral therapy, clinical benefit takes 3-6 months to be apparent. Therefore, all patients who present with hepatic decompensation should be evaluated for liver transplantation.[11] Furthermore, HCC surveillance should be continued as HCC has been reported even in patients in whom HBV DNA had been suppressed.[8,14] For patients who proceed to transplantation, viral suppression before transplantation can decrease the risk of HBV reinfection after transplantation. In addition, antiviral therapy should be continued posttransplantation, and the combination of hepatitis B immune globulin and nucleos(t)ide analogues such as lamivudine and adefovir have significantly improved patient outcomes.[15] Although most of these data are based on studies of lamivudine therapy, it is reasonable to assume that other nucleos(t)ide analogues will provide the same benefits.
Patients With Severe Hepatitis Flare
Case 2
A 41-year-old Chinese man presented with a 3-week history of fatigue. Blood test results showed ALT 725 IU/L, total bilirubin 1.7 mg/dL, INR 1.2, platelet count 145,000/mm3, HBeAgpositive, and HBV DNA 64,000 IU/mL. Repeat blood tests 1 week later showed ALT 650 IU/L, total bilirubin 2.1 mg/dL, INR 1.3, and IgM antibodies to hepatitis B core antigen (anti-HBc) positive.
Norah Terrault, MD, MPH: Treatment of cirrhotics is associated with clinical benefits such as preventing progression to decompensation, but the benefit in terms of cancer reduction is uncertain. These patients clearly should continue to be monitored for hepatocellular carcinoma.
Patrick Marcellin, MD: We do not know well the mechanisms responsible for the occurrence of hepatocellular carcinoma in cirrhotic patients. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the “precancer” cirrhotic lesions and persistent HBVinfection in the liver might explain the continuing risk for hepatocellular carcinoma. Largecohort studies with long follow-up are needed to determine the magnitude of the risk and for how long it persists.
Long-term Entecavir in Chinese Patients With Lamivudine-Refractory HBV
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Yao and colleagues[29] evaluated the long-term efficacy of entecavir monotherapy in 138Chinese patients with lamivudine-refractory chronic hepatitis B who enrolled in the ETV-056and ETV-050 studies (Increasing Rates of Virologic Suppression Through Year 3 of Entecavir Treatment in Chinese Cohort With Lamivudine Resistance). In ETV-056, patients received 12weeks of entecavir 1 mg daily or placebo followed by 36 weeks of open-label entecavir 1 mgdaily. A total of 141 patients from ETV-056 rolled over into ETV-050 and continued entecavir1 mg daily. These patients were relatively young (mean age: 35 years), 76% were male with a moderately high HBV DNA (8.78 log10 copies/mL), and 90% were HBeAg positive. In this study, the proportion of patients achieving undetectable HBV DNA increased over time, from 30% at Year 1 to 47% at Year 2 and 55% at Year 3. This contrasts with findings from thepivotal entecavir studies that showed an increasing rate of HBV DNA negativity for the first 2years in lamivudine-refractory patients, followed by a decrease in rates of undetectable HBVDNA by the third year along with the emergence of entecavir resistance (Assessment at threeyears shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients).[30]In addition, there was a fairly acceptable rate of cumulative HBeAg loss (11%, 13%, and 17%at Years 1, 2, and 3, respectively) and cumulative HBeAg seroconversion (7%, 11%, and12% at Years 1, 2, and 3). By contrast, however, the proportion of patients with ALT ≤ 1 xupper limit of normal (ULN) decreased from 85% at Year 1 to 65% at Year 3.Although entecavir monotherapy is approved for use in lamivudine-experienced patients, many experts feel that there are more effective treatment options for this patient population.
Patrick Marcellin, MD: This study confirms that patients with lamivudine-resistant HBV respond less well to entecavir than do treatment-naive patients. In addition, we know that they are at increased risk of developing entecavir resistance. Therefore, there is some consensus that it is more appropriate to use drugs without cross-resistance with lamivudine, such as adefovir ortenofovir. In addition, the use of interferon may be another option in these patients, especially in countries where adefovir or tenofovir is not available.
Preexisting Resistance Mutations in Treatment-Naive Patients
Norah Terrault, MD, MPH: It has been postulated that a proportion of treatment-naive HBV-infected patients may have resistance mutations present at baseline. Indeed, a previous study using direct sequencing reported that 10% of treatment-naive patients had preexisting lamivudine resistance mutations.[31] However, in general, only viral variants present at a prevalence of ≥ 20% among the total HBV quasispecies pool are detectable using this technique.[32.] Fung and colleagues[33] presented data using a very sensitive line probe assay, which is more sensitive than direct sequencing (lower level of detection for antiviral-resistant variants at ≥ 5% of the total HBV quasispecies pool[34]) to screen for the presence of lamivudine mutations at codons180 and 204 in 146 nucleos(t)ide-naive patients. They found that preexisting mutations in thert180/204 pathway were relatively common, with M204V/I present in 13% of patients and L180M present in 7%. This was a cross-sectional analysis, so no data were available to demonstrate whether the presence of these mutations affected subsequent response to therapy. Nevertheless, it is plausible that baseline resistance testing might influence the choice of antiviral therapy in the future. For example, if a patient had the M204V/I mutation, one might avoid nucleoside analogues such as lamivudine or entecavir as first-line therapy and instead consider nucleotides such as adefovir or tenofovir. Because this concept is still emerging, it is not yet clear how to best use this type of information. Regardless, it is important to note that even patients with no previous drug exposure can have resistance mutations present in their viral quasispecies due to the error-prone replication of HBV.
Patrick Marcellin, MD: Longitudinal studies are necessary to determine the clinical relevance of these findings by assessing the influence of these minority HBV populations on the antiviral response and the incidence of resistance.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: These data are very interesting and warrant confirmation in subsequent studies. We currently have only 1 class of drugs for treatment of chronic HBV infection—nucleos(t)ide analogues—and there is a high frequency of cross-resistance with some of the available antiviral agents. Therefore, routine baseline testing for presence of treatment-associated mutations may become clinically useful and cost-effective in the future if such mutations are found at similar rates in other studies.
Patrick Marcellin, MD: We do not know well the mechanisms responsible for the occurrence of hepatocellular carcinoma in cirrhotic patients. Even if antiviral therapy inhibits HBV replication and decreases liver necroinflammation, the “precancer” cirrhotic lesions and persistent HBVinfection in the liver might explain the continuing risk for hepatocellular carcinoma. Largecohort studies with long follow-up are needed to determine the magnitude of the risk and for how long it persists.
Long-term Entecavir in Chinese Patients With Lamivudine-Refractory HBV
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Yao and colleagues[29] evaluated the long-term efficacy of entecavir monotherapy in 138Chinese patients with lamivudine-refractory chronic hepatitis B who enrolled in the ETV-056and ETV-050 studies (Increasing Rates of Virologic Suppression Through Year 3 of Entecavir Treatment in Chinese Cohort With Lamivudine Resistance). In ETV-056, patients received 12weeks of entecavir 1 mg daily or placebo followed by 36 weeks of open-label entecavir 1 mgdaily. A total of 141 patients from ETV-056 rolled over into ETV-050 and continued entecavir1 mg daily. These patients were relatively young (mean age: 35 years), 76% were male with a moderately high HBV DNA (8.78 log10 copies/mL), and 90% were HBeAg positive. In this study, the proportion of patients achieving undetectable HBV DNA increased over time, from 30% at Year 1 to 47% at Year 2 and 55% at Year 3. This contrasts with findings from thepivotal entecavir studies that showed an increasing rate of HBV DNA negativity for the first 2years in lamivudine-refractory patients, followed by a decrease in rates of undetectable HBVDNA by the third year along with the emergence of entecavir resistance (Assessment at threeyears shows high barrier to resistance is maintained in entecavir-treated nucleoside naïve patients while resistance emergence increases over time in lamivudine refractory patients).[30]In addition, there was a fairly acceptable rate of cumulative HBeAg loss (11%, 13%, and 17%at Years 1, 2, and 3, respectively) and cumulative HBeAg seroconversion (7%, 11%, and12% at Years 1, 2, and 3). By contrast, however, the proportion of patients with ALT ≤ 1 xupper limit of normal (ULN) decreased from 85% at Year 1 to 65% at Year 3.Although entecavir monotherapy is approved for use in lamivudine-experienced patients, many experts feel that there are more effective treatment options for this patient population.
Patrick Marcellin, MD: This study confirms that patients with lamivudine-resistant HBV respond less well to entecavir than do treatment-naive patients. In addition, we know that they are at increased risk of developing entecavir resistance. Therefore, there is some consensus that it is more appropriate to use drugs without cross-resistance with lamivudine, such as adefovir ortenofovir. In addition, the use of interferon may be another option in these patients, especially in countries where adefovir or tenofovir is not available.
Preexisting Resistance Mutations in Treatment-Naive Patients
Norah Terrault, MD, MPH: It has been postulated that a proportion of treatment-naive HBV-infected patients may have resistance mutations present at baseline. Indeed, a previous study using direct sequencing reported that 10% of treatment-naive patients had preexisting lamivudine resistance mutations.[31] However, in general, only viral variants present at a prevalence of ≥ 20% among the total HBV quasispecies pool are detectable using this technique.[32.] Fung and colleagues[33] presented data using a very sensitive line probe assay, which is more sensitive than direct sequencing (lower level of detection for antiviral-resistant variants at ≥ 5% of the total HBV quasispecies pool[34]) to screen for the presence of lamivudine mutations at codons180 and 204 in 146 nucleos(t)ide-naive patients. They found that preexisting mutations in thert180/204 pathway were relatively common, with M204V/I present in 13% of patients and L180M present in 7%. This was a cross-sectional analysis, so no data were available to demonstrate whether the presence of these mutations affected subsequent response to therapy. Nevertheless, it is plausible that baseline resistance testing might influence the choice of antiviral therapy in the future. For example, if a patient had the M204V/I mutation, one might avoid nucleoside analogues such as lamivudine or entecavir as first-line therapy and instead consider nucleotides such as adefovir or tenofovir. Because this concept is still emerging, it is not yet clear how to best use this type of information. Regardless, it is important to note that even patients with no previous drug exposure can have resistance mutations present in their viral quasispecies due to the error-prone replication of HBV.
Patrick Marcellin, MD: Longitudinal studies are necessary to determine the clinical relevance of these findings by assessing the influence of these minority HBV populations on the antiviral response and the incidence of resistance.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: These data are very interesting and warrant confirmation in subsequent studies. We currently have only 1 class of drugs for treatment of chronic HBV infection—nucleos(t)ide analogues—and there is a high frequency of cross-resistance with some of the available antiviral agents. Therefore, routine baseline testing for presence of treatment-associated mutations may become clinically useful and cost-effective in the future if such mutations are found at similar rates in other studies.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I think another key issue is how tenofovir resistance is defined. At present, it is being reported that no signature mutation(s) for tenofovir resistance have been found. The investigators noted that polymorphisms are being selected for in some patients during therapy, but HBVDNA still decreases during tenofovir treatment. Therefore, the impact of those mutations on tenofovir resistance is unclear. Nevertheless, it is clear that the presence of signature mutations for adefovir was associated with a reduced rate of response to tenofovir, and so those mutations clearly confer reduced susceptibility to tenofovir.
Norah Terrault, MD, MPH: Although all the adefovir-resistant patients had documented adefovir resistance mutations, the investigators could not identify a specific mutation or pattern of mutations that was associated with a poor response and that could be, therefore, considered a tenofovir signature mutation or mutations. Even in the patients with adefovir resistance, there were no cases of virologic breakthrough observed.
Patrick Marcellin, MD: Despite the caveats of this study previously discussed, the results raise the possibility that a different potent analogue such as entecavir might be preferred in patients who developed resistance to adefovir. In vitro data support this strategy since viral strains resistant to adefovir show no cross-resistance to entecavir and less susceptibility to tenofovir.[24]
Norah Terrault, MD, MPH: Continuing our review of tenofovir use in nucleos(t)ide-experienced patients, Berg and colleagues[25] compared the safety and efficacy of tenofovir monotherapy vs coformulated tenofovir/emtricitabine in patients with persistent viremia following treatment with adefovir(Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBV-Infected Patients With Persistent Viremia on Adefovir). Coformulated tenofovir/emtricitabine iscurrently approved for the treatment of HIV and because emtricitabine has also been shown to also have efficacy against HBV, there is the potential to use a single tablet containing 2drugs with activity against HBV. Interestingly, however, there was no incremental benefit observed with the addition of emtricitabine to tenofovir, and there were no significant differences between tenofovir monotherapy and tenofovir/emtricitabine at Week 48 regarding the percentage of patients achieving HBV DNA < 400 copies/mL, normalization of ALT, or HBeAg seroconversion, and no difference in the mean reduction in HBV DNA levels.
One important aspect of the study was that the investigators analyzed the impact of adherence on treatment response. In an analysis in which both study arms were combined, there was a nonsignificant trend toward higher response rates in patients with high adherence vs low adherence (87% vs 71%, respectively; P = .15). This is what would be expected, but itwas good to see the numbers. To me, that was the most significant finding of this study.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Of note, the slope of the viral suppression curve was clearly blunted in patients with preexisting adefovir resistance mutations (A181T or N236T), consistent with the previous study demonstrating reduced efficacy of tenofovir in adefovir-resistant patients. However, theoverall rates of suppression were similar.[23]
Patrick Marcellin, MD: All of these studies confirm data from in vitro studies regarding susceptibility of adefovirresistant viruses to other nucleos(t)ide analogues. These clinical observations are notsurprising since adefovir and tenofovir are structurally closely related drugs
Adefovir Plus Lamivudine in Lamivudine-Resistant HBV
Norah Terrault, MD, MPH: Lampertico and colleagues[26] evaluated the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B (Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBVInfected Patients With Persistent Viremia on Adefovir). By a median follow-up of 57 months, more than 80% of patients achieved undetectable HBV DNA levels (< 35 copies/mL) and nearly all patients (90%) experienced ALT normalization. This study was not controlled but nevertheless touched on the important question of whether nucleos(t)ide analogue therapycan effectively reduce the risk of hepatocellular carcinoma. Data previously published by Liawand colleagues[27] suggest that treatment of cirrhosis does reduced the risk of hepatocellular carcinoma, but this study enrolled a more mixed population of whom 73% were cirrhotic. After a median follow-up of 24 months, 17 patients developed hepatocellular carcinoma, a higher number than would be predicted from Lau and colleagues[28] data in patients with similar rates of viral suppression. The investigators concluded that treating lamivudine-resistant patients by the addition of adefovir to ongoing lamivudine does provide clinical benefits and viral suppression, but the risk for hepatocellular carcinoma remains relatively high. The study population was relatively small—63 patients. Moreover, with a treatment duration of approximately 4 years, the lead time for liver cancer means that some of those patients may have developed cancer in the first or second year that then subsequently became detectable. It is therefore hard to interpret these data on hepatocellular carcinoma, although they do underscore the important message that providing antiviral treatment to a cirrhotic patient does not eliminate the risk of cancer.
Norah Terrault, MD, MPH: Although all the adefovir-resistant patients had documented adefovir resistance mutations, the investigators could not identify a specific mutation or pattern of mutations that was associated with a poor response and that could be, therefore, considered a tenofovir signature mutation or mutations. Even in the patients with adefovir resistance, there were no cases of virologic breakthrough observed.
Patrick Marcellin, MD: Despite the caveats of this study previously discussed, the results raise the possibility that a different potent analogue such as entecavir might be preferred in patients who developed resistance to adefovir. In vitro data support this strategy since viral strains resistant to adefovir show no cross-resistance to entecavir and less susceptibility to tenofovir.[24]
Norah Terrault, MD, MPH: Continuing our review of tenofovir use in nucleos(t)ide-experienced patients, Berg and colleagues[25] compared the safety and efficacy of tenofovir monotherapy vs coformulated tenofovir/emtricitabine in patients with persistent viremia following treatment with adefovir(Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBV-Infected Patients With Persistent Viremia on Adefovir). Coformulated tenofovir/emtricitabine iscurrently approved for the treatment of HIV and because emtricitabine has also been shown to also have efficacy against HBV, there is the potential to use a single tablet containing 2drugs with activity against HBV. Interestingly, however, there was no incremental benefit observed with the addition of emtricitabine to tenofovir, and there were no significant differences between tenofovir monotherapy and tenofovir/emtricitabine at Week 48 regarding the percentage of patients achieving HBV DNA < 400 copies/mL, normalization of ALT, or HBeAg seroconversion, and no difference in the mean reduction in HBV DNA levels.
One important aspect of the study was that the investigators analyzed the impact of adherence on treatment response. In an analysis in which both study arms were combined, there was a nonsignificant trend toward higher response rates in patients with high adherence vs low adherence (87% vs 71%, respectively; P = .15). This is what would be expected, but itwas good to see the numbers. To me, that was the most significant finding of this study.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Of note, the slope of the viral suppression curve was clearly blunted in patients with preexisting adefovir resistance mutations (A181T or N236T), consistent with the previous study demonstrating reduced efficacy of tenofovir in adefovir-resistant patients. However, theoverall rates of suppression were similar.[23]
Patrick Marcellin, MD: All of these studies confirm data from in vitro studies regarding susceptibility of adefovirresistant viruses to other nucleos(t)ide analogues. These clinical observations are notsurprising since adefovir and tenofovir are structurally closely related drugs
Adefovir Plus Lamivudine in Lamivudine-Resistant HBV
Norah Terrault, MD, MPH: Lampertico and colleagues[26] evaluated the long-term safety and efficacy of adefovir/lamivudine combination therapy in 63 patients with lamivudine-resistant chronic hepatitis B (Similar Efficacy of Tenofovir vs Coformulated Tenofovir/Emtricitabine in HBVInfected Patients With Persistent Viremia on Adefovir). By a median follow-up of 57 months, more than 80% of patients achieved undetectable HBV DNA levels (< 35 copies/mL) and nearly all patients (90%) experienced ALT normalization. This study was not controlled but nevertheless touched on the important question of whether nucleos(t)ide analogue therapycan effectively reduce the risk of hepatocellular carcinoma. Data previously published by Liawand colleagues[27] suggest that treatment of cirrhosis does reduced the risk of hepatocellular carcinoma, but this study enrolled a more mixed population of whom 73% were cirrhotic. After a median follow-up of 24 months, 17 patients developed hepatocellular carcinoma, a higher number than would be predicted from Lau and colleagues[28] data in patients with similar rates of viral suppression. The investigators concluded that treating lamivudine-resistant patients by the addition of adefovir to ongoing lamivudine does provide clinical benefits and viral suppression, but the risk for hepatocellular carcinoma remains relatively high. The study population was relatively small—63 patients. Moreover, with a treatment duration of approximately 4 years, the lead time for liver cancer means that some of those patients may have developed cancer in the first or second year that then subsequently became detectable. It is therefore hard to interpret these data on hepatocellular carcinoma, although they do underscore the important message that providing antiviral treatment to a cirrhotic patient does not eliminate the risk of cancer.
Durability of HBeAg Seroconversion With Telbivudine or Lamivudine
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Two large pivotal phase III trials compared telbivudine 600 mg/day or lamivudine 100 mg/day over a 2-year period in a predominantly HBeAg-positive population. The GLOBE study enrolled 1367 patients from 20 countries,[19] whereas Study 015[20] was conducted in China and enrolled 332 patients. Poynard and colleagues[21] conducted a retrospective combined analysis of these 2 studies evaluating the durability of HBeAg loss and HBeAg seroconversion, which occurred during therapy in 1211 HBeAg-positive patients (HBeAg Seroconversion Sustained for 52 Weeks in Chronic Hepatitis B Patients Treated With Telbivudine or Lamivudine Following Consolidation Therapy). These patients were subsequently treated for ≥ 6 months with consolidation therapy followed by treatment discontinuation because of efficacy at the discretion of the investigator. The inclusion criteria for this analysis required patients to have received at least 1 year of therapy and to have had HBV DNA 104 copies/mL at the start of tenofovir therapy, of whom 93%were lamivudine experienced and 85% were adefovir experienced. Of 113 available genotypic analyses from serum samples, YMDD mutations were present in 61 patients (54%)at baseline and adefovir resistance was detected in 19 patients (17%). Overall, 85% of patients achieved HBV DNA undetectability. The percentage of patients achieving undetectable HBV DNA (< 400 copies/mL) with tenofovir was not significantly affected by the presence of genotypic lamivudine resistance at baseline, but was significantly decreased by either pretreatment with adefovir (P < .0001) or the presence of adefovir genotypic resistanceat baseline (P < .0001). The probability of achieving undetectable HBV DNA was 90% inpatients without adefovir resistance vs 30% in adefovir-resistant patients (P = .001),suggesting that tenofovir may have a limited role in adefovir-resistant patients.
Norah Terrault, MD, MPH: This study involved only 19 adefovir-resistant patients, so caution is warranted before drawing conclusions about the efficacy of tenofovir in this setting. In addition, the median duration of tenofovir therapy in patients who did not achieve undetectable HBV DNA was 11 months vs18 months for patients who did achieve undetectable HBV DNA, which was a significant difference (P = .002). Therefore, it is possible that more patients may achieve undetectability if treated for a longer duration. Another baseline factor associated with response in patients with genotypic adefovir resistance was the mean HBV DNA level at baseline, which was 3.3 x108 copies/mL in nonresponders vs 1.4 x 108 copies/mL in responders (P = .047).
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I do not think the small numbers involved necessarily invalidate these conclusions because the viral kinetic response curves from this study show the 2 groups separating out quickly over time, and therefore, there is no reason to think this would be different with larger numbers.
Norah Terrault, MD, MPH: I agree that separation in the viral response curves did occur early. However, it is difficult topredict how those curves might evolve with longer durations of therapy.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Two large pivotal phase III trials compared telbivudine 600 mg/day or lamivudine 100 mg/day over a 2-year period in a predominantly HBeAg-positive population. The GLOBE study enrolled 1367 patients from 20 countries,[19] whereas Study 015[20] was conducted in China and enrolled 332 patients. Poynard and colleagues[21] conducted a retrospective combined analysis of these 2 studies evaluating the durability of HBeAg loss and HBeAg seroconversion, which occurred during therapy in 1211 HBeAg-positive patients (HBeAg Seroconversion Sustained for 52 Weeks in Chronic Hepatitis B Patients Treated With Telbivudine or Lamivudine Following Consolidation Therapy). These patients were subsequently treated for ≥ 6 months with consolidation therapy followed by treatment discontinuation because of efficacy at the discretion of the investigator. The inclusion criteria for this analysis required patients to have received at least 1 year of therapy and to have had HBV DNA 104 copies/mL at the start of tenofovir therapy, of whom 93%were lamivudine experienced and 85% were adefovir experienced. Of 113 available genotypic analyses from serum samples, YMDD mutations were present in 61 patients (54%)at baseline and adefovir resistance was detected in 19 patients (17%). Overall, 85% of patients achieved HBV DNA undetectability. The percentage of patients achieving undetectable HBV DNA (< 400 copies/mL) with tenofovir was not significantly affected by the presence of genotypic lamivudine resistance at baseline, but was significantly decreased by either pretreatment with adefovir (P < .0001) or the presence of adefovir genotypic resistanceat baseline (P < .0001). The probability of achieving undetectable HBV DNA was 90% inpatients without adefovir resistance vs 30% in adefovir-resistant patients (P = .001),suggesting that tenofovir may have a limited role in adefovir-resistant patients.
Norah Terrault, MD, MPH: This study involved only 19 adefovir-resistant patients, so caution is warranted before drawing conclusions about the efficacy of tenofovir in this setting. In addition, the median duration of tenofovir therapy in patients who did not achieve undetectable HBV DNA was 11 months vs18 months for patients who did achieve undetectable HBV DNA, which was a significant difference (P = .002). Therefore, it is possible that more patients may achieve undetectability if treated for a longer duration. Another baseline factor associated with response in patients with genotypic adefovir resistance was the mean HBV DNA level at baseline, which was 3.3 x108 copies/mL in nonresponders vs 1.4 x 108 copies/mL in responders (P = .047).
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I do not think the small numbers involved necessarily invalidate these conclusions because the viral kinetic response curves from this study show the 2 groups separating out quickly over time, and therefore, there is no reason to think this would be different with larger numbers.
Norah Terrault, MD, MPH: I agree that separation in the viral response curves did occur early. However, it is difficult topredict how those curves might evolve with longer durations of therapy.
Patrick Marcellin, MD: I agree that longer-term follow-up is necessary to see if this phenomenon is confirmed. I was surprised that HBsAg loss was observed only in HBeAg-positive patients. One might expect itto occur in HBeAg-negative patients too, as has been observed with interferon alfa–based treatments.[7] I agree, however, that a 5% HBsAg loss rate is impressive and has not been demonstrated with any other nucleos(t)ide analogue. If these rates are confirmed in subsequent studies, that could provide an advantage for using tenofovir compared with other nucleos(t)ide analogues. Moreover, if it transpires that tenofovir induces HBsAg loss and seroconversion through a different mechanism of action from interferon-based therapy, that may provide a rationale for studying the combination of both drugs, with the goal of inducing HBsAg loss in as many patients as possible, rather than keeping patients on therapy all their lives.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: It seems unlikely that simple differences in potency are sufficient to explain the phenomenon of HBsAg loss and seroconversion because although tenofovir was more potent than adefovirin these studies, comparable rates of HBV DNA suppression have been observed in separate studies with telbivudine or entecavir. Regardless of whether this observation is simply random chance or reflects some unique mechanism of action of tenofovir, this novel finding definitely bears watching closely.
Long-term Efficacy of Entecavir
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Several studies on the long-term efficacy of entecavir were presented at EASL. Leung and colleagues[14] presented 96-week data from the EARLY study of entecavir 0.5 mg/day vs adefovir 10 mg/day in 69 treatment-naive HBeAg-positive patients with high baseline HBVDNA of ≥ 108 copies/mL. The number of patients with data available at Year 2 was relatively small—29 for entecavir and 20 for adefovir—but the results were consistent with those from previous comparisons of these agents. At Week 12, the mean viral reduction from baseline was -6.23 log10 copies/mL with entecavir vs -4.42 log10 copies/mL with adefovir (P < .0001).The mean decrease in HBV DNA at Week 96 from baseline was -7.82 log10 copies/mL with entecavir vs -5.96 log10 copies/mL vs adefovir. Rates of undetectable HBV DNA for entecavir vs adefovir at Year 2 were 79% and 50%, respectively. Seroconversion rates of HBeAg were comparable (24% and 25%), and no virologic breakthroughs were reported in either arm. There were similar rates of any-grade adverse events in the entecavir and adefovir arms(83% vs 82%), but more grade 3/4 adverse events and treatment discontinuations occurred in the adefovir arm.
Patrick Marcellin, MD: Even though the number of patients was small, this head-to-head comparison of entecavir with adefovir confirms that adefovir has a less potent antiviral effect than entecavir, as was previously suggested by cross-study comparison of the pivotal studies of adefovir and entecavir.[3,4,15,16]In another small study, Mochida and colleagues[17] evaluated the safety and efficacy of entecavir 0.5 mg/day in 68 treatment-naive Japanese patients enrolled in 3 studies (ETV-047,ETV-053, and ETV-060) (Long-term Entecavir Treatment Safe and Effective in Japanese Treatment-Naive Chronic Hepatitis B Patients Through Year 3). The proportion of patients with HBV DNA < 400 copies/mL increased over time, reaching 87% after 3 years. Entecavir continued to show a high barrier to resistance, with a 1.7% cumulative rate of resistance or resistance with subsequent virologic breakthrough at Year 3. This study confirmed the findings from the pivotal studies. However, a general limitation of the pivotal studies was the difficulty in interpreting the exact incidence of entecavir resistance as the long-term follow-up of those studies (ETV-022) restricted the calculation to a subgroup of patients receiving therapy. It is, therefore, reassuring to have another independent long-term follow-up of patients on entecavir confirming the low rate of cumulative resistance. However, the number of patients in this analysis is small and the follow-up duration is currently only 3 years, whereas data from the pivotal studies through 5 years of follow-up have recently been presented.[18]
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I agree with Dr. Marcellin. Some have been critical of the resistance data from the long-term entecavir rollover treatment study because of the higher dose of entecavir used (1.0 vs 0.5mg) and the fact that not all treated patients in the pivotal trials entered the rollover long-term treatment study. However, the fact that the incidence of resistance in this study, albeit with smaller sample size, is very similar to that previously reported in the rollover study confirms the very low resistance risk with extended treatment with entecavir in nucleos(t)ide-naïve patients.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: It seems unlikely that simple differences in potency are sufficient to explain the phenomenon of HBsAg loss and seroconversion because although tenofovir was more potent than adefovirin these studies, comparable rates of HBV DNA suppression have been observed in separate studies with telbivudine or entecavir. Regardless of whether this observation is simply random chance or reflects some unique mechanism of action of tenofovir, this novel finding definitely bears watching closely.
Long-term Efficacy of Entecavir
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Several studies on the long-term efficacy of entecavir were presented at EASL. Leung and colleagues[14] presented 96-week data from the EARLY study of entecavir 0.5 mg/day vs adefovir 10 mg/day in 69 treatment-naive HBeAg-positive patients with high baseline HBVDNA of ≥ 108 copies/mL. The number of patients with data available at Year 2 was relatively small—29 for entecavir and 20 for adefovir—but the results were consistent with those from previous comparisons of these agents. At Week 12, the mean viral reduction from baseline was -6.23 log10 copies/mL with entecavir vs -4.42 log10 copies/mL with adefovir (P < .0001).The mean decrease in HBV DNA at Week 96 from baseline was -7.82 log10 copies/mL with entecavir vs -5.96 log10 copies/mL vs adefovir. Rates of undetectable HBV DNA for entecavir vs adefovir at Year 2 were 79% and 50%, respectively. Seroconversion rates of HBeAg were comparable (24% and 25%), and no virologic breakthroughs were reported in either arm. There were similar rates of any-grade adverse events in the entecavir and adefovir arms(83% vs 82%), but more grade 3/4 adverse events and treatment discontinuations occurred in the adefovir arm.
Patrick Marcellin, MD: Even though the number of patients was small, this head-to-head comparison of entecavir with adefovir confirms that adefovir has a less potent antiviral effect than entecavir, as was previously suggested by cross-study comparison of the pivotal studies of adefovir and entecavir.[3,4,15,16]In another small study, Mochida and colleagues[17] evaluated the safety and efficacy of entecavir 0.5 mg/day in 68 treatment-naive Japanese patients enrolled in 3 studies (ETV-047,ETV-053, and ETV-060) (Long-term Entecavir Treatment Safe and Effective in Japanese Treatment-Naive Chronic Hepatitis B Patients Through Year 3). The proportion of patients with HBV DNA < 400 copies/mL increased over time, reaching 87% after 3 years. Entecavir continued to show a high barrier to resistance, with a 1.7% cumulative rate of resistance or resistance with subsequent virologic breakthrough at Year 3. This study confirmed the findings from the pivotal studies. However, a general limitation of the pivotal studies was the difficulty in interpreting the exact incidence of entecavir resistance as the long-term follow-up of those studies (ETV-022) restricted the calculation to a subgroup of patients receiving therapy. It is, therefore, reassuring to have another independent long-term follow-up of patients on entecavir confirming the low rate of cumulative resistance. However, the number of patients in this analysis is small and the follow-up duration is currently only 3 years, whereas data from the pivotal studies through 5 years of follow-up have recently been presented.[18]
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: I agree with Dr. Marcellin. Some have been critical of the resistance data from the long-term entecavir rollover treatment study because of the higher dose of entecavir used (1.0 vs 0.5mg) and the fact that not all treated patients in the pivotal trials entered the rollover long-term treatment study. However, the fact that the incidence of resistance in this study, albeit with smaller sample size, is very similar to that previously reported in the rollover study confirms the very low resistance risk with extended treatment with entecavir in nucleos(t)ide-naïve patients.
Norah Terrault, MD, MPH: HBsAg titer tests are not currently commercially available in the United States. However, that would presumably change if this association is confirmed and becomes important in predicting response to peginterferon. It would be of particular interest if the investigators had been able to identify baseline predictors of HBsAg decline, which might allow us to identify a target group who would respond well to peginterferon alfa treatment and avoid the unnecessary 24-48 week treatment in patients who are unlikely to achieve a response to this treatment. It would also be particularly helpful if the ideal duration of peginterferon alfa treatment in HBeAg-negative patients could be better defined as this issue is not currently clear.
Patrick Marcellin, MD: In a related abstract, Brunetto and colleagues[11] also evaluated the association between HBsAg level reduction and HBV DNA level at end of treatment. Among patients receiving peginterferon, the mean decline in HBsAg level from baseline to Week 48 was significantly greater in patients with HBV DNA ≤ 400 copies/mL at Week 72 vs those with HBV DNA > 400copies/mL at Week 72 (1.077 vs 0.263 log10 IU/mL, respectively; P < .001). This relationship only held true for peginterferon because HBsAg levels did not decline with lamivudine, regardless of the degree of HBV DNA suppression.
Tenofovir vs Adefovir in Chronic Hepatitis B
Patrick Marcellin, MD: Updates on 2 pivotal large, randomized, controlled trials comparing tenofovir vs adefovir in treatment-naive patients with chronic hepatitis B were presented at EASL. Study 102 enrolled375 patients with HBeAg-negative chronic hepatitis B (Rapid, Persistent HBV DNA Suppression With Tenofovir Treatment in HBeAg-Negative Chronic Hepatitis B)[12] whereas Study 103 enrolled 266 patients with HBeAg-positive chronic hepatitis B (Continued Efficacy With Tenofovir Through Week 72 of Therapy in HBeAg-Positive Patients).[13] In both studies, patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks, all patients on adefovir were switched to tenofovir regardless of response to adefovir. Forty-eight–week data from these studies were previously presented at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases, in which superior potency with tenofovir was demonstrated at Week 48 in both HBeAg-positive patients (A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HbeAgpositive chronic hepatitis B (CHB)[1] and HBeAg-negative patients (A randomized, doubleblind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB)).[2] Tenofovir was associated with HBV DNA levels< 400 copies/mL at Week 48 in 93% of HBeAg-negative patients and 76% of HBeAg-positive patients (compared with 63% of HBeAg-negative and 13% of HBeAg-positive patients treated with adefovir). This high rate of undetectable HBV DNA at 48 weeks is comparable with that seen with entecavir.[3,4] Both tenofovir and adefovir were associated with biochemical responses and histologic improvement. Based on these results, tenofovir was recently approved for the treatment of chronic hepatitis B virus (HBV) infection in Europe.
The updated analyses present at EASL provide an additional 6 months of follow-up since the previous reports and also encompass 24 weeks of tenofovir therapy in patients who initially received 48 weeks of adefovir. Among the patients initially randomized to tenofovir, the investigators showed that the proportions with HBV DNA < 400 copies/mL were maintained in91% of HBeAg-negative patients and 79% of HBeAg-positive patients between Week 48 and Week 72. No cases of resistance were noted in HBeAg-positive or HBeAg-negative patients, and no new safety findings were reported. Although there had been some concern about the potential for nephrotoxicity, this was not observed at a significant rate. Importantly, rates of viral suppression increased among patients who initially received adefovir for 48 weeks and then switched to tenofovir. By Week 72, 88% of HBeAg-negative patients and 76% of HBeAg-positive switch patients had HBV DNA < 400 copies/mL, which was not significantly different from the rates of suppression observed in patients who were treated with tenofovir from the study outset.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The high rate of response to tenofovir in patients initially treated with adefovir is an important finding from these extended studies, especially for those patients who are suboptimal responders to adefovir after 48 weeks of treatment. In HBeAg-negative patients, there were no significant differences in rates of alanine aminotransferase (ALT) normalization or adverse events between those assigned to continuous tenofovir vs those who switched from adefovirto tenofovir. In HBeAg-positive patients, there were no significant differences in HBeAg loss and seroconversion rates between these groups, but higher percentages of patients who received continuous tenofovir vs those who switched therapy achieved normal serum ALT levels at Week 72 (77% vs 61%, respectively; P = .014) and HBsAg loss at Week 64 (5% vs0%, respectively; P = .004). Otherwise, it appears that exposure to 48 weeks of adefovir therapy before the switch to tenofovir did not place these patients at any particular disadvantage in follow-up to date. The rate of HBsAg loss was notable in the HBeAg-positive study. Among these patients randomized to tenofovir from the outset, rates of HBsAg loss were 3% at Week 48[1] and, as mentioned, 5% at Week 64. With the exception of interferon alfa–based treatments, no other treatment has achieved comparable rates of HBsAg loss. Rates of HBsAg seroconversion among patients receiving tenofovir were 1% at Week 48[1] and 2% at Week 64, which are quite remarkable. By contrast, none of the HBeAg-positive patients initially treated with adefovir had HBsAg loss or seroconversion. It will be important to confirm these results to demonstrate whether this is a true treatment effect of tenofovir or simply a chance occurrence.
Patrick Marcellin, MD: In a related abstract, Brunetto and colleagues[11] also evaluated the association between HBsAg level reduction and HBV DNA level at end of treatment. Among patients receiving peginterferon, the mean decline in HBsAg level from baseline to Week 48 was significantly greater in patients with HBV DNA ≤ 400 copies/mL at Week 72 vs those with HBV DNA > 400copies/mL at Week 72 (1.077 vs 0.263 log10 IU/mL, respectively; P < .001). This relationship only held true for peginterferon because HBsAg levels did not decline with lamivudine, regardless of the degree of HBV DNA suppression.
Tenofovir vs Adefovir in Chronic Hepatitis B
Patrick Marcellin, MD: Updates on 2 pivotal large, randomized, controlled trials comparing tenofovir vs adefovir in treatment-naive patients with chronic hepatitis B were presented at EASL. Study 102 enrolled375 patients with HBeAg-negative chronic hepatitis B (Rapid, Persistent HBV DNA Suppression With Tenofovir Treatment in HBeAg-Negative Chronic Hepatitis B)[12] whereas Study 103 enrolled 266 patients with HBeAg-positive chronic hepatitis B (Continued Efficacy With Tenofovir Through Week 72 of Therapy in HBeAg-Positive Patients).[13] In both studies, patients were randomized to 48 weeks of tenofovir or adefovir; after 48 weeks, all patients on adefovir were switched to tenofovir regardless of response to adefovir. Forty-eight–week data from these studies were previously presented at the 2007 Annual Meeting of the American Association for the Study of Liver Diseases, in which superior potency with tenofovir was demonstrated at Week 48 in both HBeAg-positive patients (A randomized, double-blind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HbeAgpositive chronic hepatitis B (CHB)[1] and HBeAg-negative patients (A randomized, doubleblind, comparison of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg-negative chronic hepatitis B (CHB)).[2] Tenofovir was associated with HBV DNA levels< 400 copies/mL at Week 48 in 93% of HBeAg-negative patients and 76% of HBeAg-positive patients (compared with 63% of HBeAg-negative and 13% of HBeAg-positive patients treated with adefovir). This high rate of undetectable HBV DNA at 48 weeks is comparable with that seen with entecavir.[3,4] Both tenofovir and adefovir were associated with biochemical responses and histologic improvement. Based on these results, tenofovir was recently approved for the treatment of chronic hepatitis B virus (HBV) infection in Europe.
The updated analyses present at EASL provide an additional 6 months of follow-up since the previous reports and also encompass 24 weeks of tenofovir therapy in patients who initially received 48 weeks of adefovir. Among the patients initially randomized to tenofovir, the investigators showed that the proportions with HBV DNA < 400 copies/mL were maintained in91% of HBeAg-negative patients and 79% of HBeAg-positive patients between Week 48 and Week 72. No cases of resistance were noted in HBeAg-positive or HBeAg-negative patients, and no new safety findings were reported. Although there had been some concern about the potential for nephrotoxicity, this was not observed at a significant rate. Importantly, rates of viral suppression increased among patients who initially received adefovir for 48 weeks and then switched to tenofovir. By Week 72, 88% of HBeAg-negative patients and 76% of HBeAg-positive switch patients had HBV DNA < 400 copies/mL, which was not significantly different from the rates of suppression observed in patients who were treated with tenofovir from the study outset.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The high rate of response to tenofovir in patients initially treated with adefovir is an important finding from these extended studies, especially for those patients who are suboptimal responders to adefovir after 48 weeks of treatment. In HBeAg-negative patients, there were no significant differences in rates of alanine aminotransferase (ALT) normalization or adverse events between those assigned to continuous tenofovir vs those who switched from adefovirto tenofovir. In HBeAg-positive patients, there were no significant differences in HBeAg loss and seroconversion rates between these groups, but higher percentages of patients who received continuous tenofovir vs those who switched therapy achieved normal serum ALT levels at Week 72 (77% vs 61%, respectively; P = .014) and HBsAg loss at Week 64 (5% vs0%, respectively; P = .004). Otherwise, it appears that exposure to 48 weeks of adefovir therapy before the switch to tenofovir did not place these patients at any particular disadvantage in follow-up to date. The rate of HBsAg loss was notable in the HBeAg-positive study. Among these patients randomized to tenofovir from the outset, rates of HBsAg loss were 3% at Week 48[1] and, as mentioned, 5% at Week 64. With the exception of interferon alfa–based treatments, no other treatment has achieved comparable rates of HBsAg loss. Rates of HBsAg seroconversion among patients receiving tenofovir were 1% at Week 48[1] and 2% at Week 64, which are quite remarkable. By contrast, none of the HBeAg-positive patients initially treated with adefovir had HBsAg loss or seroconversion. It will be important to confirm these results to demonstrate whether this is a true treatment effect of tenofovir or simply a chance occurrence.
Update on Hepatitis B Management, 2008.
Peginterferon alfa-2a in HBeAg-Negative Chronic Hepatitis B
Patrick Marcellin, MD: With hepatitis B, we have 2 treatment strategies: peginterferon alfa or nucleos(t)ide analogues. The advantage of peginterferon alfa is that when it works, its effects are durable and it is associated with a high rate of hepatitis B surface antigen (HBsAg) suppression. The disadvantages are its subcutaneous administration, adverse effects, and relatively low overall efficacy rate. Advantages of nucleos(t)ide analogues are ease of administration (1 pill daily), a good safety profile, and substantial efficacy with new agents, such as entecavir or tenofovir, with 70% to 90% of patients achieving undetectable HBV DNA.[1-4] The disadvantage of nucleos(t)ide analogues is that treatment must be continued for many years—possibly lifelong—and the rate of HBsAg loss or seroconversion is very low. Let us being the discussion with 2 studies that look at the use of peginterferon alfa-2a inpatients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B. Worldwide, HBeAg negative infection is the predominant form of hepatitis B and is associated with high relapse rates.[5,6] In a previously published, randomized, controlled trial conducted by a group of which I was a member, the efficacy and safety of 48 weeks of peginterferon alfa-2a, lamivudine, or acombination of the 2 treatments were evaluated in 537 patients with HBeAg-negative chronic hepatitis B.[7] In that analysis, peginterferon alfa-2a was more effective than lamivudine at achieving sustained suppression of HBV DNA to < 400 copies/mL for 6 months after completion of treatment (19% vs 7%, respectively), with the combination of peginterferon alfa-2a plus lamivudine offering no additional benefit compared with peginterferon alfa-2a alone(20% vs 19%, respectively). Loss of HBsAg occurred in 12 patients receiving peginterferonalfa with or without lamivudine vs none receiving lamivudine alone. Forty-two of the original 54 study centers participated in a long-term observational follow-up of patients. In the current analysis presented at the European Association for the Study of the Liver (EASL) in Milan, Italy, we evaluated long-term response and relapse rates 4 years after completion of treatment in 230 patients who received peginterferon alfa-2a with or without lamivudine and 85 patients who received lamivudine alone.[8] Patients entering the long-term study who had received lamivudine only were more likely to have achieved an end-of treatment response at Week 48 than those who received peginterferon alfa-2a with or without lamivudine. However, by a modified intent-to-treat analysis, significantly more patients had HBV DNA < 400 copies/mL at 4 years after end of treatment in the group who received peginterferon alfa-2a with or without lamivudine compared with those treated with lamivudine alone (17% vs 7%, respectively; P = .042). Most interestingly, the rate of HBsAg clearance increased over time after end of treatment, reaching 11% of patients in the peginterferon alfa-2a with or without lamivudine group at 4 years after end of treatment compared with 2% of patients who were treated with lamivudine alone (P = .021).These findings indicate that in 17% of patients who respond well to peginterferon alfa-2a and achieve HBV DNA < 400 copies/mL, the response is usually sustained and a increasing number of those patients (66% at 4 years) achieves HBsAg loss, which is considered to be the clinical cure of hepatitis B. The other three quarters of patients do not respond well to treatment or relapse and, in those cases, should receive alternative treatment such as nucleos(t)ide analogues because previous interferon exposure does not decrease the chance of response to these drugs. This message supports the continued inclusion of peginterferon alfa treatment as a first-line option for some patients, as detailed in many international guidelines. Clinicians must weigh the advantages and disadvantages of peginterferon vs nucleos(t)ide analogues. I do not think there is any conflict between the 2 strategies, but we must learn which strategy is best for individual patients.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Peginterferon has several unique attributes that warrant consideration of its use as a first-line therapy for chronic hepatitis B. HBeAg-positive patients without cirrhosis who have genotype A infection, especially if associated with relatively low levels of viremia and activenecro inflammation on liver biopsy, may represent ideal candidates for consideration of peginterferon as first-line therapy. I have also found peginterferon an attractive option in women of childbearing age who wish to pursue a finite course of therapy and are concerned about possible teratogenic risks with nucleos(t)ide agents.
Predicting Responses to Peginterferon alfa-2a
Patrick Marcellin, MD: Based on these results, the next important question is how to identify the approximately 25%of patients who will respond well to peginterferon. To investigate this important issue, Brunetto and colleagues[9] evaluated the association between HBsAg decline on treatment and long-term HBsAg clearance in 315 patients from the same cohort (Magnitude of HbsAg Decline on Treatment Predicts Posttreatment HBsAg Clearance Following Peginterferon alfa-2a–Based Therapy). There was a clear association between reductions in serum HbsAg levels during treatment and sustained posttreatment HBsAg clearance. Two predictors of HBsAg loss following peginterferon-based therapy were identified: achieving HBsAg 2 log10 IU/mL during therapy. HBsAg clearance was seen in 42% to 52% of patients achieving these on-treatment reductions in HBsAg.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The approximately 50% rate of HBsAg clearance among patients achieving these HbsAg reduction on therapy is very high, and if these results are confirmed, HBsAg decline may become a useful marker. The authors proposed measuring quantitative HBsAg at baseline and during therapy, perhaps at Week 24. At that point, one might consider stopping therapy inpatients not achieving an adequate rate of HBsAg decline. This is based on the concept of the 24-week milestone used for assessing response to several of the oral agents.[10]
Peginterferon alfa-2a in HBeAg-Negative Chronic Hepatitis B
Patrick Marcellin, MD: With hepatitis B, we have 2 treatment strategies: peginterferon alfa or nucleos(t)ide analogues. The advantage of peginterferon alfa is that when it works, its effects are durable and it is associated with a high rate of hepatitis B surface antigen (HBsAg) suppression. The disadvantages are its subcutaneous administration, adverse effects, and relatively low overall efficacy rate. Advantages of nucleos(t)ide analogues are ease of administration (1 pill daily), a good safety profile, and substantial efficacy with new agents, such as entecavir or tenofovir, with 70% to 90% of patients achieving undetectable HBV DNA.[1-4] The disadvantage of nucleos(t)ide analogues is that treatment must be continued for many years—possibly lifelong—and the rate of HBsAg loss or seroconversion is very low. Let us being the discussion with 2 studies that look at the use of peginterferon alfa-2a inpatients with hepatitis B e antigen (HBeAg)–negative chronic hepatitis B. Worldwide, HBeAg negative infection is the predominant form of hepatitis B and is associated with high relapse rates.[5,6] In a previously published, randomized, controlled trial conducted by a group of which I was a member, the efficacy and safety of 48 weeks of peginterferon alfa-2a, lamivudine, or acombination of the 2 treatments were evaluated in 537 patients with HBeAg-negative chronic hepatitis B.[7] In that analysis, peginterferon alfa-2a was more effective than lamivudine at achieving sustained suppression of HBV DNA to < 400 copies/mL for 6 months after completion of treatment (19% vs 7%, respectively), with the combination of peginterferon alfa-2a plus lamivudine offering no additional benefit compared with peginterferon alfa-2a alone(20% vs 19%, respectively). Loss of HBsAg occurred in 12 patients receiving peginterferonalfa with or without lamivudine vs none receiving lamivudine alone. Forty-two of the original 54 study centers participated in a long-term observational follow-up of patients. In the current analysis presented at the European Association for the Study of the Liver (EASL) in Milan, Italy, we evaluated long-term response and relapse rates 4 years after completion of treatment in 230 patients who received peginterferon alfa-2a with or without lamivudine and 85 patients who received lamivudine alone.[8] Patients entering the long-term study who had received lamivudine only were more likely to have achieved an end-of treatment response at Week 48 than those who received peginterferon alfa-2a with or without lamivudine. However, by a modified intent-to-treat analysis, significantly more patients had HBV DNA < 400 copies/mL at 4 years after end of treatment in the group who received peginterferon alfa-2a with or without lamivudine compared with those treated with lamivudine alone (17% vs 7%, respectively; P = .042). Most interestingly, the rate of HBsAg clearance increased over time after end of treatment, reaching 11% of patients in the peginterferon alfa-2a with or without lamivudine group at 4 years after end of treatment compared with 2% of patients who were treated with lamivudine alone (P = .021).These findings indicate that in 17% of patients who respond well to peginterferon alfa-2a and achieve HBV DNA < 400 copies/mL, the response is usually sustained and a increasing number of those patients (66% at 4 years) achieves HBsAg loss, which is considered to be the clinical cure of hepatitis B. The other three quarters of patients do not respond well to treatment or relapse and, in those cases, should receive alternative treatment such as nucleos(t)ide analogues because previous interferon exposure does not decrease the chance of response to these drugs. This message supports the continued inclusion of peginterferon alfa treatment as a first-line option for some patients, as detailed in many international guidelines. Clinicians must weigh the advantages and disadvantages of peginterferon vs nucleos(t)ide analogues. I do not think there is any conflict between the 2 strategies, but we must learn which strategy is best for individual patients.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: Peginterferon has several unique attributes that warrant consideration of its use as a first-line therapy for chronic hepatitis B. HBeAg-positive patients without cirrhosis who have genotype A infection, especially if associated with relatively low levels of viremia and activenecro inflammation on liver biopsy, may represent ideal candidates for consideration of peginterferon as first-line therapy. I have also found peginterferon an attractive option in women of childbearing age who wish to pursue a finite course of therapy and are concerned about possible teratogenic risks with nucleos(t)ide agents.
Predicting Responses to Peginterferon alfa-2a
Patrick Marcellin, MD: Based on these results, the next important question is how to identify the approximately 25%of patients who will respond well to peginterferon. To investigate this important issue, Brunetto and colleagues[9] evaluated the association between HBsAg decline on treatment and long-term HBsAg clearance in 315 patients from the same cohort (Magnitude of HbsAg Decline on Treatment Predicts Posttreatment HBsAg Clearance Following Peginterferon alfa-2a–Based Therapy). There was a clear association between reductions in serum HbsAg levels during treatment and sustained posttreatment HBsAg clearance. Two predictors of HBsAg loss following peginterferon-based therapy were identified: achieving HBsAg 2 log10 IU/mL during therapy. HBsAg clearance was seen in 42% to 52% of patients achieving these on-treatment reductions in HBsAg.
Kris V. Kowdley, MD, FACP, FACG, FASGE, AGAF: The approximately 50% rate of HBsAg clearance among patients achieving these HbsAg reduction on therapy is very high, and if these results are confirmed, HBsAg decline may become a useful marker. The authors proposed measuring quantitative HBsAg at baseline and during therapy, perhaps at Week 24. At that point, one might consider stopping therapy inpatients not achieving an adequate rate of HBsAg decline. This is based on the concept of the 24-week milestone used for assessing response to several of the oral agents.[10]
His laboratory studies revealed the following:
Glycosylated hemoglobin: 5.8%
HBV DNA: 62,500 IU/mL
HBsAg (+), HBsAb (-), HBeAg (-) and HBeAb (+)
AFP: 6 ng/mL
ALT: 40 IU/L
AST: 35 IU/L
Total bilirubin: 0.9 mg/dL
Creatinine: 0.9 mg/dL
Blood urea nitrogen: 25 mg/dL
Evaluation of 12-month follow-up. The patient was receiving treatment for metabolic syndrome. His HBV DNA became positive after being undetectable for more than 1 year while on lamivudine.
On the basis of these findings, we suspected that the patient had a virologic breakthrough most probably as a result of development of the YMDD mutation and resistance to lamivudine. At this point in management, adefovir 10 mg/day was added to continued lamivudine therapy.
Lamivudine Resistance
Currently available antiviral agents for chronic hepatitis B are either nucleoside (lamivudine, entecavir, telbivudine) or nucleotide (adefovir, tenofovir**) analogs. Using oral antivirals requires long-term therapy (and in most patients, indefinite treatment) to maintain viral suppression. Long duration of therapy increases the risk for antiviral drug resistance. Lamivudine resistance occurs in approximately 20% of patients after 1 year and in up to 65% after 5 years.[6] The characteristic mutations occur in the YMDD motif of the HBV DNA polymerase. When this mutation occurs, the sensitivity to lamivudine decreases greater than 100-fold. Lamivudine-resistant mutations confer cross-resistance to other nucleosides, such as emtricitabine,** telbivudine, and clevudine.** They also decrease susceptibility to entecavir. The main approach to managing lamivudine resistance is to add adefovir or tenofovir (when approved) to ongoing lamivudine therapy.[7]
Until now, the recommended approach to managing HBV infection has involved the use of monotherapy, which is associated with a high risk of developing drug resistance. It has been recommended that patients should be closely monitored for virologic and biochemical response every 3-6 months. When viral breakthrough occurs, the mutant virus replicates, and its titer increases; this is then followed by an increase in aminotransferase levels (biochemical breakthrough) and histopathologic changes on liver biopsy.[2,7]
Strategies for the Management of Drug-Resistant HBV Infection Close follow-up allows for early detection of viral breakthrough and implementation of appropriate management strategies (Table 7) before the patient develops biochemical breakthrough and histopathologic deterioration.[1,2,7]
Table 7. Potential Management of HBV Antiviral Drug Resistance[1,2,7]
Resistance to HBV Antivirals Strategy
Lamivudine Add adefovir or tenofovir**or switch to tenofovir/emtricitabine**
Adefovir Add lamivudine or telbivudine or add/switch to entecavir if not prior
lamivudine resistance or switch to tenofovir/emtricitabine**
Telbivudine Add adefovir or tenofovir** or switch to tenofovir/emtricitabine**
Entecavir Switch to or add adefovir or tenofovir** Switch to
emtricitabine/tenofovir**
**Not currently approved by US FDA
Continued Management (2008)
Since mid-2003, the patient has been on lamivudine 100 mg daily in combination with adefovir 10 mg daily. His current laboratory values are as follows:
ALT: 28 IU/L
AST: 32 IU/L
HBV DNA: < 29 IU/mL
HBsAg: positive
HBsAb: negative
HBeAg: negative
HBeAb: positive.
Platelets: 189 x 103/mm3
AFP: 5 ng/mL
Total bilirubin: 1.1 mg/dL
Albumin: 4.8 g/dL.
Cholesterol: 161 mg/dL
Serum triglycerides: 136 mg/dL
High-density lipoprotein: 57 mg/dL
Low-density lipoprotein: 77 mg/dL
Glycosylated hemoglobin: 6.6%
Long-term Management Plan
The patient continues his clinic visits for follow-up of his HBV infection at 6-month intervals, during which time he undergoes laboratory work-up to assess his liver enzyme levels and serum HBV DNA. He undergoes biannual screening for hepatocellular carcinoma mainly with ultrasound examination. Serum AFP as a single test for hepatocellular carcinoma has lost favor, although it is commonly done in conjunction with an ultrasound of the liver.[8-10]
Conclusion
When screening, diagnosing, and managing hepatitis B infection, clinicians should always consider the "rule of 3's":
3 tests to screen: HBcAb, HBsAg, HBsAb
3 tests to diagnose: HBeAg, HBeAb, HBV DNA
3 findings to contemplate therapy:
HBsAg positivity and
HBV DNA ™ 2000 IU/mL (if HBeAg negative) or ™ 20,000 IU/mL (if HBeAg positive), and
Elevated ALT or normal ALT and a liver biopsy showing chronic active hepatitis
3 findings indicating when to stop treatment of oral antivirals: HBV DNA undetectable, HBsAg-negative, and HBsAb-positive (the stopping rules apply for all types of HBV, and they are rarely achievable) Patients with chronic hepatitis B, in any of the various phases of the infection, require close observation and frequent testing to initiate treatment and to monitor response to therapy. Failure to respond after the first 6 months of treatment (primary treatment failure), or virologic breakthrough after achieving initial response (secondary treatment failure), requires adding another agent to the initial therapy or switching therapies. Lamivudine resistance is very common, and patients who continue to use lamivudine should be closely monitored to detect any genotypic mutations. They should be managed by adding either adefovir or tenofovir** before they develop biochemical breakthrough and lose the histopathologic improvement that they gained from previous therapy. Currently, lamivudine is no longer recommended as initial therapy due to the high rate of resistance. The oral antiviral drugs with a high genetic barrier to resistance and/or high potency (eg, entecavir or tenofovir) are generally recommended as initial treatment.[1,2] The current strategy for managing the development of resistance to any monotherapy involves adding a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug when resistance to a nucleoside agent is detected, and vice versa; Table 7).
Glycosylated hemoglobin: 5.8%
HBV DNA: 62,500 IU/mL
HBsAg (+), HBsAb (-), HBeAg (-) and HBeAb (+)
AFP: 6 ng/mL
ALT: 40 IU/L
AST: 35 IU/L
Total bilirubin: 0.9 mg/dL
Creatinine: 0.9 mg/dL
Blood urea nitrogen: 25 mg/dL
Evaluation of 12-month follow-up. The patient was receiving treatment for metabolic syndrome. His HBV DNA became positive after being undetectable for more than 1 year while on lamivudine.
On the basis of these findings, we suspected that the patient had a virologic breakthrough most probably as a result of development of the YMDD mutation and resistance to lamivudine. At this point in management, adefovir 10 mg/day was added to continued lamivudine therapy.
Lamivudine Resistance
Currently available antiviral agents for chronic hepatitis B are either nucleoside (lamivudine, entecavir, telbivudine) or nucleotide (adefovir, tenofovir**) analogs. Using oral antivirals requires long-term therapy (and in most patients, indefinite treatment) to maintain viral suppression. Long duration of therapy increases the risk for antiviral drug resistance. Lamivudine resistance occurs in approximately 20% of patients after 1 year and in up to 65% after 5 years.[6] The characteristic mutations occur in the YMDD motif of the HBV DNA polymerase. When this mutation occurs, the sensitivity to lamivudine decreases greater than 100-fold. Lamivudine-resistant mutations confer cross-resistance to other nucleosides, such as emtricitabine,** telbivudine, and clevudine.** They also decrease susceptibility to entecavir. The main approach to managing lamivudine resistance is to add adefovir or tenofovir (when approved) to ongoing lamivudine therapy.[7]
Until now, the recommended approach to managing HBV infection has involved the use of monotherapy, which is associated with a high risk of developing drug resistance. It has been recommended that patients should be closely monitored for virologic and biochemical response every 3-6 months. When viral breakthrough occurs, the mutant virus replicates, and its titer increases; this is then followed by an increase in aminotransferase levels (biochemical breakthrough) and histopathologic changes on liver biopsy.[2,7]
Strategies for the Management of Drug-Resistant HBV Infection Close follow-up allows for early detection of viral breakthrough and implementation of appropriate management strategies (Table 7) before the patient develops biochemical breakthrough and histopathologic deterioration.[1,2,7]
Table 7. Potential Management of HBV Antiviral Drug Resistance[1,2,7]
Resistance to HBV Antivirals Strategy
Lamivudine Add adefovir or tenofovir**or switch to tenofovir/emtricitabine**
Adefovir Add lamivudine or telbivudine or add/switch to entecavir if not prior
lamivudine resistance or switch to tenofovir/emtricitabine**
Telbivudine Add adefovir or tenofovir** or switch to tenofovir/emtricitabine**
Entecavir Switch to or add adefovir or tenofovir** Switch to
emtricitabine/tenofovir**
**Not currently approved by US FDA
Continued Management (2008)
Since mid-2003, the patient has been on lamivudine 100 mg daily in combination with adefovir 10 mg daily. His current laboratory values are as follows:
ALT: 28 IU/L
AST: 32 IU/L
HBV DNA: < 29 IU/mL
HBsAg: positive
HBsAb: negative
HBeAg: negative
HBeAb: positive.
Platelets: 189 x 103/mm3
AFP: 5 ng/mL
Total bilirubin: 1.1 mg/dL
Albumin: 4.8 g/dL.
Cholesterol: 161 mg/dL
Serum triglycerides: 136 mg/dL
High-density lipoprotein: 57 mg/dL
Low-density lipoprotein: 77 mg/dL
Glycosylated hemoglobin: 6.6%
Long-term Management Plan
The patient continues his clinic visits for follow-up of his HBV infection at 6-month intervals, during which time he undergoes laboratory work-up to assess his liver enzyme levels and serum HBV DNA. He undergoes biannual screening for hepatocellular carcinoma mainly with ultrasound examination. Serum AFP as a single test for hepatocellular carcinoma has lost favor, although it is commonly done in conjunction with an ultrasound of the liver.[8-10]
Conclusion
When screening, diagnosing, and managing hepatitis B infection, clinicians should always consider the "rule of 3's":
3 tests to screen: HBcAb, HBsAg, HBsAb
3 tests to diagnose: HBeAg, HBeAb, HBV DNA
3 findings to contemplate therapy:
HBsAg positivity and
HBV DNA ™ 2000 IU/mL (if HBeAg negative) or ™ 20,000 IU/mL (if HBeAg positive), and
Elevated ALT or normal ALT and a liver biopsy showing chronic active hepatitis
3 findings indicating when to stop treatment of oral antivirals: HBV DNA undetectable, HBsAg-negative, and HBsAb-positive (the stopping rules apply for all types of HBV, and they are rarely achievable) Patients with chronic hepatitis B, in any of the various phases of the infection, require close observation and frequent testing to initiate treatment and to monitor response to therapy. Failure to respond after the first 6 months of treatment (primary treatment failure), or virologic breakthrough after achieving initial response (secondary treatment failure), requires adding another agent to the initial therapy or switching therapies. Lamivudine resistance is very common, and patients who continue to use lamivudine should be closely monitored to detect any genotypic mutations. They should be managed by adding either adefovir or tenofovir** before they develop biochemical breakthrough and lose the histopathologic improvement that they gained from previous therapy. Currently, lamivudine is no longer recommended as initial therapy due to the high rate of resistance. The oral antiviral drugs with a high genetic barrier to resistance and/or high potency (eg, entecavir or tenofovir) are generally recommended as initial treatment.[1,2] The current strategy for managing the development of resistance to any monotherapy involves adding a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug when resistance to a nucleoside agent is detected, and vice versa; Table 7).
Patients chronically infected with HBV do not always remain in the same phase of infection. The interaction between the virus and the immune system of the patient affect viral replication, the extent of liver injury, and the patient's symptomatology. Over the lifetime of the infection, patients who perinatally acquired HBV can present with one of 4 main phases of infection (Table 4).[3] Early in the course of infection, when the patient is still an infant, the immune system does not mount a reaction against the viral infection. During that time, the patient is considered to be in the immune-tolerant phase, which can last for decades. However, some patients develop fluctuations in their serum aminotransferases, usually associated with active inflammation on liver biopsy. This phase is considered the HBeAg-positive phase and is characterized by HBeAg positivity. Although HBV DNA levels fluctuate, they remain significantly elevated and is associated with elevated aminotransferases. In this phase, there is immune-mediated lysis of the HBV-infected hepatocytes. In most patients this phase precedes another phase in which HBeAg loss occurs and HBeAb develops (seroconversion). As patients move out of this phase, they may progress to the inactive carrier state or the HBeAg-negative state. The inactive carrier state is characterized by HBeAg negativity, low viral titer or HBV DNA negativity, normal aminotransferases, and the absence of active inflammation on liver biopsy. The HBeAg-negative state is characterized by HBeAg loss, but viral replication continues, albeit at a lower level than it was in the HBeAg-positive phase of infection. This phase is also associated with elevated aminotransferases and active inflammation on liver biopsy. Although patients may remain in one phase for the life of the infection, movement across phases is more common. It is rare that a patient spontaneously loses HBsAg (seroclearance) and develops HBsAb. These patients have undetectable HBV DNA, normal liver enzymes, and no active inflammation on liver biopsy.[3]
Table 4. Phases of Chronic Hepatitis B[3]
Phases Laboratory Findings
Immune tolerant HBsAg (+); HBeAg (+);HBV DNA> 20,000 IU/mL; normal ALT
HBeAg-positive HBsAg (+); HBeAg (+); HBV DNA> 20,000 IU/mL; elevated ALT
Inactive carrier HBsAg (+); HBeAg (-); HBV DNA (-) or 2000 IU/mL; elevated ALT
Diagnosis
The patient was diagnosed with chronic active hepatitis B infection (HBsAg positive> 6 months); phase: HBeAg negative with high viral replication (HBV DNA> 2000 IU/mL and elevated ALT [130 IU/L]).
Treatment
In some patients, chronic HBV infection can lead to chronic progressive hepatitis, fibrosis, and cirrhosis. Patients who develop cirrhosis are at high risk for liver decompensation and death. In addition, chronic HBV infection is the main cause of liver cancer worldwide.[4] Chronically infected patients could develop hepatocellular carcinoma even in the absence of liver fibrosis or cirrhosis. Treatment of HBV infection is essential and involves either boosting the immune system through the use of immune modulators or using oral antiviral agents to suppress viral replication and allow the immune system to control further viral replication when therapy ends. The more commonly applied therapeutic approach is oral antiviral therapy to suppress viral replication and decrease or eliminate the chronic inflammatory process in the liver. This normalizes aminotransferases, regresses fibrosis, and possibly decreases the risk of developing hepatocellular carcinoma. Some patients require long-term treatment with the oral antiviral agents.[4] The FDA has approved a number of medications for patients with chronic actively replicating hepatitis B virus who present with increased aminotransferase levels and/or histopathologic hepatitis (Table 5). These include interferon alfa-2b, pegylated interferon alfa-2a, and the oral antiviral agents lamivudine (nucleoside analog), adefovir (nucleotide analog), entecavir (nucleoside analog), and telbivudine (nucleoside analog).
Table 5. Therapies for Hepatitis B
Therapy Comments
Interferon alfa-2b
(daily or 3-times-weekly injection) Immune modulator
Pegylated interferon alfa-2a
(once-weekly injection) Immune modulator
Lamivudine First nucleoside analog used in the treatment of HBV; not
recommended as initial therapy due to high risk for resistance
Adefovir, entecavir, telbivudine* First-line viral suppressors
Tenofovir** Under FDA review for likely approval in 2008; first-line therapy
following licensure (will likely replace adefovir)
Emtricitabine**, clevudine** In clinical trials
*Alternative option
**The US Food and Drug Administration has not approved this medication for
this use.
Our patient had 3 of the major criteria for therapy (Table 6). He is
HBsAg-positive and HBeAg-negative, with high viral replication and elevated
serum ALT. Therefore, he was a candidate for antiviral therapy.
Table 6. Whom to Treat (3 Criteria)
HBsAg positive
HBV DNA> 2000 IU/mL
Elevated serum ALT or normal ALT and chronic active hepatitis on liver biopsy
The patient was started on lamivudine 100 mg/day (standard treatment in 2002)[5] and was encouraged to stop smoking and to minimize his alcohol intake. He was advised to adhere to a diabetic diet and continued treatment for his diabetes (glipizide).
3-Month Follow-up Visit
At 3 months, the patient had no complaints, was feeling well, and reported that his energy had improved. His HBV DNA level was < 50 IU/mL and his serum ALT and AST levels were 34 IU/L and 23 IU/L, respectively.
6-Month Follow-up Visit
At 6 months, the patient returned for evaluation. He continued to feel well and had no symptoms. His HBV DNA level was still < 50 IU/mL, and he was HBeAg-negative and HBeAb-positive. His serum ALT and AST were 18 IU/L and 20 IU/L, respectively.
12-Month Follow-up Visit
At 12 months, the patient was doing well, but was diagnosed with the metabolic syndrome (hypertension, hyperlipidemia, and diabetes mellitus). His primary care provider started him on lisinopril, ezetimibe, and gemfibrozil.
Table 4. Phases of Chronic Hepatitis B[3]
Phases Laboratory Findings
Immune tolerant HBsAg (+); HBeAg (+);HBV DNA> 20,000 IU/mL; normal ALT
HBeAg-positive HBsAg (+); HBeAg (+); HBV DNA> 20,000 IU/mL; elevated ALT
Inactive carrier HBsAg (+); HBeAg (-); HBV DNA (-) or 2000 IU/mL; elevated ALT
Diagnosis
The patient was diagnosed with chronic active hepatitis B infection (HBsAg positive> 6 months); phase: HBeAg negative with high viral replication (HBV DNA> 2000 IU/mL and elevated ALT [130 IU/L]).
Treatment
In some patients, chronic HBV infection can lead to chronic progressive hepatitis, fibrosis, and cirrhosis. Patients who develop cirrhosis are at high risk for liver decompensation and death. In addition, chronic HBV infection is the main cause of liver cancer worldwide.[4] Chronically infected patients could develop hepatocellular carcinoma even in the absence of liver fibrosis or cirrhosis. Treatment of HBV infection is essential and involves either boosting the immune system through the use of immune modulators or using oral antiviral agents to suppress viral replication and allow the immune system to control further viral replication when therapy ends. The more commonly applied therapeutic approach is oral antiviral therapy to suppress viral replication and decrease or eliminate the chronic inflammatory process in the liver. This normalizes aminotransferases, regresses fibrosis, and possibly decreases the risk of developing hepatocellular carcinoma. Some patients require long-term treatment with the oral antiviral agents.[4] The FDA has approved a number of medications for patients with chronic actively replicating hepatitis B virus who present with increased aminotransferase levels and/or histopathologic hepatitis (Table 5). These include interferon alfa-2b, pegylated interferon alfa-2a, and the oral antiviral agents lamivudine (nucleoside analog), adefovir (nucleotide analog), entecavir (nucleoside analog), and telbivudine (nucleoside analog).
Table 5. Therapies for Hepatitis B
Therapy Comments
Interferon alfa-2b
(daily or 3-times-weekly injection) Immune modulator
Pegylated interferon alfa-2a
(once-weekly injection) Immune modulator
Lamivudine First nucleoside analog used in the treatment of HBV; not
recommended as initial therapy due to high risk for resistance
Adefovir, entecavir, telbivudine* First-line viral suppressors
Tenofovir** Under FDA review for likely approval in 2008; first-line therapy
following licensure (will likely replace adefovir)
Emtricitabine**, clevudine** In clinical trials
*Alternative option
**The US Food and Drug Administration has not approved this medication for
this use.
Our patient had 3 of the major criteria for therapy (Table 6). He is
HBsAg-positive and HBeAg-negative, with high viral replication and elevated
serum ALT. Therefore, he was a candidate for antiviral therapy.
Table 6. Whom to Treat (3 Criteria)
HBsAg positive
HBV DNA> 2000 IU/mL
Elevated serum ALT or normal ALT and chronic active hepatitis on liver biopsy
The patient was started on lamivudine 100 mg/day (standard treatment in 2002)[5] and was encouraged to stop smoking and to minimize his alcohol intake. He was advised to adhere to a diabetic diet and continued treatment for his diabetes (glipizide).
3-Month Follow-up Visit
At 3 months, the patient had no complaints, was feeling well, and reported that his energy had improved. His HBV DNA level was < 50 IU/mL and his serum ALT and AST levels were 34 IU/L and 23 IU/L, respectively.
6-Month Follow-up Visit
At 6 months, the patient returned for evaluation. He continued to feel well and had no symptoms. His HBV DNA level was still < 50 IU/mL, and he was HBeAg-negative and HBeAb-positive. His serum ALT and AST were 18 IU/L and 20 IU/L, respectively.
12-Month Follow-up Visit
At 12 months, the patient was doing well, but was diagnosed with the metabolic syndrome (hypertension, hyperlipidemia, and diabetes mellitus). His primary care provider started him on lisinopril, ezetimibe, and gemfibrozil.
Notes on “Strategies in the Management of Chronic Hepatitis B CME,” Deanna L. Oliver, BS Tarek Hassanein, MD, FACP, FACG, Hepatitis B: Advances in Screening, Diagnosis, and Clinical Management -- Volume 2, 2008.
History of Present Illness
A 32-year-old Korean-American man who worked as a software engineer came to the clinic in July 2002 complaining of fatigue, low energy, and right upper quadrant discomfort. The discomfort was dull in character and radiated to the back. He denied nausea, vomiting, and diarrhea. He reported weight loss of 30 pounds in 8 months. He also complained of polyuria, polydipsia, and dry mouth. The patient was diagnosed 1 year ago with non-insulin-dependent diabetes mellitus and was being treated with glipizide. However, he was not adherent to his therapy. He admitted to smoking a pack of cigarettes per day and to regularly drinking alcoholic beverages. His family history was significant for hepatitis B infection in one brother and diabetes mellitus in both parents. His physical examination showed no peripheral signs of chronic liver disease and no hepatomegaly, splenomegaly, or ascites.
Hepatitis B virus (HBV) is highly endemic in areas such as Southeast Asia and Africa, and individuals from regions with high or intermediate prevalence of HBV should be offered screening.[1] Other populations who would benefit from screening include individuals of Asian descent and close contacts of HBV-infected individuals.[1]
This patient was an Asian American who had a family history of hepatitis B. Accordingly, he should be screened for HBV infection. The standard serologic markers used to screen for HBV include hepatitis B core antibody (anti-HBc), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb). See Table 1.[1,2] HBcAb positivity indicates prior exposure and infection with HBV; HBcAb-IgG class indicates previous exposure, whereas the HBcAb-IgM class defines acute infection or viral reactivation and should be screened for in patients with jaundice and signs of acute hepatitis. The presence of HBsAg positivity for more than 6 months defines chronic infection, whereas HBsAb indicates immunity.
Table 1. Screening for Hepatitis B Infection
3 tests:
Hepatitis B core antibody (IgG HBcAb)
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antibody (HBsAb)
Initial Evaluation
The patient underwent the following laboratory investigations:
Complete blood count (CBC) with differential and coagulation parameters
Comprehensive metabolic panel, gamma-glutamyl transferase (GGT), total protein, uric acid, iron, iron binding capacity, ferritin, lipid panel, thyroid-stimulating hormone (TSH), alpha-fetoprotein (AFP), and glycosylated hemoglobin
Viral serologies
Hepatitis B virus (HBcAb, HBsAg, HBsAb)
Others: hepatitis A virus antibody (HAV Ab), hepatitis C virus antibody (HCV Ab), HIV Ab
Autoantibodies: Antinuclear antibodies (ANA), and anti-smooth muscle antibody (ASMA)
The patient also underwent ultrasound examination of the abdomen and liver.
Results of key initial laboratory investigations are shown in Table 2.
Table 2. Results of Initial Laboratory Investigations
Test Comment
Serologies
HBcAb: positive
HBsAg: positive
HBsAb: negative Indicates patient has chronic hepatitis B infection
CBC
WBC: 5.8 103/mm3
Hemoglobin: 14.5 g/dL
Platelets: 154 x 103/mm3 Low platelet count
Chemistries
Alanine aminotransferase (ALT): 154 IU/L
Aspartate aminotransferase (AST): 261 IU/L
Alkaline phosphatase: 85 IU/L
Glucose: 198 mg/dL
AFP: 11 ng/mL
Total bilirubin: 1.1 mg/dL
Creatinine: 0.8 mg/dL
Total protein: 7.0 g/dL
Albumin 4.7 g/dL
Globulin: 2.3
ANA: negative
ASMA: negative Indicates active liver inflammation (ALT/AST high), normal synthetic liver functions (albumin, total bilirubin normal), diabetes (fasting glucose), no renal dysfunction (normal creatinine), and no autoimmune hepatitis (negative ANA and ASMA)
Ultrasound
Liver measured 14.4 cm by long axis; echogenicity was within normal limits; spleen was normal in size; no ascites Indicates no signs of portal hypertension
Follow-up Visit
The patient returned for his first follow-up visit 4 weeks later. At this time, he was diagnosed with chronic hepatitis B infection in addition to his diabetes mellitus type 2.
Additional serologic and virologic work-up was ordered to fully characterize the status/type of chronic active hepatitis B. Specifically, the patient was tested for hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), and antibody to hepatitis D virus (HDV Ab), and viral load (HBV DNA) was determined. In addition, glycosylated hemoglobin was measured. See Table 3.
Table 3. Additional Tests for Characterizing Status of Chronic Hepatitis B Infection
3 tests:
HBeAg
HBeAb
HBV DNA
Patients with chronic hepatitis B infection (HBsAg -positive) present in different immune stages. The presence of HBeAg and HBeAb, while the virus is replicating at high levels (HBV-DNA> 104 or 105 IU/mL) in the presence of elevated ALT due to viral-induced hepatitis, are the benchmarks for considering antiviral therapy. Accordingly, any patient with HBsAg positivity should be further classified according to their HBeAg, HBeAb, and HBV DNA titer (Table 4).[3] In addition, any patient with chronic hepatitis B infection should be screened for HDV infection as well, as it might modify the therapy of an HBV-infected patient.
Results of these additional laboratory investigations revealed the following:
HBeAg: negative; HBeAb: positive; HBV DNA: positive; 7.5 million copies/mL (1.5 million IU/mL)
HDV Ab: negative
Glycosylated hemoglobin: 5.3%
ALT: 130 IU/L; AST: 199 IU/L
History of Present Illness
A 32-year-old Korean-American man who worked as a software engineer came to the clinic in July 2002 complaining of fatigue, low energy, and right upper quadrant discomfort. The discomfort was dull in character and radiated to the back. He denied nausea, vomiting, and diarrhea. He reported weight loss of 30 pounds in 8 months. He also complained of polyuria, polydipsia, and dry mouth. The patient was diagnosed 1 year ago with non-insulin-dependent diabetes mellitus and was being treated with glipizide. However, he was not adherent to his therapy. He admitted to smoking a pack of cigarettes per day and to regularly drinking alcoholic beverages. His family history was significant for hepatitis B infection in one brother and diabetes mellitus in both parents. His physical examination showed no peripheral signs of chronic liver disease and no hepatomegaly, splenomegaly, or ascites.
Hepatitis B virus (HBV) is highly endemic in areas such as Southeast Asia and Africa, and individuals from regions with high or intermediate prevalence of HBV should be offered screening.[1] Other populations who would benefit from screening include individuals of Asian descent and close contacts of HBV-infected individuals.[1]
This patient was an Asian American who had a family history of hepatitis B. Accordingly, he should be screened for HBV infection. The standard serologic markers used to screen for HBV include hepatitis B core antibody (anti-HBc), hepatitis B surface antigen (HBsAg), and hepatitis B surface antibody (HBsAb). See Table 1.[1,2] HBcAb positivity indicates prior exposure and infection with HBV; HBcAb-IgG class indicates previous exposure, whereas the HBcAb-IgM class defines acute infection or viral reactivation and should be screened for in patients with jaundice and signs of acute hepatitis. The presence of HBsAg positivity for more than 6 months defines chronic infection, whereas HBsAb indicates immunity.
Table 1. Screening for Hepatitis B Infection
3 tests:
Hepatitis B core antibody (IgG HBcAb)
Hepatitis B surface antigen (HBsAg)
Hepatitis B surface antibody (HBsAb)
Initial Evaluation
The patient underwent the following laboratory investigations:
Complete blood count (CBC) with differential and coagulation parameters
Comprehensive metabolic panel, gamma-glutamyl transferase (GGT), total protein, uric acid, iron, iron binding capacity, ferritin, lipid panel, thyroid-stimulating hormone (TSH), alpha-fetoprotein (AFP), and glycosylated hemoglobin
Viral serologies
Hepatitis B virus (HBcAb, HBsAg, HBsAb)
Others: hepatitis A virus antibody (HAV Ab), hepatitis C virus antibody (HCV Ab), HIV Ab
Autoantibodies: Antinuclear antibodies (ANA), and anti-smooth muscle antibody (ASMA)
The patient also underwent ultrasound examination of the abdomen and liver.
Results of key initial laboratory investigations are shown in Table 2.
Table 2. Results of Initial Laboratory Investigations
Test Comment
Serologies
HBcAb: positive
HBsAg: positive
HBsAb: negative Indicates patient has chronic hepatitis B infection
CBC
WBC: 5.8 103/mm3
Hemoglobin: 14.5 g/dL
Platelets: 154 x 103/mm3 Low platelet count
Chemistries
Alanine aminotransferase (ALT): 154 IU/L
Aspartate aminotransferase (AST): 261 IU/L
Alkaline phosphatase: 85 IU/L
Glucose: 198 mg/dL
AFP: 11 ng/mL
Total bilirubin: 1.1 mg/dL
Creatinine: 0.8 mg/dL
Total protein: 7.0 g/dL
Albumin 4.7 g/dL
Globulin: 2.3
ANA: negative
ASMA: negative Indicates active liver inflammation (ALT/AST high), normal synthetic liver functions (albumin, total bilirubin normal), diabetes (fasting glucose), no renal dysfunction (normal creatinine), and no autoimmune hepatitis (negative ANA and ASMA)
Ultrasound
Liver measured 14.4 cm by long axis; echogenicity was within normal limits; spleen was normal in size; no ascites Indicates no signs of portal hypertension
Follow-up Visit
The patient returned for his first follow-up visit 4 weeks later. At this time, he was diagnosed with chronic hepatitis B infection in addition to his diabetes mellitus type 2.
Additional serologic and virologic work-up was ordered to fully characterize the status/type of chronic active hepatitis B. Specifically, the patient was tested for hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), and antibody to hepatitis D virus (HDV Ab), and viral load (HBV DNA) was determined. In addition, glycosylated hemoglobin was measured. See Table 3.
Table 3. Additional Tests for Characterizing Status of Chronic Hepatitis B Infection
3 tests:
HBeAg
HBeAb
HBV DNA
Patients with chronic hepatitis B infection (HBsAg -positive) present in different immune stages. The presence of HBeAg and HBeAb, while the virus is replicating at high levels (HBV-DNA> 104 or 105 IU/mL) in the presence of elevated ALT due to viral-induced hepatitis, are the benchmarks for considering antiviral therapy. Accordingly, any patient with HBsAg positivity should be further classified according to their HBeAg, HBeAb, and HBV DNA titer (Table 4).[3] In addition, any patient with chronic hepatitis B infection should be screened for HDV infection as well, as it might modify the therapy of an HBV-infected patient.
Results of these additional laboratory investigations revealed the following:
HBeAg: negative; HBeAb: positive; HBV DNA: positive; 7.5 million copies/mL (1.5 million IU/mL)
HDV Ab: negative
Glycosylated hemoglobin: 5.3%
ALT: 130 IU/L; AST: 199 IU/L
Notes on “The case for combination antiviral therapy for chronic hepatitis B virus infection,” Kathryn L Nash, THE LANCET INFECTIOUS DISEASES, Volume 8, Issue 7, July 2008, Pages 444-448
Summary: The treatment of hepatitis B virus (HBV) infection has been revolutionised in the past decade by the increased availability of effective antiviral agents. Many studies have shown the benefits of single agent therapy, but there is an alarming and rising rate of viral resistance, and clear evidence that viruses that harbour resistant mutations can cause liver disease and death. Current national guidelines for the treatment of HBV recommend a programme that starts with monotherapy, followed by sequential monotherapy or add-on therapy for those infections in which mutations have arisen. Very few studies starting with combination therapy have been undertaken, so there is little evidence of the clinical benefit of this approach to treatment. The studies that have been done have been short term and have concentrated on clinical parameters rather than virological resistance, which is likely to be the key determinant in the longer term. We argue that we should not wait for the evidence to use combination therapy for the treatment of HBV, since such trials may never be done and it would take several years for a benefit to become apparent. In the meantime, multidrug-resistant strains continue to hinder HBV control.
Summary: The treatment of hepatitis B virus (HBV) infection has been revolutionised in the past decade by the increased availability of effective antiviral agents. Many studies have shown the benefits of single agent therapy, but there is an alarming and rising rate of viral resistance, and clear evidence that viruses that harbour resistant mutations can cause liver disease and death. Current national guidelines for the treatment of HBV recommend a programme that starts with monotherapy, followed by sequential monotherapy or add-on therapy for those infections in which mutations have arisen. Very few studies starting with combination therapy have been undertaken, so there is little evidence of the clinical benefit of this approach to treatment. The studies that have been done have been short term and have concentrated on clinical parameters rather than virological resistance, which is likely to be the key determinant in the longer term. We argue that we should not wait for the evidence to use combination therapy for the treatment of HBV, since such trials may never be done and it would take several years for a benefit to become apparent. In the meantime, multidrug-resistant strains continue to hinder HBV control.
Notes on “Hepatitis B Patients Face Broad Discrimination in China. Ostracized and unable to secure jobs, victims turn to a support web site, now banned by the communist regime.” Wu Xue'er, Epoch Times Staff Jul 04, 2008
Yirenping Center General Coordinator Lu Jun speaks in Hong Kong on the government's interference with the forum. (Wu Xue'Er/The Epoch Times) HONG KONG—Having passed a civil service exam, a Zhejiang University graduate was subsequently rejected when he was found to have hepatitis B. In a fury, he killed the recruiting official. It was 2003, and he had graduated from one of China's finest schools. The court found him guilty of murder and handed down the death penalty. He tore the court document stating his sentence into pieces. A Ph.D. from Xiamen University was unable to secure a job when he was found to be a carrier of hepatitis B. He ended his life by hanging himself in a bathroom. Many such tragedies occur in China every year, according to Lu Jun, coordinator of the Yirenping Center in Beijing and host of the "Liver and Gallbladder Care" Web site. Hepatitis B patients face serious discrimination in China. Lu says that such discrimination leads directly to hatred, social exclusion, and tragedies such as these. People with hepatitis B have difficulty finding employment or attending school. Eighty percent of foreign companies with branches in China also refuse to hire people with hepatitis B. It is estimated that approximately 100 million people in China carry the hepatitis B virus. Since 2003, many have connected through the "Liver and Gallbladder Care Forum" (bbs.hbvhbv.com). The forum has become a home for hepatitis B patients who seek information and basic human rights. It enables them to fight discrimination, including organizing anti-discrimination lawsuits against government agencies. Instead of supporting the forum, however, Lu says that the Chinese communist regime has responded by suppressing and banning it. This has led to much anger and disappointment among those affected. Lu identifies three factors that have contributed to the widespread discrimination against hepatitis B patients. First, a lack of government regulation of advertising practices used by pharmaceutical companies resulted in exaggerated claims of the infectious nature of hepatitis B. Though their intention was to increase sales, their tactics led the public to fear and misunderstand the disease. Second, the government process for hiring civil service employees included screening for hepatitis B beginning in 1997. Many private enterprises followed suit, rejecting hepatitis B patients from employment. Third, laws have been passed banning hepatitis patients in China from holding certain jobs, including janitor, elevator operator, cashier, schoolteacher, and all jobs in the food industry. These laws, over 20 in number, have deprived hepatitis B patients of their basic rights.
Yirenping Center General Coordinator Lu Jun speaks in Hong Kong on the government's interference with the forum. (Wu Xue'Er/The Epoch Times) HONG KONG—Having passed a civil service exam, a Zhejiang University graduate was subsequently rejected when he was found to have hepatitis B. In a fury, he killed the recruiting official. It was 2003, and he had graduated from one of China's finest schools. The court found him guilty of murder and handed down the death penalty. He tore the court document stating his sentence into pieces. A Ph.D. from Xiamen University was unable to secure a job when he was found to be a carrier of hepatitis B. He ended his life by hanging himself in a bathroom. Many such tragedies occur in China every year, according to Lu Jun, coordinator of the Yirenping Center in Beijing and host of the "Liver and Gallbladder Care" Web site. Hepatitis B patients face serious discrimination in China. Lu says that such discrimination leads directly to hatred, social exclusion, and tragedies such as these. People with hepatitis B have difficulty finding employment or attending school. Eighty percent of foreign companies with branches in China also refuse to hire people with hepatitis B. It is estimated that approximately 100 million people in China carry the hepatitis B virus. Since 2003, many have connected through the "Liver and Gallbladder Care Forum" (bbs.hbvhbv.com). The forum has become a home for hepatitis B patients who seek information and basic human rights. It enables them to fight discrimination, including organizing anti-discrimination lawsuits against government agencies. Instead of supporting the forum, however, Lu says that the Chinese communist regime has responded by suppressing and banning it. This has led to much anger and disappointment among those affected. Lu identifies three factors that have contributed to the widespread discrimination against hepatitis B patients. First, a lack of government regulation of advertising practices used by pharmaceutical companies resulted in exaggerated claims of the infectious nature of hepatitis B. Though their intention was to increase sales, their tactics led the public to fear and misunderstand the disease. Second, the government process for hiring civil service employees included screening for hepatitis B beginning in 1997. Many private enterprises followed suit, rejecting hepatitis B patients from employment. Third, laws have been passed banning hepatitis patients in China from holding certain jobs, including janitor, elevator operator, cashier, schoolteacher, and all jobs in the food industry. These laws, over 20 in number, have deprived hepatitis B patients of their basic rights.
Notes on “Approach to Managing the Pregnant Woman With Chronic Hepatitis B and Detectable Viral Load?” William F. Balistreri, from Medscape Gastroenterology, Ask the Experts about Liver Disease, Posted 07/09/2008
Question: Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?
Response:
Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases.[1] Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg.[1] Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced.[1] Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series.[2] This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations>107 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.[3]
In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.
HBIG: In a prospective randomized controlled trial, Xu and colleagues[4] administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.
Specific Antiviral Therapy: The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and colleagues[5] treated 8 highly viremic (HBV DNA>1.2 x 109 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy.[6-9] Li and colleagues[6] investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P .05). No side effects occurred in the pregnant women or their newborns.
Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues[8] reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.
A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications.[1,3] In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine.[9] And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans.[3] With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.[3,10]
The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.
Question: Should pregnant women with chronic hepatitis B with detectable viral load be treated with antiviral agents during pregnancy to decrease the risk for transmission to the baby?
Response:
Let me first frame the question -- what problem are we trying to solve? Infection with hepatitis B virus (HBV) in infancy or early childhood often leads to persistent infection, as evidenced by the fact that in countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases.[1] Approximately 90% of untreated infants born to mothers positive for hepatitis B e-antigen (HBeAg) will develop "immune tolerance." This is traditionally explained by transplacental transfer of viral antigens, which induces a specific nonresponsiveness of helper T cells to HBeAg and hepatitis B core antigen (HBcAg). Spontaneous HBeAg seroconversion (to anti-HBe positive) may develop with time, but liver damage may occur during the process of immune clearance of HBeAg.[1] Screening for maternal hepatitis B surface antigen (HBsAg), followed by administration of HBV vaccine and hepatitis B-specific immunoglobulin (HBIG) to the newborn within 24 hours of birth, is the most effective way to prevent perinatal HBV infection. The first universal HBV immunization program in the world was launched in Taiwan over 20 years ago; thus, the HBV infection rate and the incidence of hepatocellular carcinoma and fulminant hepatitis in children have been reduced.[1] Current published guidelines state that newborns of HBV-infected mothers should receive passive-active immunoprophylaxis with HBIG and hepatitis B vaccine at delivery and complete the recommended vaccination series.[2] This strategy is approximately 95% effective in reducing the risk for HBV transmission, but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. Maternal serum HBV DNA concentrations>107 IU/mL have been associated with a 5% to 10% failure of immunoprophylaxis.[3]
In highly viremic HBsAg-positive mothers, reduction of viremia in the last month of pregnancy may be an effective and safe measure to decrease the risk for failure of prophylaxis. Two separate strategies have been used to reduce the "viral burden" during pregnancy: prenatal HBIG administration and specific antiviral therapy. However, prophylactic therapy is complex, controversial, and not well studied.
HBIG: In a prospective randomized controlled trial, Xu and colleagues[4] administered either placebo or HBIG (200 IU intravenously every 4 weeks for 3 times) from the 28th week of gestation in HBsAg-positive mothers. There was a significant difference in the rate of HBeAg and HBV DNA positivity in the newborns (positivity rates: 25% in those born to mothers who received HBIG vs 83% in placebo recipients). In addition, the HBV DNA load of newborns was lower than that of their treated mothers and significantly lower than that of untreated controls.
Specific Antiviral Therapy: The only oral antiviral agent studied in this setting is lamivudine. When given in the last 4 weeks of pregnancy, lamivudine has been shown to reduce high-level viremia. van Zonneveld and colleagues[5] treated 8 highly viremic (HBV DNA>1.2 x 109 IU/mL) mothers with 150 mg of lamivudine daily during the last month of pregnancy. Children (n = 24) born to untreated HBsAg-positive mothers with similar HBV DNA levels served as controls. All children received passive-active immunization with HBIG and HBV vaccine at birth and were followed up for 12 months. Seven of the 8 lamivudine-treated mothers had a decrease in their serum HBV DNA concentrations. One of the 8 children (12.5%) in the lamivudine group remained HBsAg- and HBV DNA-positive at the age of 12 months; all other children seroconverted to anti-HBs. In the untreated control group, perinatal transmission occurred in 7 of 25 children (28%). Other studies have evaluated the efficacy and safety of lamivudine for the treatment of chronic hepatitis B in pregnancy.[6-9] Li and colleagues[6] investigated the effect of lamivudine vs HBIG on HBV intrauterine transmission. HBsAg-positive pregnant women (n = 56) were given either 200 IU of HBIG intramuscularly every 4 weeks from the 28th week of gestation, or lamivudine (n = 43) 100 mg orally every day from the 28th week of gestation until the 30th day after labor. Subjects in the control group (n = 52) received no specific treatment. The rate of neonatal HBV infection was significantly lower among those patients receiving HBIG (16%) or lamivudine (16%) compared with those in the control group (33%; P .05). No side effects occurred in the pregnant women or their newborns.
Lamivudine therapy may not prevent perinatal transmission of HBV infection in every newborn. Kazim and colleagues[8] reported the development of chronic HBV infection in a newborn despite suppression of HBV DNA to undetectable levels in the mother by prolonged lamivudine therapy. The newborn received neonatal vaccination and treatment with HBIG, yet had still had increased aminotransferase levels and was persistently positive for HBV DNA. On HBV DNA sequencing, complete sequence homology and a similar precore mutation was found in the mother and child, indicating vertical transmission.
A major question, in addition to efficacy, is, of course, safety. Again, to place the issue in perspective, it is important to remember that hepatitis B during pregnancy does not increase maternal morbidity or mortality or the risk for fetal complications.[1,3] In addition, the use of lamivudine did not directly lead to adverse events in the infected mothers. However, in one study, when compared with untreated women, there was a significant increase in liver disease activity after delivery in those patients treated with lamivudine.[9] And what about the potential effects of these drugs on the fetus? Lamivudine, adefovir, and entecavir are designated as category C drugs, which indicates that these drugs are capable of exerting teratogenic or embryocidal effects in animals; however, there are no controlled studies in humans.[3] With the emergence of additional nucleos(t)ide analogs (telbivudine and tenofovir [currently undergoing review by the FDA for use in chronic hepatitis B], which are category B drugs), studies are needed to evaluate their role in reducing viral burden during pregnancy.[3,10]
The bottom line: The strategy of using antiviral therapy to reduce viremia during pregnancy to decrease the risk for transmission of HBV to the baby is reasonable. However, at present, the data are not sufficient to make broad recommendations. The approach should be evaluated in a large controlled trial using new antiviral agents in combination with HBIG to prevent intrauterine HBV infection.
Notes on “CHINA: "China Cuts Off Hepatitis Patients" Toronto Star, (07.11.08
On May 29, a popular Web site for people in China living with hepatitis B went silent, at least, for people in China. It has not been seen there since. "At first I thought it was just a technical glitch, maybe a problem with the server," said Lu Jun, a former IT specialist who devotes his time to helping people with hepatitis B. But the site may be another victim of Chinese government efforts to heighten social control before the Beijing Olympic Games in August. The Web site offered support to hepatitis B virus (HBV) patients, and it also informed patients about their rights. Though about 95 million people live with HBV in China, discrimination against patients is widespread, HBV awareness is poor, and many believe the infection can be casually transmitted. From 2005, government departments have been prohibited from barring applicants with HBV. "Still, today there are 20 different laws that contain articles that discriminate against [HBV] carriers," Lu said. For example, people with HBV cannot work as teachers, bus drivers or as department store shop assistants. Under Lu's nonprofit Beijing Yirenping Center, 40 lawsuits have been filed on behalf of HBV patients since 2003, and 10 of the last 13 have been successful. "Many people have told me the government doesn't want any 'noise,' either before or during the Olympic Games," said Lu. The shutdown of the Web site "has caused a lot of anger among the HBV community," he said, "toward the Games, the government and the [Communist] Party." Some expressed their frustration at the popular Tianya Web site. The Olympics is making it difficult for all non-governmental organizations, said Nicholas Bequelin of the Human Rights Watch Hong Kong office. "People pointing to a defect in the public health system, or issues of discrimination" would annoy the government, he said.
On May 29, a popular Web site for people in China living with hepatitis B went silent, at least, for people in China. It has not been seen there since. "At first I thought it was just a technical glitch, maybe a problem with the server," said Lu Jun, a former IT specialist who devotes his time to helping people with hepatitis B. But the site may be another victim of Chinese government efforts to heighten social control before the Beijing Olympic Games in August. The Web site offered support to hepatitis B virus (HBV) patients, and it also informed patients about their rights. Though about 95 million people live with HBV in China, discrimination against patients is widespread, HBV awareness is poor, and many believe the infection can be casually transmitted. From 2005, government departments have been prohibited from barring applicants with HBV. "Still, today there are 20 different laws that contain articles that discriminate against [HBV] carriers," Lu said. For example, people with HBV cannot work as teachers, bus drivers or as department store shop assistants. Under Lu's nonprofit Beijing Yirenping Center, 40 lawsuits have been filed on behalf of HBV patients since 2003, and 10 of the last 13 have been successful. "Many people have told me the government doesn't want any 'noise,' either before or during the Olympic Games," said Lu. The shutdown of the Web site "has caused a lot of anger among the HBV community," he said, "toward the Games, the government and the [Communist] Party." Some expressed their frustration at the popular Tianya Web site. The Olympics is making it difficult for all non-governmental organizations, said Nicholas Bequelin of the Human Rights Watch Hong Kong office. "People pointing to a defect in the public health system, or issues of discrimination" would annoy the government, he said.
Notes on “VIRAL LOAD IS A STRONG PREDICTOR OF LIVER CIRRHOSIS RISK IN PEOPLE CHRONICALLY INFECTED WITH HEPATITIS B VIRUS REGARDLESS OF HEPATITIS B E ANTIGEN STATUS,” C.J. Chen, et al. 2005.
Introduction: HBeAg is considered a marker of active viral replication often associated with high levels of viremia. This study was carried out to examine the impact of HBV DNA level on the risk of disease progression to cirrhosis stratified by HBeAg status.
Methods: A population based prospective cohort of 3,851 subjects chronically infected with HBV was established was from seven townships in Taiwan between 1991 and 1992. Subjects were prospectively followed by hepatologists by clinical examinations including ultrasonography through June 30th 2004. The diagnosis of cirrhosis was based on ultrasonographic findings. All cirrhosis cases diagnosed within 6 months of enrollment were excluded from analyses. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.
Results: Overall, 3774 subjects with 42,115 person years of follow up contributed data to this analysis. There were 395 cases of cirrhosis. Of the 3774 participants, 3,214 (85%) were seronegative for HBeAg, of which 1082 (34%) had serum HBV DNA level ³104 copies/mL; 560 (15%) were HBeAg positive of which 538 (96%) had serum HBV DNA ³104 copies/mL at enrollment. There was a dose dependent relationship between HBV DNA and cirrhosis risk within the HBeAg strata. With the HBeAg negative undetectable DNA group as reference, the highest risk of progression was found in the HBeAg positive group with HBD DNA over 105 copies/mL.
Conclusion: Elevated serum HBV DNA is a strong predictor of cirrhosis risk in HBV infected persons regardless of HBeAg status. Effective suppression of HBV DNA to very low levels especially in HBeAg negative persons could reduce progression of CHB to cirrhosis.
Introduction: HBeAg is considered a marker of active viral replication often associated with high levels of viremia. This study was carried out to examine the impact of HBV DNA level on the risk of disease progression to cirrhosis stratified by HBeAg status.
Methods: A population based prospective cohort of 3,851 subjects chronically infected with HBV was established was from seven townships in Taiwan between 1991 and 1992. Subjects were prospectively followed by hepatologists by clinical examinations including ultrasonography through June 30th 2004. The diagnosis of cirrhosis was based on ultrasonographic findings. All cirrhosis cases diagnosed within 6 months of enrollment were excluded from analyses. Multivariable adjusted relative risks (RRadj) were derived using Cox proportional hazard models.
Results: Overall, 3774 subjects with 42,115 person years of follow up contributed data to this analysis. There were 395 cases of cirrhosis. Of the 3774 participants, 3,214 (85%) were seronegative for HBeAg, of which 1082 (34%) had serum HBV DNA level ³104 copies/mL; 560 (15%) were HBeAg positive of which 538 (96%) had serum HBV DNA ³104 copies/mL at enrollment. There was a dose dependent relationship between HBV DNA and cirrhosis risk within the HBeAg strata. With the HBeAg negative undetectable DNA group as reference, the highest risk of progression was found in the HBeAg positive group with HBD DNA over 105 copies/mL.
Conclusion: Elevated serum HBV DNA is a strong predictor of cirrhosis risk in HBV infected persons regardless of HBeAg status. Effective suppression of HBV DNA to very low levels especially in HBeAg negative persons could reduce progression of CHB to cirrhosis.
Notes on “Milk thistle does not reduce deaths from liver diseases,” best studies find, Center for the Advancement of Health, 2-May-2005.
Milk thistle, a widely used alternative medicine, is not proven effective in lowering mortality in alcoholic or hepatitis B or C liver disease, according to a systematic review of current evidence.While some studies found that liver-related mortality may be significantly reduced in patients treated with milk thistle, these findings were not duplicated in the higher quality clinical trials.
However, milk thistle was found safe to us with no serious side effects and with participants perceiving improvement in symptoms -- although no more than with placebo.
Dr. Andrea Rambaldi, visiting researcher at the of the Centre for Clinical Intervention Research at Copenhagen University Hospital, led a team that reviewed 13 randomized clinical trials involving 915 patients who were treated with milk thistle or its extracts.
Participants had acute or chronic alcoholic liver cirrhosis, liver fibrosis, hepatitis and/or steatosis, and viral-induced liver disease (hepatitis B and/or hepatitis C). Patients with rarer specific forms of liver disease were excluded.
All the trials compared the efficacy of milk thistle or any milk thistle constituent versus placebo or no intervention in patients with liver disease. "There is no evidence supporting or refuting milk thistle for alcoholic and/or hepatitis B or C virus liver diseases," the authors found.
The review appears in the most recent issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
According to the Centers for Disease Control and Prevention, 170 million people worldwide are infected with hepatitis C, and 2 billion are infected with hepatitis B.
While a vaccine exists to prevent hepatitis B, there is no vaccine for hepatitis C.
Although the virus can be cleared in a handful of patients, many strains are resistant to treatment. Drug therapies that focus on long-term suppression of the virus are expensive, and many patients develop a resistance. The current gold standard treatment, which combines injections of interferon and ribavirin, has serious side effects and is hard for patients to tolerate.
With lack of effective treatment for liver disease, researchers have been looking for alternative therapies that curb symptoms with minimum adverse effects on patients. Milk thistle and its extracts have been used since the time of ancient Greece for medicinal purposes, are currently widely used in Europe for liver disease, and are readily available in the United States at alternative medicine outlets and outdoor markets.
G. Thomas Strickland, M.D., Ph.D., professor at the University of Maryland School of Medicine, has been studying the role of silymarin, an extract of milk thistle, in preventing complications of chronic hepatitis virus infection. Strickland says that the exact mechanism of action of silymarin is unclear.
A problem with current trials, according to Dr. Strickland, is that the dose of silymarin administered, typically 140 mg three times daily, is too low. "I would certainly double it," he says, "especially since at the current dose we're not seeing any improvement in acute viral or chronic hepatitis, and we've shown that silymarin is totally safe."
"The problem is, there is no cure for viral hepatitis except bed rest and diet, and treatments like silymarin are worth pursuing," Strickland says, calling for more research funding.
"We should consider doing randomized clinical trials with higher doses of silymarin," Dr. Rambaldi concurs.
According to the National Center for Complementary and Alternative Medicine , a part of the National Institutes of Health, studies in laboratory animals suggest that silymarin may benefit the liver by promoting the growth of certain types of liver cells, demonstrating a protective effect, fighting oxidation (a chemical process that damages cells) and inhibiting inflammation.
In their review, Dr. Rambaldi and colleagues conclude, "Milk thistle could potentially affect alcoholic and/or hepatitis B or C virus liver diseases. Therefore, large-scale randomized clinical trials on milk thistle for alcoholic and/or hepatitis B or C liver diseases versus placebo may be needed."
Milk thistle, a widely used alternative medicine, is not proven effective in lowering mortality in alcoholic or hepatitis B or C liver disease, according to a systematic review of current evidence.While some studies found that liver-related mortality may be significantly reduced in patients treated with milk thistle, these findings were not duplicated in the higher quality clinical trials.
However, milk thistle was found safe to us with no serious side effects and with participants perceiving improvement in symptoms -- although no more than with placebo.
Dr. Andrea Rambaldi, visiting researcher at the of the Centre for Clinical Intervention Research at Copenhagen University Hospital, led a team that reviewed 13 randomized clinical trials involving 915 patients who were treated with milk thistle or its extracts.
Participants had acute or chronic alcoholic liver cirrhosis, liver fibrosis, hepatitis and/or steatosis, and viral-induced liver disease (hepatitis B and/or hepatitis C). Patients with rarer specific forms of liver disease were excluded.
All the trials compared the efficacy of milk thistle or any milk thistle constituent versus placebo or no intervention in patients with liver disease. "There is no evidence supporting or refuting milk thistle for alcoholic and/or hepatitis B or C virus liver diseases," the authors found.
The review appears in the most recent issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
According to the Centers for Disease Control and Prevention, 170 million people worldwide are infected with hepatitis C, and 2 billion are infected with hepatitis B.
While a vaccine exists to prevent hepatitis B, there is no vaccine for hepatitis C.
Although the virus can be cleared in a handful of patients, many strains are resistant to treatment. Drug therapies that focus on long-term suppression of the virus are expensive, and many patients develop a resistance. The current gold standard treatment, which combines injections of interferon and ribavirin, has serious side effects and is hard for patients to tolerate.
With lack of effective treatment for liver disease, researchers have been looking for alternative therapies that curb symptoms with minimum adverse effects on patients. Milk thistle and its extracts have been used since the time of ancient Greece for medicinal purposes, are currently widely used in Europe for liver disease, and are readily available in the United States at alternative medicine outlets and outdoor markets.
G. Thomas Strickland, M.D., Ph.D., professor at the University of Maryland School of Medicine, has been studying the role of silymarin, an extract of milk thistle, in preventing complications of chronic hepatitis virus infection. Strickland says that the exact mechanism of action of silymarin is unclear.
A problem with current trials, according to Dr. Strickland, is that the dose of silymarin administered, typically 140 mg three times daily, is too low. "I would certainly double it," he says, "especially since at the current dose we're not seeing any improvement in acute viral or chronic hepatitis, and we've shown that silymarin is totally safe."
"The problem is, there is no cure for viral hepatitis except bed rest and diet, and treatments like silymarin are worth pursuing," Strickland says, calling for more research funding.
"We should consider doing randomized clinical trials with higher doses of silymarin," Dr. Rambaldi concurs.
According to the National Center for Complementary and Alternative Medicine , a part of the National Institutes of Health, studies in laboratory animals suggest that silymarin may benefit the liver by promoting the growth of certain types of liver cells, demonstrating a protective effect, fighting oxidation (a chemical process that damages cells) and inhibiting inflammation.
In their review, Dr. Rambaldi and colleagues conclude, "Milk thistle could potentially affect alcoholic and/or hepatitis B or C virus liver diseases. Therefore, large-scale randomized clinical trials on milk thistle for alcoholic and/or hepatitis B or C liver diseases versus placebo may be needed."
Notes on “Your Child's Immunizations,” KidsHealth.org, 2005.
When a child is born, she usually has immunity to certain diseases. This is a result of the disease-fighting antibodies that have passed through the placenta from the mother to the unborn child. After birth, the breastfed baby gets the continued benefits of additional antibodies in breast milk. But in both cases, the immunity is only temporary.
Immunization (vaccination) is an artificial way of creating immunity to certain diseases - by using relatively harmless substances called antigens that come from or are similar to the components of microorganisms that cause the diseases.
Microorganisms can be viruses, such as measles virus, or they can be bacteria, such as pneumococcus. Vaccines stimulate the immune system into reacting as if there were a real infection. The immune system then fights off the "infection" and remembers the organism so it can fight it off quickly if it enters the body at some future time.
Some parents may hesitate to give their children a vaccine because they are concerned about complications or their children developing the illness the vaccine is supposed to prevent. Although it's true that some vaccines could have these effects, the likelihood of that happening is very small. Not immunizing your child exposes her to greater health risks associated with contracting the disease the vaccine is intended to prevent.
Immunization is one of the best means of protecting your child against contagious diseases. The following vaccinations and schedule are recommended by the American Academy of Pediatrics (AAP). Please note that some variations are acceptable and that changes in recommendations frequently occur as new vaccines are developed; your child's doctor will determine the best vaccinations and schedule for your child.
Hep B
Hepatitis B (HBV) is a virus that infects the liver. Those who are infected can become lifelong carriers of the virus and may develop long-term problems such as cirrhosis (liver disease) or cancer of the liver.
Immunization Schedule
Hepatitis B vaccine usually is given as a series of three injections. The first shot is given to infants shortly after birth. If the mother of a newborn carries the hepatitis B virus in her blood, the infant needs to receive the first shot within 12 hours after birth. If a newborn's mother shows no evidence of HBV in her blood, the infant may receive the shot any time prior to leaving the hospital. It also may be deferred until the 4- or 8-week visit to the child's doctor.
If the first shot is given shortly after birth, the second shot is given at 1 to 2 months and the third at 6 months. For infants who do not receive the first shot until 4 to 8 weeks, the second shot is given at 3 to 4 months and the third at 6 to 18 months. In either case, the second and third shots usually are given in conjunction with other routine childhood immunizations.
Why Receive the Vaccine?
The hepatitis B vaccine probably creates lifelong immunity. Infants who receive the HBV series should be protected from hepatitis B infection not only throughout their childhood but also into the adult years. Eliminating the risk of HBV infections also decreases risk for cirrhosis of the liver, chronic liver disease, and liver cancer. Young adults and adolescents should also receive the vaccine if they did not as infants.
Possible Risks
Serious problems associated with receiving the HBV vaccine are rare. Problems that do occur tend to be minor, such as fever or redness or tenderness at the injection site.
When to Delay or Avoid the Immunization
if your child is currently sick, although simple colds or other minor illnesses should not prevent immunization
if severe allergic reaction (anaphylaxis) occurs after an injection of the HBV vaccine
How to Care for Your Child After the Immunization
The vaccine may cause mild soreness and redness at the place the shot was given; this may be treated with pain relievers like acetaminophen or ibuprofen.
When to Call Your Child's Doctor
if you are not sure of the recommended schedule for the hepatitis B vaccine
if you have concerns about your own HBV carrier state
if moderate or serious adverse effects appear after an HBV injection has been given to your child.
When a child is born, she usually has immunity to certain diseases. This is a result of the disease-fighting antibodies that have passed through the placenta from the mother to the unborn child. After birth, the breastfed baby gets the continued benefits of additional antibodies in breast milk. But in both cases, the immunity is only temporary.
Immunization (vaccination) is an artificial way of creating immunity to certain diseases - by using relatively harmless substances called antigens that come from or are similar to the components of microorganisms that cause the diseases.
Microorganisms can be viruses, such as measles virus, or they can be bacteria, such as pneumococcus. Vaccines stimulate the immune system into reacting as if there were a real infection. The immune system then fights off the "infection" and remembers the organism so it can fight it off quickly if it enters the body at some future time.
Some parents may hesitate to give their children a vaccine because they are concerned about complications or their children developing the illness the vaccine is supposed to prevent. Although it's true that some vaccines could have these effects, the likelihood of that happening is very small. Not immunizing your child exposes her to greater health risks associated with contracting the disease the vaccine is intended to prevent.
Immunization is one of the best means of protecting your child against contagious diseases. The following vaccinations and schedule are recommended by the American Academy of Pediatrics (AAP). Please note that some variations are acceptable and that changes in recommendations frequently occur as new vaccines are developed; your child's doctor will determine the best vaccinations and schedule for your child.
Hep B
Hepatitis B (HBV) is a virus that infects the liver. Those who are infected can become lifelong carriers of the virus and may develop long-term problems such as cirrhosis (liver disease) or cancer of the liver.
Immunization Schedule
Hepatitis B vaccine usually is given as a series of three injections. The first shot is given to infants shortly after birth. If the mother of a newborn carries the hepatitis B virus in her blood, the infant needs to receive the first shot within 12 hours after birth. If a newborn's mother shows no evidence of HBV in her blood, the infant may receive the shot any time prior to leaving the hospital. It also may be deferred until the 4- or 8-week visit to the child's doctor.
If the first shot is given shortly after birth, the second shot is given at 1 to 2 months and the third at 6 months. For infants who do not receive the first shot until 4 to 8 weeks, the second shot is given at 3 to 4 months and the third at 6 to 18 months. In either case, the second and third shots usually are given in conjunction with other routine childhood immunizations.
Why Receive the Vaccine?
The hepatitis B vaccine probably creates lifelong immunity. Infants who receive the HBV series should be protected from hepatitis B infection not only throughout their childhood but also into the adult years. Eliminating the risk of HBV infections also decreases risk for cirrhosis of the liver, chronic liver disease, and liver cancer. Young adults and adolescents should also receive the vaccine if they did not as infants.
Possible Risks
Serious problems associated with receiving the HBV vaccine are rare. Problems that do occur tend to be minor, such as fever or redness or tenderness at the injection site.
When to Delay or Avoid the Immunization
if your child is currently sick, although simple colds or other minor illnesses should not prevent immunization
if severe allergic reaction (anaphylaxis) occurs after an injection of the HBV vaccine
How to Care for Your Child After the Immunization
The vaccine may cause mild soreness and redness at the place the shot was given; this may be treated with pain relievers like acetaminophen or ibuprofen.
When to Call Your Child's Doctor
if you are not sure of the recommended schedule for the hepatitis B vaccine
if you have concerns about your own HBV carrier state
if moderate or serious adverse effects appear after an HBV injection has been given to your child.
Notes on “Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications,” Yuen Mf. et al. Gut. 2005 May 4.
BACKGROUND: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.
AIM: To determine risk factors for the development of complications in Asian CHB patients.
PATIENTS AND METHODS: 3,233 Chinese CHB patients (mean follow-up 46.8 months) were monitored for liver biochemistry, viral serology, HBV DNA levels, acute exacerbation, HBeAg seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. RESULTS: The median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years respectively. Patients with alanine aminotransferase (ALT) levels of 0.5 - 1 X upper limit of normal (ULN) and 1 - 2 X ULN had increased risk for the development of complications compared to patients with ALT levels < 0.5 X ULN (p<0.0001 for both). HBeAg/ anti- HBe status, and the number of episodes, duration and peak ALT levels of acute exacerbations were not associated with increased risk of complications. In patients with complications, 43.6% had the HBV DNA levels less than 1.42 X 105 copies/ml. Male gender, stigmata of chronic liver disease, old age, low albumin and high AFP levels on presentation were independently associated with increased cumulative risk of complications. Male gender, presence of hepatitis symptoms, old age, low albumin level and presence of complications on presentation were independently associated with shorter survival.
CONCLUSION: Prolonged low-level viremia causing insidious and continual liver damage as reflected by ALT levels of 0.5 - 2 X ULN is the most likely pathway for the development of complications in Asian CHB patients.
BACKGROUND: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.
AIM: To determine risk factors for the development of complications in Asian CHB patients.
PATIENTS AND METHODS: 3,233 Chinese CHB patients (mean follow-up 46.8 months) were monitored for liver biochemistry, viral serology, HBV DNA levels, acute exacerbation, HBeAg seroconversion, and development of cirrhotic complications and hepatocellular carcinoma. RESULTS: The median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years respectively. Patients with alanine aminotransferase (ALT) levels of 0.5 - 1 X upper limit of normal (ULN) and 1 - 2 X ULN had increased risk for the development of complications compared to patients with ALT levels < 0.5 X ULN (p<0.0001 for both). HBeAg/ anti- HBe status, and the number of episodes, duration and peak ALT levels of acute exacerbations were not associated with increased risk of complications. In patients with complications, 43.6% had the HBV DNA levels less than 1.42 X 105 copies/ml. Male gender, stigmata of chronic liver disease, old age, low albumin and high AFP levels on presentation were independently associated with increased cumulative risk of complications. Male gender, presence of hepatitis symptoms, old age, low albumin level and presence of complications on presentation were independently associated with shorter survival.
CONCLUSION: Prolonged low-level viremia causing insidious and continual liver damage as reflected by ALT levels of 0.5 - 2 X ULN is the most likely pathway for the development of complications in Asian CHB patients.
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