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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.
Notes from "Chronic Hepatitis B: Preventing, Detecting, and Managing Viral Resistance" by Keeffe, Emmet B., Dieterich, Douglas T., Pawlotsky, Jean-Michael, and Benhamou, Yves in Clinical Gastroenterology and Hepatology 2008;6:268-274.
Full paper in http://www.sciencedirect.com/science/journal/15423565
1. Monotherapy using lamivudine has the longest history of use and shows highest rate of resistance. A 2003 study of 998 patients showed 65% lamivudine-resistance mutations in 5 years. Lamivudine should no longer be used as monotherapy.
2. Monotherapy using adefovir has 29% mutation probability in 240 weeks, according to a 2006 study of 125 patients.
3. Entecavir is 100-fold more potent than lamivudine or adefovir. In a 2006 study of 673 patients using monotherapy of entecavir 3% showed virologic rebound in 96 weeks of which 3 patients had lamivudine-resistant virus at start of treatment. A 2007 study indicated that the cumulative probability of virologic breakthrough associated with entecavir resistance was 0.8% over 4 years.
4. Combination therapy (CT) using telbivudine plus lamivudine and monotherapy (MT) using telbivudine alone in a 2005 comparison of 104 patients did not show a difference in effectiveness.
5. Combination therapy (CT) using lamivudind plus adefovir and monotherapy (MT) using lamivudine alone in a 2003 comparison showed CT superiority: by week 52, CT group remained virally suppressed, HBV DNA levels increased in the MT group.
6. Combination therapy (CT) using adefovir plus emtricitabine and monotherapy (MT) using adefovir in a 2004 comparison of 30 patients showed greater antiviral activity with CT.
7. Combination therapy (CT) using lamivudine plus peginterferon alfa-2a, monotherapy (MT1) using lamivudine, and monotherapy (MT2) using peginterferon alfa-2a in a 2004 study of 537 patients showed 18% resistance with MT1 and 1% resistance with CT at week 48.
"A combination of 2 potent nucleosides/nucleotides with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B."
"Drugs such as entecavir and tenofovir have such low rates of resistance..."
"Current treatment of HIV infection is based on creating a high genetic barrier to resistance. ... Current guidelines for initial treatment of patients with HIV infection reflect that view by recommending a combination of 3 or more agents from different classes having different mechanisms of action. ... Although data are not available for all antiviral agents used to treat HBV infection, it is becoming clear that single-drug therapy may not provide a sufficiently high barrier to resistance."
Full paper in http://www.sciencedirect.com/science/journal/15423565
1. Monotherapy using lamivudine has the longest history of use and shows highest rate of resistance. A 2003 study of 998 patients showed 65% lamivudine-resistance mutations in 5 years. Lamivudine should no longer be used as monotherapy.
2. Monotherapy using adefovir has 29% mutation probability in 240 weeks, according to a 2006 study of 125 patients.
3. Entecavir is 100-fold more potent than lamivudine or adefovir. In a 2006 study of 673 patients using monotherapy of entecavir 3% showed virologic rebound in 96 weeks of which 3 patients had lamivudine-resistant virus at start of treatment. A 2007 study indicated that the cumulative probability of virologic breakthrough associated with entecavir resistance was 0.8% over 4 years.
4. Combination therapy (CT) using telbivudine plus lamivudine and monotherapy (MT) using telbivudine alone in a 2005 comparison of 104 patients did not show a difference in effectiveness.
5. Combination therapy (CT) using lamivudind plus adefovir and monotherapy (MT) using lamivudine alone in a 2003 comparison showed CT superiority: by week 52, CT group remained virally suppressed, HBV DNA levels increased in the MT group.
6. Combination therapy (CT) using adefovir plus emtricitabine and monotherapy (MT) using adefovir in a 2004 comparison of 30 patients showed greater antiviral activity with CT.
7. Combination therapy (CT) using lamivudine plus peginterferon alfa-2a, monotherapy (MT1) using lamivudine, and monotherapy (MT2) using peginterferon alfa-2a in a 2004 study of 537 patients showed 18% resistance with MT1 and 1% resistance with CT at week 48.
"A combination of 2 potent nucleosides/nucleotides with different resistance profiles may prove to be the optimal first-line treatment for chronic hepatitis B."
"Drugs such as entecavir and tenofovir have such low rates of resistance..."
"Current treatment of HIV infection is based on creating a high genetic barrier to resistance. ... Current guidelines for initial treatment of patients with HIV infection reflect that view by recommending a combination of 3 or more agents from different classes having different mechanisms of action. ... Although data are not available for all antiviral agents used to treat HBV infection, it is becoming clear that single-drug therapy may not provide a sufficiently high barrier to resistance."
Notes on "On-Treatment Management Strategies for Chronic Hepatitis B" Clinical Care Options, by Ira Jacobson.
1. "In hepatitis B, where treatment is usually long term and where viral resistance is a significant problem, the issue is not so much whether one can stop early because of either a high likelihood of success or the inevitability of ultimate failure, but optimization of treatment to ensure the greatest likelihood of long-term viral suppression with a minimal risk of resistance."
2. "resistance is much more likely to occur when viral suppression is incomplete."
3. "The clinical consequences of HBV resistance are extremely important. When resistance occurs, it puts the patient at short-term risk of a hepatitis flare, which is particularly of concern in patients with advanced liver disease, and at long-term risk, the progression to cirrhosis and hepatocellular carcinoma, even if the patient currently has mild liver disease. Resistance also complicates therapy because changes in the regimen are required and there is cross-resistance among the various HBV antiviral drugs."
4. Early, Profound Suppression Leads to Greater Sustained Response: The 2006 study of 1367 patients by Zeuzem S, Lai CL, Gane E, et al., "Optimal virologic and clinical efficacy at one year is associated with maximal early HBV suppression in nucleoside-treated hepatitis B patients." (Program and abstracts of the 41st Annual Meeting of the European Association for the Study of the Liver; April 26-30, 2006; Vienna, Austria.) showed that greater virologic suppression at Week 24 of telbivudine or lamivudine treatment was associated with superior clinical outcomes at Week 52.
5. "To date, we have no data demonstrating additive viral suppression from combinations of HBV drugs,...so far, the viral suppression achieved with combinations represents the level of suppression attained with the more potent drug. The authors of this publication concluded that there is no basis for combination therapy at this time, except in established resistance, because of the data showing that adefovir plus lamivudine is better than lamivudine alone in lamivudine-resistant patients." But, "even if combination therapy does not confer additive viral suppression, it may well prevent resistance from emerging in patients who are at risk of resistance because of incomplete viral suppression."
6. Road Map for On-Treatment Management of Chronic Hepatitis B, Expert Viewpoint August 2007, by Keeffe, Emmet B.:
A. Assess for primary nonresponse at Week 12; go to B
B. Assess early predictors of efficacy at Week 24; go to 1 of C
C1. If complete response (HBV DNA negative by PCR) then continue and monitor every 6 months.
C2. If partial response (HBV DNA 60 to =2000IU/ml) then add a more potent drug and monitor every 3 months.
C3. If inadequate response (HBV DNA >=2000IU/ml) then add a more potent drug and monitor every 3 months.
7. Conclusion:
"In conclusion, we have seen a major shift from a reactive to a proactive approach in the prevention of resistance during hepatitis B therapy. We feel that we should not wait for virologic breakthrough, certainly should no longer wait for alanine aminotransferase breakthroughs to occur in patients taking long-term therapy and that we should not even wait for virologic breakthrough, but rather, in patients with residual viremia, at time points that might be associated with the emergence of genotypic resistance, we should check for that, we should become familiar, if we are not already, with the genomic sequencing assays that are available commercially and use them in this situation. Viral genomic sequencing should be done whenever viral resistance might be present, such as in patients with residual viremia at 1 year or beyond, and any time there is a virologic breakthrough.
The goal in all patients should now be HBV DNA undetectability. This is attainable in the great majority of our patients with currently available drugs. Residual viremia, and this represents the proactive approach to which I have referred repeatedly during this discussion, at pivotal time points should lead to a change in the regimen, such that one need not even wait to monitor for genotypic resistance, much less viral or alanine aminotransferase breakthrough. We have robust data now that give clear guidance in the case of several of our drugs as to what levels of viremia early in therapy, such as at 24 weeks, and I think we will see more data at even earlier time points, should make us think that down the line we are likely to sustain unacceptable risks of emergent resistance.
In patients who have residual viremia at pivotal time points, in whom we think the regimen should be changed, there is increasing emphasis among many experts about an add-on paradigm rather than switch, and increasingly the add-on paradigm applies to suboptimal response as well as to resistance, although I think there are more data bearing on this point in resistance, whereas the arguments in patients with suboptimal response are more theoretical, and we do need more data. I want emphasize that add-on therapy is always preferred in patients with established resistance rather than switching to another monotherapy."
1. "In hepatitis B, where treatment is usually long term and where viral resistance is a significant problem, the issue is not so much whether one can stop early because of either a high likelihood of success or the inevitability of ultimate failure, but optimization of treatment to ensure the greatest likelihood of long-term viral suppression with a minimal risk of resistance."
2. "resistance is much more likely to occur when viral suppression is incomplete."
3. "The clinical consequences of HBV resistance are extremely important. When resistance occurs, it puts the patient at short-term risk of a hepatitis flare, which is particularly of concern in patients with advanced liver disease, and at long-term risk, the progression to cirrhosis and hepatocellular carcinoma, even if the patient currently has mild liver disease. Resistance also complicates therapy because changes in the regimen are required and there is cross-resistance among the various HBV antiviral drugs."
4. Early, Profound Suppression Leads to Greater Sustained Response: The 2006 study of 1367 patients by Zeuzem S, Lai CL, Gane E, et al., "Optimal virologic and clinical efficacy at one year is associated with maximal early HBV suppression in nucleoside-treated hepatitis B patients." (Program and abstracts of the 41st Annual Meeting of the European Association for the Study of the Liver; April 26-30, 2006; Vienna, Austria.) showed that greater virologic suppression at Week 24 of telbivudine or lamivudine treatment was associated with superior clinical outcomes at Week 52.
5. "To date, we have no data demonstrating additive viral suppression from combinations of HBV drugs,...so far, the viral suppression achieved with combinations represents the level of suppression attained with the more potent drug. The authors of this publication concluded that there is no basis for combination therapy at this time, except in established resistance, because of the data showing that adefovir plus lamivudine is better than lamivudine alone in lamivudine-resistant patients." But, "even if combination therapy does not confer additive viral suppression, it may well prevent resistance from emerging in patients who are at risk of resistance because of incomplete viral suppression."
6. Road Map for On-Treatment Management of Chronic Hepatitis B, Expert Viewpoint August 2007, by Keeffe, Emmet B.:
A. Assess for primary nonresponse at Week 12; go to B
B. Assess early predictors of efficacy at Week 24; go to 1 of C
C1. If complete response (HBV DNA negative by PCR) then continue and monitor every 6 months.
C2. If partial response (HBV DNA 60 to =2000IU/ml) then add a more potent drug and monitor every 3 months.
C3. If inadequate response (HBV DNA >=2000IU/ml) then add a more potent drug and monitor every 3 months.
7. Conclusion:
"In conclusion, we have seen a major shift from a reactive to a proactive approach in the prevention of resistance during hepatitis B therapy. We feel that we should not wait for virologic breakthrough, certainly should no longer wait for alanine aminotransferase breakthroughs to occur in patients taking long-term therapy and that we should not even wait for virologic breakthrough, but rather, in patients with residual viremia, at time points that might be associated with the emergence of genotypic resistance, we should check for that, we should become familiar, if we are not already, with the genomic sequencing assays that are available commercially and use them in this situation. Viral genomic sequencing should be done whenever viral resistance might be present, such as in patients with residual viremia at 1 year or beyond, and any time there is a virologic breakthrough.
The goal in all patients should now be HBV DNA undetectability. This is attainable in the great majority of our patients with currently available drugs. Residual viremia, and this represents the proactive approach to which I have referred repeatedly during this discussion, at pivotal time points should lead to a change in the regimen, such that one need not even wait to monitor for genotypic resistance, much less viral or alanine aminotransferase breakthrough. We have robust data now that give clear guidance in the case of several of our drugs as to what levels of viremia early in therapy, such as at 24 weeks, and I think we will see more data at even earlier time points, should make us think that down the line we are likely to sustain unacceptable risks of emergent resistance.
In patients who have residual viremia at pivotal time points, in whom we think the regimen should be changed, there is increasing emphasis among many experts about an add-on paradigm rather than switch, and increasingly the add-on paradigm applies to suboptimal response as well as to resistance, although I think there are more data bearing on this point in resistance, whereas the arguments in patients with suboptimal response are more theoretical, and we do need more data. I want emphasize that add-on therapy is always preferred in patients with established resistance rather than switching to another monotherapy."
Anyone get hold of presentation by Dr Anna Lok titled "Antiviral Drug-Resistant Hepatitis B: Can we Prevent this Monster from growing" over the weekend hosted by HBV Foundation?
Notes on "Utilization rates, complications and costs of percutaneous liver biopsies: a population-base study including 4,275 biopsies, April 13, 2008, by Myers, RP, Fong A, Shaheen, AA.
1. Of 3627 patients with liver biopsies, 0.75% had significant biopsy-related complications, 0.51% had pain requiring admission, 0.35% had bleeding, and 6 patients (0.14%) died.
2. This procedure is safe.
1. Of 3627 patients with liver biopsies, 0.75% had significant biopsy-related complications, 0.51% had pain requiring admission, 0.35% had bleeding, and 6 patients (0.14%) died.
2. This procedure is safe.
"Antiviral Drug-Resistant Hepatitis B: Can we Prevent this Monster from growing" , presented by Anna Lok, MD
Save it while you can:
http://www.uwgi.org/calendar/presentations/2005_2006/20060414_lok.pdf
Which begs the question, why are people still not considering combo as first-line treatment? why?
Save it while you can:
http://www.uwgi.org/calendar/presentations/2005_2006/20060414_lok.pdf
Which begs the question, why are people still not considering combo as first-line treatment? why?
This is copied from a HR post, relating to treatment strategies:
Pegasys as initial treatment - this is unusual these days. Sometimes IFN gets even an e-Ag neg disease into a state of relative stable remission, by activating "reserve Tcell responses'. But in most cases, after two or three years, the extra level of immune control is lost again and the sides are pretty bad.
BUT this has to be said; For permanent resistance control a starting course of IFN, followed by even a single potent antiviral like Entecavir or Tenofovir as a permanent treatment is very likely to be a very successful strategy.
As to combo HBV antivirals: Many seem not to need them - so far so good - but by the time that it is clear that you would have needed them it is too late to correct the mistake in the long term sense.
One strategy, that to my chagrin and estranged amusement is never mentioned in the liver meeting thus far - it will, in the future- is to start with a super potent combo while the Vl is -as initially - high and push the virus down through the zone of early resistance danger with the cross-protective power until the reproductive capacity - and the resistance forming capacity - is low, that is the UND range. THEN it is less dangerous to let go of the combo and switch to a potent mono like Entecavir or Tenofovir, all also depending on how fast you went to UND - a powerful predictor ,as Dr. Jabocsons presentation has nicely shown. And then, once UND for a few month and having then, after several of UND month still on the combo switched to the potent permamono, monitor as frequently as your insurance and doc will let you.
Pegasys as initial treatment - this is unusual these days. Sometimes IFN gets even an e-Ag neg disease into a state of relative stable remission, by activating "reserve Tcell responses'. But in most cases, after two or three years, the extra level of immune control is lost again and the sides are pretty bad.
BUT this has to be said; For permanent resistance control a starting course of IFN, followed by even a single potent antiviral like Entecavir or Tenofovir as a permanent treatment is very likely to be a very successful strategy.
As to combo HBV antivirals: Many seem not to need them - so far so good - but by the time that it is clear that you would have needed them it is too late to correct the mistake in the long term sense.
One strategy, that to my chagrin and estranged amusement is never mentioned in the liver meeting thus far - it will, in the future- is to start with a super potent combo while the Vl is -as initially - high and push the virus down through the zone of early resistance danger with the cross-protective power until the reproductive capacity - and the resistance forming capacity - is low, that is the UND range. THEN it is less dangerous to let go of the combo and switch to a potent mono like Entecavir or Tenofovir, all also depending on how fast you went to UND - a powerful predictor ,as Dr. Jabocsons presentation has nicely shown. And then, once UND for a few month and having then, after several of UND month still on the combo switched to the potent permamono, monitor as frequently as your insurance and doc will let you.
Notes on "What Is the Best End Point for Hepatitis B Treatment?", by Degertekin, R, Lok, A, Ann Intern Med. 2008 Apr 1;148(7):560-561.
1. "The safety of lifetime use of nucleoside or nucleotide analogues for hepatitis B has not been established. Adefovir is associated with a small risk for nephrotoxicity. Entecavir at high doses in rodents was associated with a variety of tumors, prompting the manufacturer to pledge a 10-year follow-up study to establish its long-term safety in humans. Furthermore, currently available hepatitis B treatments are very expensive, and their efficacy in maintaining viral suppression is diminished by the selection of drug-resistant mutations during long-term therapy."
2. "We completely agree that cirrhosis and hepatocellular carcinoma are the key outcomes of chronic HBV infection. However, as Drs. Lai and Yuen indicated, a persistently high HBV DNA level is the most important predictor of these outcomes. Thus, the risk for adverse outcomes after treatment discontinuation is related to the risk for reactivation of viral replication."
3. "A recent analysis of 74 patients who lost HBeAg after 48 weeks of entecavir therapy found that 70 had HBeAg seroconversion, 71 had undetectable HBV DNA by polymerase chain reaction, and 63 had normalization of aminotransferases. These findings support the idea that most patients who achieve HBeAg seroconversion during nucleoside or nucleotide analogue therapy meet the
strict definition of HBeAg seroconversion."
1. "The safety of lifetime use of nucleoside or nucleotide analogues for hepatitis B has not been established. Adefovir is associated with a small risk for nephrotoxicity. Entecavir at high doses in rodents was associated with a variety of tumors, prompting the manufacturer to pledge a 10-year follow-up study to establish its long-term safety in humans. Furthermore, currently available hepatitis B treatments are very expensive, and their efficacy in maintaining viral suppression is diminished by the selection of drug-resistant mutations during long-term therapy."
2. "We completely agree that cirrhosis and hepatocellular carcinoma are the key outcomes of chronic HBV infection. However, as Drs. Lai and Yuen indicated, a persistently high HBV DNA level is the most important predictor of these outcomes. Thus, the risk for adverse outcomes after treatment discontinuation is related to the risk for reactivation of viral replication."
3. "A recent analysis of 74 patients who lost HBeAg after 48 weeks of entecavir therapy found that 70 had HBeAg seroconversion, 71 had undetectable HBV DNA by polymerase chain reaction, and 63 had normalization of aminotransferases. These findings support the idea that most patients who achieve HBeAg seroconversion during nucleoside or nucleotide analogue therapy meet the
strict definition of HBeAg seroconversion."
Just came back from seeing GI, he explained clearly on the treatment options. He analogus this to war fighting, you leave them alone if they don't fight (hep B virus)....fight them once they wake up and attack you. This is where you have to have all the weapons ready (antiviral) to bluff them. After a while, the viruses reliazed they are being trick and then they mutate...and attack again. The you need new weapon again.....
Baraclude ($12/pill) is the best so far...less problematic. Since my ALT still normal, he would like to monitor for a while. He is strong advocate of ALT vs biospy...
He explained to you that if you fight them with medium-sized arrows they will find a way to escape the arrows. He then says that at that point you switch to bigger arrows. Problem is that the virus already knows about arrows and before too long they can figure out that these are the same arrows...just bigger. They can find a way to escape the larger ones too. Then, your quiver is empty.
But if you barrage them immediately with the medium arrows AND the big arrows at the same time, they are too busy retreating to regroup long enough to figure out where to start fighting. Then after the shower of arrows of varying size, there are too few virus surviving to mount a effective defense.
That's the hope with combo therapy.
But if you barrage them immediately with the medium arrows AND the big arrows at the same time, they are too busy retreating to regroup long enough to figure out where to start fighting. Then after the shower of arrows of varying size, there are too few virus surviving to mount a effective defense.
That's the hope with combo therapy.
But then the tricks are almost the same w/ current antiviral medication. He said that they are very smart and very soon they will have a way to fight you again.......
Notes on "Combination therapy of thymosin alpha-1 and lamivudine for HBeAg positive chronic hepatitis B: A prospective randomized, comparative pilot study," Lee, HW, et al, Journal of Gastroenterology and Hepatology 23 (5):729-735.
1. A pilot study.
2. Is combination of thymosin alpha-1 and lamivudine superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naive patients with chronic hepatitis B?
3. Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received thymosin alpha-1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously.
4. Results: The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201).
5. Conclusions: The combination treatment of thymosin alpha-1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of thymosin alpha-1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs.
1. A pilot study.
2. Is combination of thymosin alpha-1 and lamivudine superior to lamivudine monotherapy in hepatitis B e antigen (HBeAg) positive naive patients with chronic hepatitis B?
3. Sixty-seven patients were assigned to two different groups in a randomized manner. The combination group (n = 34) received thymosin alpha-1 (1.6 mg subcutaneously, twice a week) and lamivudine (100 mg orally, daily) for 24 weeks, followed by continuous lamivudine therapy. The monotherapy group (n = 33) received lamivudine monotherapy continuously.
4. Results: The incidence of HBeAg seroconversion at 24 weeks was 26.5% (9/34) in the combination group and 6.1% (2/33) in the monotherapy group (P = 0.024). However, there was no statistically significant difference between 26.5% (9/34) in the combination group and 12.1% (4/33) in the monotherapy group at 52 weeks (P = 0.138). The emergence of viral breakthrough gradually increased to 35.3% (12/34) in the combination group, and to 21.2% (7/33) in the monotherapy group at 52 weeks (P = 0.201).
5. Conclusions: The combination treatment of thymosin alpha-1 and lamivudine did not have an obvious benefit of virological and biochemical response as compared to the lamivudine monotherapy during the combination period. In addition, after the cessation of thymosin alpha-1 treatment, the combination therapy did not prevent the occurrence of viral and biochemical breakthroughs.
Notes on "New data and recommendations of antiviral therapy of chronic hepatitis B and C.," by Niederau, C., Internist (Berl), March 15, 2008.
According to the new German guidelines therapy of chronic hepatitis B is recommended when HBV-DNA is >10.000 copies/ml and when GPT is >twice the ULN or biopsy shows inflammation/fibrosis. When patients are not suitable for interferon therapy, mono-therapy with adefovir, entecavir, telbivudine of lamivudine may be initiated provided that HBV-DNA is <1 Mio. copies/ml and cirrhosis is absent. When viral load is high, entecavir should be preferred. HBV-DNA need to be checked for early detection of non-response or resistance. When resistance is present, combination therapy is recommended.New studies warrant individualization of previous recommendation for therapy of hepatitis C because one can now early evaluate how successful and long the therapy shall be. When viral load is low and HCV-RNA becomes negative after 4 weeks, therapy may be shortened to 24 weeks. Without such rapid response HCV-RNA needs to be checked after 12 and 24 weeks: when HCV-RNA becomes negative only after 24 weeks, a prolongation of therapy might be advisable.
According to the new German guidelines therapy of chronic hepatitis B is recommended when HBV-DNA is >10.000 copies/ml and when GPT is >twice the ULN or biopsy shows inflammation/fibrosis. When patients are not suitable for interferon therapy, mono-therapy with adefovir, entecavir, telbivudine of lamivudine may be initiated provided that HBV-DNA is <1 Mio. copies/ml and cirrhosis is absent. When viral load is high, entecavir should be preferred. HBV-DNA need to be checked for early detection of non-response or resistance. When resistance is present, combination therapy is recommended.New studies warrant individualization of previous recommendation for therapy of hepatitis C because one can now early evaluate how successful and long the therapy shall be. When viral load is low and HCV-RNA becomes negative after 4 weeks, therapy may be shortened to 24 weeks. Without such rapid response HCV-RNA needs to be checked after 12 and 24 weeks: when HCV-RNA becomes negative only after 24 weeks, a prolongation of therapy might be advisable.
DOW JONES NEWSWIRES, March 24, 2008:
Bristol-Myers Squibb Co. (BMY) reported new Baraclude data demonstrated a continued low incidence of resistance in nucleoside-naive chronic hepatitis B patients through five years of treatment. In the patients analyzed, no additional patients developed resistance in the fifth year, the biopharmaceutical and health-care products company said
Monday. Through five years of treatment, the cumulative probability of developing mutations in the virus that confer resistance to Baraclude was 1.2%. In lamivudine-refractory patients who received Baraclude after treatment with lamivudine failed, the cumulative probability of genotypic Baraclude resistance was 51% through the fifth year. This finding is consistent with prior observations, the company said.
Bristol-Myers Squibb Co. (BMY) reported new Baraclude data demonstrated a continued low incidence of resistance in nucleoside-naive chronic hepatitis B patients through five years of treatment. In the patients analyzed, no additional patients developed resistance in the fifth year, the biopharmaceutical and health-care products company said
Monday. Through five years of treatment, the cumulative probability of developing mutations in the virus that confer resistance to Baraclude was 1.2%. In lamivudine-refractory patients who received Baraclude after treatment with lamivudine failed, the cumulative probability of genotypic Baraclude resistance was 51% through the fifth year. This finding is consistent with prior observations, the company said.
Notes on "Tenofovir plus lamivudine as rescue therapy for adefovir-resistant chronic hepatitis B in hepatitis B e antigen-positive patients with liver cirrhosis," Choe WH et al.,
1. Background/Aims: There is no consensus on the management of patients with adefovir (ADV)-resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non-response to ADV.
2. Methods: Six patients with HBV-related cirrhosis, viral breakthrough during LMV therapy and viral breakthrough or non-response during ADV therapy were treated daily with TDF plus LMV for at least 6 months. The HBV DNA level, alanine aminotransferase (ALT), the Child-Pugh score and serum creatinine were monitored. Genotypic LMV- or ADV-resistant mutations were measured in stored samples.
3. Results: In five of six patients, ADV-resistant mutations at rt181 or rt236 were detected during ADV therapy. At 6 months of starting TDF/LMV combination, HBV DNA levels became undetectable (detection limit, 400 copies/ml) in four of six patients. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in four of six patients. These responses persisted up to the end of the observation period (median duration 16.5 months, range 6-21 months). The Child-Pugh scores improved in two of three patients with hepatic decompensation. No significant changes in serum creatinine were observed.
4. Conclusion: Our data demonstrated that TDF plus LMV safely and markedly suppressed HBV replication in patients with resistance to or non-response to ADV. This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing LMV resistance.
1. Background/Aims: There is no consensus on the management of patients with adefovir (ADV)-resistant hepatitis B virus (HBV) infection. The aim of this study was to investigate whether tenofovir disoproxil fumarate (TDF) combined with lamivudine (LMV) is effective and safe in patients with resistance to or non-response to ADV.
2. Methods: Six patients with HBV-related cirrhosis, viral breakthrough during LMV therapy and viral breakthrough or non-response during ADV therapy were treated daily with TDF plus LMV for at least 6 months. The HBV DNA level, alanine aminotransferase (ALT), the Child-Pugh score and serum creatinine were monitored. Genotypic LMV- or ADV-resistant mutations were measured in stored samples.
3. Results: In five of six patients, ADV-resistant mutations at rt181 or rt236 were detected during ADV therapy. At 6 months of starting TDF/LMV combination, HBV DNA levels became undetectable (detection limit, 400 copies/ml) in four of six patients. Within 12 months, HBV DNA levels became undetectable in all patients, and ALT levels were normalized in four of six patients. These responses persisted up to the end of the observation period (median duration 16.5 months, range 6-21 months). The Child-Pugh scores improved in two of three patients with hepatic decompensation. No significant changes in serum creatinine were observed.
4. Conclusion: Our data demonstrated that TDF plus LMV safely and markedly suppressed HBV replication in patients with resistance to or non-response to ADV. This study suggests that this combination may be a promising rescue therapy for these patients, particularly those with liver cirrhosis or pre-existing LMV resistance.
Re: Apr 16, 2008 01:44PM
WOW...that's really something. So after 5 years, the resistance for Entecavir is 1.2%, but that jumps to a staggering 51% if you have LAM resistance to begin with.
I hope that person who was considering waiting for the LAM resistance to occur before switching to Entecavir is reading this.
If you really grasp the concept of resistance, none of this research should be too surprising.
FYI: I read there are patients on triple-combo therapy, with ETV, TDF, and FTC. I read that this is the best there is and still the pts appeared to be fine in terms of sides / toxicity. So don't let your doctor scare your with double-combo. It really should be a worthwhile discussion.
WOW...that's really something. So after 5 years, the resistance for Entecavir is 1.2%, but that jumps to a staggering 51% if you have LAM resistance to begin with.
I hope that person who was considering waiting for the LAM resistance to occur before switching to Entecavir is reading this.
If you really grasp the concept of resistance, none of this research should be too surprising.
FYI: I read there are patients on triple-combo therapy, with ETV, TDF, and FTC. I read that this is the best there is and still the pts appeared to be fine in terms of sides / toxicity. So don't let your doctor scare your with double-combo. It really should be a worthwhile discussion.
Notes on "Treatment of the HBV-Infected Patient: When to Start, When to Stop, and When to Change Therapy," Keeffe, E.B. March 5, 2008.
Tables unable to be posted.
1. "Therapeutic options to control viral replication and disease progression fortunately continue to expand, and these advances will likely result in more patients undergoing treatment and deriving long-term benefits with a reduced incidence of cirrhosis and HCC."
2. "The natural history of chronic HBV infection can be divided into 4 phases: immune tolerance, immune clearance (hepatitis B e antigen [HBeAg]-positive chronic hepatitis B), inactive HBsAg carrier state, and reactivation (HBeAg-negative chronic hepatitis B). The immune tolerance phase, present in those patients infected at birth or early childhood, is characterized by the presence of HBeAg, high serum HBV DNA levels (at least > 20,000 IU/mL and usually much higher), and persistently normal alanine aminotransferase (ALT) levels. This phase is followed by an immune clearance phase of variable duration, with serum HBV DNA levels remaining high, but with serum ALT levels that are persistently or intermittently elevated and features of chronic hepatitis with or without fibrosis present on liver biopsy. Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) usually results in transition to the inactive HBsAg carrier state, typified by serum HBV DNA levels that are 2000 IU/mL, persistently or intermittently elevated ALT levels, and progressive liver damage on liver biopsy."
3. When to Start Therapy: Treatment is indicated in patients in the immune clearance and reactivation phases (ie, in those individuals with high serum HBV DNA levels, elevated ALT levels, and/or necroinflammation on liver biopsy, and who are predicted to have the highest chance of response to therapy). ... The primary goal of therapy for chronic hepatitis B is long-term suppression of serum HBV DNA, which will likely decrease progression to cirrhosis and HCC. ... The medications currently approved by the US Food and Drug Administration (FDA) for the initial treatment of chronic hepatitis B include interferon alfa-2b, peginterferon alfa-2a, and the oral nucleoside/nucleotide analogs lamivudine, adefovir dipivoxil, entecavir, and telbivudine, with tenofovir under FDA review for likely approval in 2008.
3a. Each of these drugs has a number of advantages and disadvantages. Issues for consideration in the selection of therapy include efficacy, safety, incidence of resistance, method of administration, and cost. Peginterferon alfa-2a has the advantages of a 1-year finite duration of therapy, higher rate of HBeAg seroconversion at 1 year, lack of resistance, and higher likelihood of HBsAg loss and seroconversion. Disadvantages of peginterferon therapy are parenteral administration, frequent side effects (especially flu-like symptoms, depression or irritability, and cytopenias), need for more intensive laboratory monitoring, contraindication in advanced liver disease, and higher cost. Genotyping may be useful to help decide whether treatment with peginterferon alfa-2a is warranted based on the highest rate of efficacy being in patients with genotype A and lowest efficacy being in those infected with HBV genotype D. The nucleoside/nucleotide agents have the advantages of oral administration, excellent tolerance, use in advanced liver disease, and high potency in lowering serum HBV DNA levels. The primary disadvantages of these agents are the need for long-term administration and variable rates of antiviral drug resistance. Oral drugs with a high genetic barrier to resistance and/or high potency (eg, entecavir or tenofovir) are generally preferred to reduce the likelihood of resistance. The preferred options for the treatment of chronic hepatitis B in 2008 will likely include peginterferon alfa-2a, entecavir, tenofovir, and potentially telbivudine, providing serum HBV DNA is undetectable after 24 weeks of therapy, which predicts the absence or very low rate of resistance at year 1 and year 2 of therapy with this agent. Interferon alfa-2b is no longer used given the availability and convenience of peginterferon alfa-2a, and lamivudine is not recommended as initial therapy on the basis of an unacceptably high rate of resistance and proven inferiority to both entecavir and telbivudine in pivotal trials. Tenofovir, which was recently shown to be superior to adefovir, will likely replace adefovir as a preferred initial therapy in 2008 following its approval by the FDA and regulatory agencies in other countries.
3b. December 2007 treatment algorithm:
3c. For patients with compensated cirrhosis, a serum HBV DNA threshold of ≥ 2000 IU/mL is sufficient for initiation of therapy, irrespective of HBeAg status and regardless of whether ALT levels are elevated (Table 3). For those with chronic hepatitis B and decompensated cirrhosis, a serum HBV DNA level of ≥ 200 IU/mL is sufficient to begin treatment with an oral agent as well as to consider candidacy for liver transplantation. Recent trends are to treat patients with compensated or decompensated cirrhosis associated with any detection of serum HBV DNA, irrespective of the level. Oral agents are preferred when treating patients with cirrhosis, and peginterferon is either relatively or absolutely contraindicated in these patients. There are also increasing trends toward using combination nucleoside/nucleotide agents in treating cirrhotic patients, as well as in treating patients with HBV and HIV coinfection and individuals post liver transplantation performed for HBV infection.
Tables unable to be posted.
1. "Therapeutic options to control viral replication and disease progression fortunately continue to expand, and these advances will likely result in more patients undergoing treatment and deriving long-term benefits with a reduced incidence of cirrhosis and HCC."
2. "The natural history of chronic HBV infection can be divided into 4 phases: immune tolerance, immune clearance (hepatitis B e antigen [HBeAg]-positive chronic hepatitis B), inactive HBsAg carrier state, and reactivation (HBeAg-negative chronic hepatitis B). The immune tolerance phase, present in those patients infected at birth or early childhood, is characterized by the presence of HBeAg, high serum HBV DNA levels (at least > 20,000 IU/mL and usually much higher), and persistently normal alanine aminotransferase (ALT) levels. This phase is followed by an immune clearance phase of variable duration, with serum HBV DNA levels remaining high, but with serum ALT levels that are persistently or intermittently elevated and features of chronic hepatitis with or without fibrosis present on liver biopsy. Clearance of HBeAg and development of anti-HBe (HBeAg seroconversion) usually results in transition to the inactive HBsAg carrier state, typified by serum HBV DNA levels that are 2000 IU/mL, persistently or intermittently elevated ALT levels, and progressive liver damage on liver biopsy."
3. When to Start Therapy: Treatment is indicated in patients in the immune clearance and reactivation phases (ie, in those individuals with high serum HBV DNA levels, elevated ALT levels, and/or necroinflammation on liver biopsy, and who are predicted to have the highest chance of response to therapy). ... The primary goal of therapy for chronic hepatitis B is long-term suppression of serum HBV DNA, which will likely decrease progression to cirrhosis and HCC. ... The medications currently approved by the US Food and Drug Administration (FDA) for the initial treatment of chronic hepatitis B include interferon alfa-2b, peginterferon alfa-2a, and the oral nucleoside/nucleotide analogs lamivudine, adefovir dipivoxil, entecavir, and telbivudine, with tenofovir under FDA review for likely approval in 2008.
3a. Each of these drugs has a number of advantages and disadvantages. Issues for consideration in the selection of therapy include efficacy, safety, incidence of resistance, method of administration, and cost. Peginterferon alfa-2a has the advantages of a 1-year finite duration of therapy, higher rate of HBeAg seroconversion at 1 year, lack of resistance, and higher likelihood of HBsAg loss and seroconversion. Disadvantages of peginterferon therapy are parenteral administration, frequent side effects (especially flu-like symptoms, depression or irritability, and cytopenias), need for more intensive laboratory monitoring, contraindication in advanced liver disease, and higher cost. Genotyping may be useful to help decide whether treatment with peginterferon alfa-2a is warranted based on the highest rate of efficacy being in patients with genotype A and lowest efficacy being in those infected with HBV genotype D. The nucleoside/nucleotide agents have the advantages of oral administration, excellent tolerance, use in advanced liver disease, and high potency in lowering serum HBV DNA levels. The primary disadvantages of these agents are the need for long-term administration and variable rates of antiviral drug resistance. Oral drugs with a high genetic barrier to resistance and/or high potency (eg, entecavir or tenofovir) are generally preferred to reduce the likelihood of resistance. The preferred options for the treatment of chronic hepatitis B in 2008 will likely include peginterferon alfa-2a, entecavir, tenofovir, and potentially telbivudine, providing serum HBV DNA is undetectable after 24 weeks of therapy, which predicts the absence or very low rate of resistance at year 1 and year 2 of therapy with this agent. Interferon alfa-2b is no longer used given the availability and convenience of peginterferon alfa-2a, and lamivudine is not recommended as initial therapy on the basis of an unacceptably high rate of resistance and proven inferiority to both entecavir and telbivudine in pivotal trials. Tenofovir, which was recently shown to be superior to adefovir, will likely replace adefovir as a preferred initial therapy in 2008 following its approval by the FDA and regulatory agencies in other countries.
3b. December 2007 treatment algorithm:
3c. For patients with compensated cirrhosis, a serum HBV DNA threshold of ≥ 2000 IU/mL is sufficient for initiation of therapy, irrespective of HBeAg status and regardless of whether ALT levels are elevated (Table 3). For those with chronic hepatitis B and decompensated cirrhosis, a serum HBV DNA level of ≥ 200 IU/mL is sufficient to begin treatment with an oral agent as well as to consider candidacy for liver transplantation. Recent trends are to treat patients with compensated or decompensated cirrhosis associated with any detection of serum HBV DNA, irrespective of the level. Oral agents are preferred when treating patients with cirrhosis, and peginterferon is either relatively or absolutely contraindicated in these patients. There are also increasing trends toward using combination nucleoside/nucleotide agents in treating cirrhotic patients, as well as in treating patients with HBV and HIV coinfection and individuals post liver transplantation performed for HBV infection.
3d. Finally, patients who require cancer chemotherapy or treatment with an anti-tumor necrosis factor (TNF)-alpha agent and who have detectable HBsAg, whether they are inactive carriers or have chronic hepatitis B that has not been treated, should receive an oral antiviral agent as prophylaxis against reactivation of HBV infection. The antiviral agent should be started just before and continued for 6 to 12 months after discontinuation of chemotherapy or the anti-TNF agent, or should be used long-term if the patient meets standard criteria for treatment of chronic hepatitis B.
4. When to Stop Therapy: Patients should be monitored at least every 3 to 6 months while receiving therapy with the oral agents, and more frequently when treated with peginterferon alfa-2a due to higher rates of side effects and potential inability to tolerate therapy. Patients who are treated with peginterferon alfa-2a receive therapy for a fixed duration of 1 year, but it is possible that a shorter duration of therapy may achieve the same outcomes. Therapy is stopped prior to the standard treatment period of 1 year only if side effects are intolerable, which occurs in less than 5% of patients. The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B who are treated with the oral antiviral agents is HBeAg seroconversion to anti-HBe in association with very low or undetectable serum HBV DNA. Based on the experience with lamivudine showing a lower rate of relapse when therapy is continued an additional 6 to 12 months beyond this point, this practice has also been applied to the other oral agents. Some guidelines suggest that patients with cirrhosis should be treated long-term with oral agents, even after HBeAg seroconversion has been achieved, to avoid the risk of relapse. Because patients with HBeAg-negative chronic hepatitis B invariably relapse when therapy is stopped after 1 year, even when serum HBV DNA is undetectable, current guidelines recommend long-term therapy. Although some recent studies have demonstrated that relapse rates are lower if treatment with lamivudine or adefovir is stopped after several years of undetectable serum HBV DNA, current recommendations for the management of patients with HBeAg-negative chronic hepatitis B continue to support long-term treatment. It is unknown but possible that loss of HBsAg with seroconversion to anti-HBs is an acceptable endpoint in patients with HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a long course of antiviral therapy for chronic hepatitis B with the goal of reducing the potential complications of cirrhosis or HCC are often reassured by the analogy of long-term treatment of hypercholesterolemia, hypertension, or diabetes mellitus to prevent stroke or heart disease.
5. When to Change Therapy: An appropriate time to alter therapy by switching to or adding another drug is treatment failure, either primary treatment failure or an inadequate response while receiving treatment with oral agents. The definition of primary treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from baseline at week 12 of treatment, whereas an inadequate virologic response is defined as a serum HBV DNA ≥ 2000 IU/mL at week 24 of treatment. The first step in the evaluation of potential primary treatment failure is to exclude patient nonadherence to prescribed therapy as a potential cause. With respect to oral antiviral therapy, if the agent has indeed been taken on a regular/prescribed basis, the patient is considered to have primary treatment failure and should be switched to a more potent drug or possibly a combination of drugs. An inadequate virologic response (serum HBV DNA ≥ 2000 IU/mL after 24 weeks of oral antiviral therapy) is a much more common reason for altering therapy, and a "roadmap" outlining the management of these patients was recently published. Patients who have an inadequate response need to have their treatment changed to an alternative regimen, with either a different drug that is more potent and not cross-resistant or the addition of a second drug. Patients who only achieve a partial response after 24 weeks of treatment (serum HBV DNA ≥ 60 IU/mL to < 2000 IU/mL) may also need to change to a different therapeutic regimen. For some, a second drug can be added that is not cross-resistant with the first drug. However, if patients are being treated with a drug that has a low rate of resistance development, such as entecavir, they can continue treatment to and beyond 48 weeks. In this situation, patients should undergo serum HBV DNA testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed antiviral effect. These patients should remain on therapy but be monitored every 3 months, with further assessment after 48 weeks of therapy. If their response remains partial or becomes inadequate at this time point, as defined by the "roadmap" concept, therapy should be changed. Chronic hepatitis B patients with an inadequate response after 24 weeks of therapy with a drug with a risk of resistance, such as telbivudine, need to switch to a different, more effective drug. Alternatively, a second drug without cross-resistance to the first drug can be added to the regimen. The patient should then be monitored every 3 months up to week 48. If the serum HBV DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6 months. However, patients with advanced disease should continue to be monitored every 3 months, regardless of their response to treatment. Another appropriate time to alter therapy by switching or adding another drug to the treatment regimen is when there is development of HBV antiviral drug resistance. Treatment with adefovir is associated with a 29% rate of resistance in HBeAg-negative patients after 5 years of therapy. Entecavir is associated with one of the lowest cumulative rates of resistance in treatment-naive patients, < 1% after 4 years of therapy. Resistance with telbivudine occurs at intermediate rates, with 25% of HBeAg-positive patients and 11% of HBeAg-negative patients experiencing resistance after 2 years of therapy. The pivotal telbivudine trial demonstrated that the greater the degree of viral suppression at week 24 of therapy, the better the outcomes after 1 and 2 years of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT normalization, and rate of HBV antiviral drug resistance. Finally, HBV antiviral resistance was not noted in the tenofovir pivotal trials in HBeAg-positive and HBeAg-negative patients treated for 1 year. Table 4 summarizes the potential management of HBV antiviral resistance based on the US treatment algorithm and the AASLD guidelines. The general principle of the recommendations outlined in Table 4 is to add a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine, or entecavir is detected. The opposite concept applies to the patient with adefovir resistance (ie, add a nucleoside agent). This strategy of adding a second drug vs sequential treatment is supported by studies showing that the rate of subsequent adefovir resistance is considerably higher using the switch strategy in the setting of preexisting lamivudine resistance.
6. Conclusion: The treatment of chronic hepatitis B has evolved rapidly over the past 10 years since the licensure of lamivudine as the first oral agent in 1998. The future prospects for yet improved therapy are bright and will bring new drugs, such as tenofovir, as well as better approaches to on-treatment management that will reduce the likelihood of resistance and optimize outcomes.
4. When to Stop Therapy: Patients should be monitored at least every 3 to 6 months while receiving therapy with the oral agents, and more frequently when treated with peginterferon alfa-2a due to higher rates of side effects and potential inability to tolerate therapy. Patients who are treated with peginterferon alfa-2a receive therapy for a fixed duration of 1 year, but it is possible that a shorter duration of therapy may achieve the same outcomes. Therapy is stopped prior to the standard treatment period of 1 year only if side effects are intolerable, which occurs in less than 5% of patients. The endpoint of treatment for patients with HBeAg-positive chronic hepatitis B who are treated with the oral antiviral agents is HBeAg seroconversion to anti-HBe in association with very low or undetectable serum HBV DNA. Based on the experience with lamivudine showing a lower rate of relapse when therapy is continued an additional 6 to 12 months beyond this point, this practice has also been applied to the other oral agents. Some guidelines suggest that patients with cirrhosis should be treated long-term with oral agents, even after HBeAg seroconversion has been achieved, to avoid the risk of relapse. Because patients with HBeAg-negative chronic hepatitis B invariably relapse when therapy is stopped after 1 year, even when serum HBV DNA is undetectable, current guidelines recommend long-term therapy. Although some recent studies have demonstrated that relapse rates are lower if treatment with lamivudine or adefovir is stopped after several years of undetectable serum HBV DNA, current recommendations for the management of patients with HBeAg-negative chronic hepatitis B continue to support long-term treatment. It is unknown but possible that loss of HBsAg with seroconversion to anti-HBs is an acceptable endpoint in patients with HBeAg-negative chronic hepatitis B. Patients who are about to embark on such a long course of antiviral therapy for chronic hepatitis B with the goal of reducing the potential complications of cirrhosis or HCC are often reassured by the analogy of long-term treatment of hypercholesterolemia, hypertension, or diabetes mellitus to prevent stroke or heart disease.
5. When to Change Therapy: An appropriate time to alter therapy by switching to or adding another drug is treatment failure, either primary treatment failure or an inadequate response while receiving treatment with oral agents. The definition of primary treatment failure is a serum HBV DNA decline of less than 1 log10 IU/mL from baseline at week 12 of treatment, whereas an inadequate virologic response is defined as a serum HBV DNA ≥ 2000 IU/mL at week 24 of treatment. The first step in the evaluation of potential primary treatment failure is to exclude patient nonadherence to prescribed therapy as a potential cause. With respect to oral antiviral therapy, if the agent has indeed been taken on a regular/prescribed basis, the patient is considered to have primary treatment failure and should be switched to a more potent drug or possibly a combination of drugs. An inadequate virologic response (serum HBV DNA ≥ 2000 IU/mL after 24 weeks of oral antiviral therapy) is a much more common reason for altering therapy, and a "roadmap" outlining the management of these patients was recently published. Patients who have an inadequate response need to have their treatment changed to an alternative regimen, with either a different drug that is more potent and not cross-resistant or the addition of a second drug. Patients who only achieve a partial response after 24 weeks of treatment (serum HBV DNA ≥ 60 IU/mL to < 2000 IU/mL) may also need to change to a different therapeutic regimen. For some, a second drug can be added that is not cross-resistant with the first drug. However, if patients are being treated with a drug that has a low rate of resistance development, such as entecavir, they can continue treatment to and beyond 48 weeks. In this situation, patients should undergo serum HBV DNA testing every 3 to 6 months. Some drugs, such as adefovir, have a delayed antiviral effect. These patients should remain on therapy but be monitored every 3 months, with further assessment after 48 weeks of therapy. If their response remains partial or becomes inadequate at this time point, as defined by the "roadmap" concept, therapy should be changed. Chronic hepatitis B patients with an inadequate response after 24 weeks of therapy with a drug with a risk of resistance, such as telbivudine, need to switch to a different, more effective drug. Alternatively, a second drug without cross-resistance to the first drug can be added to the regimen. The patient should then be monitored every 3 months up to week 48. If the serum HBV DNA falls to undetectable levels by week 48, HBV DNA testing may occur every 6 months. However, patients with advanced disease should continue to be monitored every 3 months, regardless of their response to treatment. Another appropriate time to alter therapy by switching or adding another drug to the treatment regimen is when there is development of HBV antiviral drug resistance. Treatment with adefovir is associated with a 29% rate of resistance in HBeAg-negative patients after 5 years of therapy. Entecavir is associated with one of the lowest cumulative rates of resistance in treatment-naive patients, < 1% after 4 years of therapy. Resistance with telbivudine occurs at intermediate rates, with 25% of HBeAg-positive patients and 11% of HBeAg-negative patients experiencing resistance after 2 years of therapy. The pivotal telbivudine trial demonstrated that the greater the degree of viral suppression at week 24 of therapy, the better the outcomes after 1 and 2 years of therapy in terms of undetectable serum HBV DNA, HBeAg seroconversion, ALT normalization, and rate of HBV antiviral drug resistance. Finally, HBV antiviral resistance was not noted in the tenofovir pivotal trials in HBeAg-positive and HBeAg-negative patients treated for 1 year. Table 4 summarizes the potential management of HBV antiviral resistance based on the US treatment algorithm and the AASLD guidelines. The general principle of the recommendations outlined in Table 4 is to add a second drug that is not cross-resistant with the first (eg, adding a nucleotide drug such as adefovir or tenofovir when resistance to a nucleoside agent such as lamivudine, telbivudine, or entecavir is detected. The opposite concept applies to the patient with adefovir resistance (ie, add a nucleoside agent). This strategy of adding a second drug vs sequential treatment is supported by studies showing that the rate of subsequent adefovir resistance is considerably higher using the switch strategy in the setting of preexisting lamivudine resistance.
6. Conclusion: The treatment of chronic hepatitis B has evolved rapidly over the past 10 years since the licensure of lamivudine as the first oral agent in 1998. The future prospects for yet improved therapy are bright and will bring new drugs, such as tenofovir, as well as better approaches to on-treatment management that will reduce the likelihood of resistance and optimize outcomes.
Notes on "Clinical Evaluation of the HBV-Infected Patient," Henkel, A.S., Flamm, S.L., March 5, 2008.
1. Initial Screening Tests: Standard serologic markers used in the diagnosis of HBV infection include HBsAg, hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). HBsAg becomes detectable in serum generally within 4 to 10 weeks of exposure to HBV and is generally present in serum before there is significant elevation in serum aminotransferases. If the acute infection is cleared, HBsAg will disappear within 4 to 6 months and anti-HBs will become detectable in serum several weeks later. Chronic HBV infection is defined as the persistence of HBsAg-positivity beyond 6 months. During the period after which HBsAg has cleared but anti-HBs has not yet become detectable (often referred to as the "window period"), the only detectable marker of infection is the hepatitis B core IgM antibody (anti-HBc IgM). This scenario is rarely encountered in clinical practice. A positive HBsAg indicates the presence of an acute or chronic HBV infection. A positive anti-HBs, in the setting of a negative HBsAg, indicates immunity to HBV infection resulting from either vaccination or resolution of a prior infection. Occasionally, both anti-HBs and HBsAg are positive in the setting of chronic infection. In this case, although the HBs antibody is present, it is unable to neutralize the HBsAg, and the host remains chronically infected. A positive anti-HBc indicates that an individual has been exposed to HBV but does not distinguish between current and remote infection. Anti-HBc can remain positive even years after an HBV infection has been cleared. As such, if anti-HBc is positive, HBsAg and anti-HBs serology should then be obtained. An isolated anti-HBc (with negative HBsAg and anti-HBs) can occur in 3 settings: during the window period as discussed above; in chronically infected patients in whom HBsAg has fallen to undetectable levels (which is rare); and in patients with remote infection in whom anti-HBs has fallen to undetectable levels (which is common). The presence of anti-HBc IgM indicates an acute infection or reactivation of a chronic infection.
2. Additional Evaluation of the HBsAg-Positive Patient: Patients who are found to be HBsAg positive should undergo additional serologic and virologic work-up to fully characterize the status of the hepatitis B infection. Specifically, the physician should test for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe), and determine HBV DNA viral load. The results of these tests provide prognostic information and will guide recommendations regarding antiviral treatment. The clinical utility of hepatitis B genotype is not yet well defined.
3. Hepatitis B e Antigen: Chronic hepatitis B may be subclassified into HBeAg-positive and HBeAg-negative disease, which demonstrate different disease patterns and response to treatment. HBeAg is a soluble viral protein, the presence of which indicates active viral replication and, therefore, a greater risk of infectivity. Whereas many patients with chronic HBV infection with HBeAg negativity do not have substantial viral replication and are in the inactive carrier state, active replication and liver injury may occur even in the absence of HBeAg. Mutations in the precore region or core promoter region of the HBV genome render the host unable to produce HBeAg; therefore, HBeAg remains undetectable despite ongoing viral replication. Patients who are HBeAg-negative with active disease generally have a less favorable long-term prognosis than patients who are HBeAg-positive.
4. Hepatitis B e Antibody: Seroconversion from HBeAg to anti-HBe generally occurs early in patients who spontaneously clear an acute HBV infection. Patients with chronic hepatitis B can also undergo seroconversion to anti-HBe; this occurs at a rate of about 5% to 10% per year in chronically infected individuals. Anti-HBe may be present in HBeAg-negative patients with a precore or core promoter mutation. Seroconversion is an important endpoint in successful antiviral treatment in HBeAg-positive patients, as this may confer a lower risk of disease progression.
5. Hepatitis B DNA Viral Load: In recent years, a quantitative assay has been developed to measure HBV DNA in serum using polymerase chain reaction technology. HBV DNA viral load has become an important part of the evaluation of patients with chronic hepatitis B. The HBV DNA level provides prognostic information and has become a key factor in determining whether to initiate antiviral therapy. A high HBV DNA level has been correlated with increased risk of progression to cirrhosis and HCC. HBV DNA levels tend to be higher in HBeAg-positive patients compared with HBeAg-negative patients.
6. Hepatitis B Virus Genotype: There are currently 8 known HBV genotypes, designated A through H. The geographic distribution of these genotypes throughout the world is widely variable. The clinical utility of HBV genotype has not yet been clearly defined; however, there are emerging data to indicate that HBV genotype may affect the disease course, risk for HCC, and response to therapy. For example, studies have suggested that HBV genotype B is associated with a lower frequency of decompensated liver disease and HCC than genotype C. Furthermore, genotypes A and B appear to respond more favorably to interferon-based therapy than genotypes C and D.[21] As more data accrue, HBV genotype may become an important factor in influencing the management of HBV-infected patients.
1. Initial Screening Tests: Standard serologic markers used in the diagnosis of HBV infection include HBsAg, hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). HBsAg becomes detectable in serum generally within 4 to 10 weeks of exposure to HBV and is generally present in serum before there is significant elevation in serum aminotransferases. If the acute infection is cleared, HBsAg will disappear within 4 to 6 months and anti-HBs will become detectable in serum several weeks later. Chronic HBV infection is defined as the persistence of HBsAg-positivity beyond 6 months. During the period after which HBsAg has cleared but anti-HBs has not yet become detectable (often referred to as the "window period"), the only detectable marker of infection is the hepatitis B core IgM antibody (anti-HBc IgM). This scenario is rarely encountered in clinical practice. A positive HBsAg indicates the presence of an acute or chronic HBV infection. A positive anti-HBs, in the setting of a negative HBsAg, indicates immunity to HBV infection resulting from either vaccination or resolution of a prior infection. Occasionally, both anti-HBs and HBsAg are positive in the setting of chronic infection. In this case, although the HBs antibody is present, it is unable to neutralize the HBsAg, and the host remains chronically infected. A positive anti-HBc indicates that an individual has been exposed to HBV but does not distinguish between current and remote infection. Anti-HBc can remain positive even years after an HBV infection has been cleared. As such, if anti-HBc is positive, HBsAg and anti-HBs serology should then be obtained. An isolated anti-HBc (with negative HBsAg and anti-HBs) can occur in 3 settings: during the window period as discussed above; in chronically infected patients in whom HBsAg has fallen to undetectable levels (which is rare); and in patients with remote infection in whom anti-HBs has fallen to undetectable levels (which is common). The presence of anti-HBc IgM indicates an acute infection or reactivation of a chronic infection.
2. Additional Evaluation of the HBsAg-Positive Patient: Patients who are found to be HBsAg positive should undergo additional serologic and virologic work-up to fully characterize the status of the hepatitis B infection. Specifically, the physician should test for hepatitis B e antigen (HBeAg), hepatitis B e antibody (anti-HBe), and determine HBV DNA viral load. The results of these tests provide prognostic information and will guide recommendations regarding antiviral treatment. The clinical utility of hepatitis B genotype is not yet well defined.
3. Hepatitis B e Antigen: Chronic hepatitis B may be subclassified into HBeAg-positive and HBeAg-negative disease, which demonstrate different disease patterns and response to treatment. HBeAg is a soluble viral protein, the presence of which indicates active viral replication and, therefore, a greater risk of infectivity. Whereas many patients with chronic HBV infection with HBeAg negativity do not have substantial viral replication and are in the inactive carrier state, active replication and liver injury may occur even in the absence of HBeAg. Mutations in the precore region or core promoter region of the HBV genome render the host unable to produce HBeAg; therefore, HBeAg remains undetectable despite ongoing viral replication. Patients who are HBeAg-negative with active disease generally have a less favorable long-term prognosis than patients who are HBeAg-positive.
4. Hepatitis B e Antibody: Seroconversion from HBeAg to anti-HBe generally occurs early in patients who spontaneously clear an acute HBV infection. Patients with chronic hepatitis B can also undergo seroconversion to anti-HBe; this occurs at a rate of about 5% to 10% per year in chronically infected individuals. Anti-HBe may be present in HBeAg-negative patients with a precore or core promoter mutation. Seroconversion is an important endpoint in successful antiviral treatment in HBeAg-positive patients, as this may confer a lower risk of disease progression.
5. Hepatitis B DNA Viral Load: In recent years, a quantitative assay has been developed to measure HBV DNA in serum using polymerase chain reaction technology. HBV DNA viral load has become an important part of the evaluation of patients with chronic hepatitis B. The HBV DNA level provides prognostic information and has become a key factor in determining whether to initiate antiviral therapy. A high HBV DNA level has been correlated with increased risk of progression to cirrhosis and HCC. HBV DNA levels tend to be higher in HBeAg-positive patients compared with HBeAg-negative patients.
6. Hepatitis B Virus Genotype: There are currently 8 known HBV genotypes, designated A through H. The geographic distribution of these genotypes throughout the world is widely variable. The clinical utility of HBV genotype has not yet been clearly defined; however, there are emerging data to indicate that HBV genotype may affect the disease course, risk for HCC, and response to therapy. For example, studies have suggested that HBV genotype B is associated with a lower frequency of decompensated liver disease and HCC than genotype C. Furthermore, genotypes A and B appear to respond more favorably to interferon-based therapy than genotypes C and D.[21] As more data accrue, HBV genotype may become an important factor in influencing the management of HBV-infected patients.
7. Phases of Chronic Hepatitis B Infection: In cases of adult-acquired chronic hepatitis B, the serum alanine aminotransferase (ALT) level generally correlates well with the HBV DNA level and the severity of disease activity. However, in young patients with perinatally acquired hepatitis B, it is not uncommon to have a normal serum ALT level yet a markedly elevated HBV DNA level.[22] This is described as the immune-tolerant phase of the disease. Hepatic histologic damage tends to be minimal if a biopsy is performed. Patients may remain in the immune-tolerant phase for decades. Patients with perinatally acquired HBV infection often transition from an immune-tolerant phase to an immune clearance phase of the disease in the second to third decade of life. In HBeAg-positive patients, seroconversion to anti-HBe may occur during this phase, which may trigger a rise in serum aminotransferase levels and HBV DNA level. Although often asymptomatic, this transition can provoke symptoms of acute hepatitis, occasionally resulting in hepatic decompensation. Some patients who are HBsAg-positive have persistently low or undetectable HBV DNA and no elevation in serum ALT. These patients, referred to as inactive carriers, have little or no active viral replication. They are generally HBeAg-negative and anti-HBe-positive. It should be recognized, however, that chronic hepatitis B is a dynamic disease; conversion from an inactive to an active, replicative state can occur in carriers, particularly if they are immunocompromised. Although often mild or asymptomatic, such a reactivation can be severe enough to cause fulminant hepatic failure.
8. Role of Liver Biopsy: Most experts agree that a liver biopsy is not necessary in every patient diagnosed with chronic hepatitis B. However, a liver biopsy provides useful information regarding HBV disease activity and, in some settings, is an important factor in determining whether to initiate antiviral therapy. Serum ALT and HBV DNA levels are, in general, good surrogate markers of disease activity; however, in some cases marked inflammation may be present on liver biopsy in the setting of a normal ALT and minimally elevated HBV DNA. Similarly, the liver may appear histologically normal despite a markedly elevated HBV DNA level. Generally, a liver biopsy should be considered in patients with a normal serum ALT yet an increased HBV DNA.[15] In such patients, the disease activity found on liver biopsy will often influence the decision to begin antiviral therapy.
9. Counseling of the HBsAg-Positive Patient: Patients who screen positive for HBsAg should be advised on lifestyle modifications to avoid additional insults to the liver and to minimize risk of transmission of the virus. The patient should receive education on the potential modes of transmission including sexual transmission, blood exposure, and vertical transmission. Close contacts should be tested for HBV and should be vaccinated if not immune. Additionally, patients with HBV infection should be tested for other relevant hepatotropic viruses including hepatitis A and hepatitis C viruses. Hepatitis D virus should also be tested for, as coinfection with HBV is seen on occasion. HIV testing should also be done given that coinfection confers an increased risk of disease progression and may have an impact on the choice of antiviral therapy. Risk factors for the acquisition of these other viruses should also be addressed. Those who are not immune to hepatitis A should be offered vaccination. Abstinence from alcohol is recommended as there is no definitive amount of alcohol that is safe. Patients should be advised to avoid hepatotoxic medications if possible, with specific attention to herbal supplements and other over-the-counter agents.
10. Screening for HCC: Patients with chronic HBV infection have a 0.5% annual incidence of HCC, placing them at 100-times-greater risk of developing HCC than individuals without HBV infection. In patients with chronic HBV infection, HCC can arise even in the absence of cirrhosis. The American Association for the Study of Liver Diseases practice guidelines for the management of HCC recommend screening for HCC in the following patients with chronic hepatitis B: Asian men older than 40 years old, Asian women older than 50 years old, black patients over age 20 years, all patients with cirrhosis, and all patients with a family history of HCC. Asian hepatitis B carriers who lose HBsAg-positivity should continue to undergo surveillance indefinitely. Until recently, the preferred method for HCC screening included both liver ultrasound examination and measurement of serum alpha-fetoprotein (AFP). However, recent guidelines question the utility of AFP monitoring in HCC screening. Using 20 ng/mL as a cutoff value for abnormal AFP levels, serum AFP has a sensitivity of only 60%. Liver ultrasound exam has a sensitivity ranging between 65% and 80% and a specificity of more than 90% for the detection of HCC. In some patients, the utility of ultrasound examination may be limited, such as in those with obesity. In this population, screening with a more sensitive test such as magnetic resonance imaging with contrast or triphasic computed tomography scan should be considered. The preferred interval for screening ultrasound is every 6 months. There are some data to indicate that annual screening may be as effective as biannual screening; however, there is no clear survival benefit to screening more frequently than every 6 months.
8. Role of Liver Biopsy: Most experts agree that a liver biopsy is not necessary in every patient diagnosed with chronic hepatitis B. However, a liver biopsy provides useful information regarding HBV disease activity and, in some settings, is an important factor in determining whether to initiate antiviral therapy. Serum ALT and HBV DNA levels are, in general, good surrogate markers of disease activity; however, in some cases marked inflammation may be present on liver biopsy in the setting of a normal ALT and minimally elevated HBV DNA. Similarly, the liver may appear histologically normal despite a markedly elevated HBV DNA level. Generally, a liver biopsy should be considered in patients with a normal serum ALT yet an increased HBV DNA.[15] In such patients, the disease activity found on liver biopsy will often influence the decision to begin antiviral therapy.
9. Counseling of the HBsAg-Positive Patient: Patients who screen positive for HBsAg should be advised on lifestyle modifications to avoid additional insults to the liver and to minimize risk of transmission of the virus. The patient should receive education on the potential modes of transmission including sexual transmission, blood exposure, and vertical transmission. Close contacts should be tested for HBV and should be vaccinated if not immune. Additionally, patients with HBV infection should be tested for other relevant hepatotropic viruses including hepatitis A and hepatitis C viruses. Hepatitis D virus should also be tested for, as coinfection with HBV is seen on occasion. HIV testing should also be done given that coinfection confers an increased risk of disease progression and may have an impact on the choice of antiviral therapy. Risk factors for the acquisition of these other viruses should also be addressed. Those who are not immune to hepatitis A should be offered vaccination. Abstinence from alcohol is recommended as there is no definitive amount of alcohol that is safe. Patients should be advised to avoid hepatotoxic medications if possible, with specific attention to herbal supplements and other over-the-counter agents.
10. Screening for HCC: Patients with chronic HBV infection have a 0.5% annual incidence of HCC, placing them at 100-times-greater risk of developing HCC than individuals without HBV infection. In patients with chronic HBV infection, HCC can arise even in the absence of cirrhosis. The American Association for the Study of Liver Diseases practice guidelines for the management of HCC recommend screening for HCC in the following patients with chronic hepatitis B: Asian men older than 40 years old, Asian women older than 50 years old, black patients over age 20 years, all patients with cirrhosis, and all patients with a family history of HCC. Asian hepatitis B carriers who lose HBsAg-positivity should continue to undergo surveillance indefinitely. Until recently, the preferred method for HCC screening included both liver ultrasound examination and measurement of serum alpha-fetoprotein (AFP). However, recent guidelines question the utility of AFP monitoring in HCC screening. Using 20 ng/mL as a cutoff value for abnormal AFP levels, serum AFP has a sensitivity of only 60%. Liver ultrasound exam has a sensitivity ranging between 65% and 80% and a specificity of more than 90% for the detection of HCC. In some patients, the utility of ultrasound examination may be limited, such as in those with obesity. In this population, screening with a more sensitive test such as magnetic resonance imaging with contrast or triphasic computed tomography scan should be considered. The preferred interval for screening ultrasound is every 6 months. There are some data to indicate that annual screening may be as effective as biannual screening; however, there is no clear survival benefit to screening more frequently than every 6 months.
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