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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.
Case 4: 62yo man of Greek origin presents with fatigue, otherwise healthy, by Anna S.F. Lok
A 62-year-old man presented to his primary care physician in June of 2000 with fatigue. He gave a history of two similar episodes of extreme fatigue in the past five years. During one of these episodes, elevated liver enzymes were found. He did not seek further attention at that time. An examination showed that he was otherwise healthy. He was not on medications, and he denied drinking. He had no known family history of liver disease. He had been born in Greece, and moved to the United States in 1980. Physical examination did not reveal any significant findings. There was no evidence of jaundice.
Laboratory Results:
AST: 349
ALT: 452
Total bilirubin: 0.9
Platelet count: 210k
HBsAg: positive
Anti-HCV: negative
The patient was referred to a gastroenterologist. By August of 2000, when he first saw the gastroenterologist, his symptoms had resolved. Repeat testing at this time showed the following:
Laboratory Results:
AST: 55
ALT: 68
Total bilirubin: 0.7
HBeAg: negative
Anti-HBe: positive
HBV DNA: 125,000 copies/mL
What is your diagnosis?
1. Acute antigen-negative hepatitis B
2. Chronic antigen-negative hepatitis B
3. Clinically resolved case of hepatitis B
Dr. Lok (OC): This is very classical of patients with E-antigen negative chronic Hepatitis, they tend to run a fluctuating course. The fact that he's E-antigen negative, does not mean that he does not have active virus replication, because we now know that there's a variant of Hepatitis B virus these patients can continue to have active HBV DNA level and active liver disease.
Which would you do?
1. Nothing; monitor patient
2. Begin anti-viral therapy
3. Order more tests
Dr. Lok (OC): Given the fact that we know that most patients with E-antigen negative chronic Hepatitis will require a very long duration of therapy. We want to have a much better understanding of the severity of his liver disease before committing him to this long course of therapy.
Which test(s) would you order?
1. Anti-HDV
2. Liver biopsy
3. Both
Dr. Lok: ....Because he came from Greece, it is possible that he actually acquired Hepatitis B way back in his childhood and therefore it is important to test him for the Delta virus.... We also did the liver biopsy on him because of the fact that by the time he came to see us, his liver enzymes were close to normal.
Subsequent test results showed the following:
Anti-HDV: negative
Liver biopsy: moderate inflammation, fibrosis
Adefovir was not available at this time. Which treatment would you choose?
1. Interferon
2. Lamivudine
Dr. Lok: Well in August in 2000, there're really two choices of therapy. One is interferon and the other is lamivudine. In fact, both choices were being discussed with the patient....The downside of interferon obviously is the side effects. And to some extent, cost because for patients of E-antigen negative chronic Hepatitis, one would have to give the patients at least a 12-month pulse and some studies would actually suggest that you should be giving 24 months treatment. The advantage of interferon is that you can stop treatment in some patients. And certainly with 12 months treatment about 15-20 percent of patients would have a sustained response with two years treatment... Whereas in patients treated with lamivudine we know that if we try to stop treatment after one year, the likelihood of relapse is more than 90 percent and most of these patients end up receiving very long durations of therapy, which then is associated with increasing risks of drug resistance.... If we had seen this patient now, we would have a third option which would be adefovir therapy.... The benefit of adefovir is that the risk of drug resistance is very low, so continuation of treatment is going to be associated with maintained response in majority of patients, but that's going to be a fairly expensive therapy if we keep going year after year.
The patient chose oral therapy. He began lamivudine 100 mg/d. He responded well. His virus level became barely detectable, his liver enzymes became normal, and he felt significantly better. Two years after starting lamivudine treatment, the laboratory reported the following:
Laboratory Results
AST: 42
ALT: 59
Total bilirubin: 0.8
HBV DNA: 6,500,000 copies/mL
Which would you do?
1. Stop lamivudine; do not treat with any anti-viral therapy; monitor patient
2. Continue lamivudine; do not add another anti-viral drug; monitor patient
3. Stop lamivudine, treat with adefovir
4. Continue lamivudine, add adefovir
The attending physician had the capability to test for mutation resistance. A sample from the patient tested positive for YMDD mutation. Although the patient's liver enzymes were still well controlled, the attending physician decided to initiate salvage therapy because of the marked increase in HBV DNA levels.
Dr. Lok (OC): There is indeed one study-granted on a very small number of patients, 19 patients in each arm-showing that in patients who've developed lamivudine resistance, you can stop lamivudine and just switch them over to adefovir therapy and it results in a similar rate of viral suppression. However, there is a small risk of Hepatitis flairs during the transition period. And we now know that by putting the patient on adefovir alone, instead of leaving them on combination of lamivudine and adefovir, there is perhaps some higher chance of resistance to adefovir over time.... Because the two drugs select for different resistance mutation, continuation of both drugs might minimize selection of adefovir resistant mutation.... That's the reason why we chose to leave this patient on lamivudine and just add adefovir.
Dr. Lok (OC to VO): Adefovir dipivoxil 10 milligram daily was started in January of 2003. He had a very slow drop in HBV DNA level but it kept coming down. And in May of 2004, his HBV DNA level was still detectable by PCRSA, but at extremely low levels.
A 62-year-old man presented to his primary care physician in June of 2000 with fatigue. He gave a history of two similar episodes of extreme fatigue in the past five years. During one of these episodes, elevated liver enzymes were found. He did not seek further attention at that time. An examination showed that he was otherwise healthy. He was not on medications, and he denied drinking. He had no known family history of liver disease. He had been born in Greece, and moved to the United States in 1980. Physical examination did not reveal any significant findings. There was no evidence of jaundice.
Laboratory Results:
AST: 349
ALT: 452
Total bilirubin: 0.9
Platelet count: 210k
HBsAg: positive
Anti-HCV: negative
The patient was referred to a gastroenterologist. By August of 2000, when he first saw the gastroenterologist, his symptoms had resolved. Repeat testing at this time showed the following:
Laboratory Results:
AST: 55
ALT: 68
Total bilirubin: 0.7
HBeAg: negative
Anti-HBe: positive
HBV DNA: 125,000 copies/mL
What is your diagnosis?
1. Acute antigen-negative hepatitis B
2. Chronic antigen-negative hepatitis B
3. Clinically resolved case of hepatitis B
Dr. Lok (OC): This is very classical of patients with E-antigen negative chronic Hepatitis, they tend to run a fluctuating course. The fact that he's E-antigen negative, does not mean that he does not have active virus replication, because we now know that there's a variant of Hepatitis B virus these patients can continue to have active HBV DNA level and active liver disease.
Which would you do?
1. Nothing; monitor patient
2. Begin anti-viral therapy
3. Order more tests
Dr. Lok (OC): Given the fact that we know that most patients with E-antigen negative chronic Hepatitis will require a very long duration of therapy. We want to have a much better understanding of the severity of his liver disease before committing him to this long course of therapy.
Which test(s) would you order?
1. Anti-HDV
2. Liver biopsy
3. Both
Dr. Lok: ....Because he came from Greece, it is possible that he actually acquired Hepatitis B way back in his childhood and therefore it is important to test him for the Delta virus.... We also did the liver biopsy on him because of the fact that by the time he came to see us, his liver enzymes were close to normal.
Subsequent test results showed the following:
Anti-HDV: negative
Liver biopsy: moderate inflammation, fibrosis
Adefovir was not available at this time. Which treatment would you choose?
1. Interferon
2. Lamivudine
Dr. Lok: Well in August in 2000, there're really two choices of therapy. One is interferon and the other is lamivudine. In fact, both choices were being discussed with the patient....The downside of interferon obviously is the side effects. And to some extent, cost because for patients of E-antigen negative chronic Hepatitis, one would have to give the patients at least a 12-month pulse and some studies would actually suggest that you should be giving 24 months treatment. The advantage of interferon is that you can stop treatment in some patients. And certainly with 12 months treatment about 15-20 percent of patients would have a sustained response with two years treatment... Whereas in patients treated with lamivudine we know that if we try to stop treatment after one year, the likelihood of relapse is more than 90 percent and most of these patients end up receiving very long durations of therapy, which then is associated with increasing risks of drug resistance.... If we had seen this patient now, we would have a third option which would be adefovir therapy.... The benefit of adefovir is that the risk of drug resistance is very low, so continuation of treatment is going to be associated with maintained response in majority of patients, but that's going to be a fairly expensive therapy if we keep going year after year.
The patient chose oral therapy. He began lamivudine 100 mg/d. He responded well. His virus level became barely detectable, his liver enzymes became normal, and he felt significantly better. Two years after starting lamivudine treatment, the laboratory reported the following:
Laboratory Results
AST: 42
ALT: 59
Total bilirubin: 0.8
HBV DNA: 6,500,000 copies/mL
Which would you do?
1. Stop lamivudine; do not treat with any anti-viral therapy; monitor patient
2. Continue lamivudine; do not add another anti-viral drug; monitor patient
3. Stop lamivudine, treat with adefovir
4. Continue lamivudine, add adefovir
The attending physician had the capability to test for mutation resistance. A sample from the patient tested positive for YMDD mutation. Although the patient's liver enzymes were still well controlled, the attending physician decided to initiate salvage therapy because of the marked increase in HBV DNA levels.
Dr. Lok (OC): There is indeed one study-granted on a very small number of patients, 19 patients in each arm-showing that in patients who've developed lamivudine resistance, you can stop lamivudine and just switch them over to adefovir therapy and it results in a similar rate of viral suppression. However, there is a small risk of Hepatitis flairs during the transition period. And we now know that by putting the patient on adefovir alone, instead of leaving them on combination of lamivudine and adefovir, there is perhaps some higher chance of resistance to adefovir over time.... Because the two drugs select for different resistance mutation, continuation of both drugs might minimize selection of adefovir resistant mutation.... That's the reason why we chose to leave this patient on lamivudine and just add adefovir.
Dr. Lok (OC to VO): Adefovir dipivoxil 10 milligram daily was started in January of 2003. He had a very slow drop in HBV DNA level but it kept coming down. And in May of 2004, his HBV DNA level was still detectable by PCRSA, but at extremely low levels.
S401 Case 3: 53yo Vietnamese woman with abnormal liver test, no signs of chronic liver disease on physical examination, by Robert P. Perrillo.
During a routine screening, a 53-year-old Vietnamese woman was found to have abnormal ALT and AST. A physical examination did not reveal signs of chronic liver disease.
Laboratory Results:
HbsAg: positive
HbeAg: positive
HBV DNA: 3 x 106 copies/mL
ALT: 180 U/L
Bilirubin: within normal limits
Albumin: within normal limits
Would you recommend a liver biopsy?
1. Yes
2. No
Dr. Perillo (OC): This is obviously a case in which there is ongoing viral replication and it's what we would call E-antigen positive chronic Hepatitis B.... And that's why liver biopsy is so important because it really shows changes consistent with chronic Hepatitis B. Otherwise, if you did not have a biopsy, it's possible that this individual does have ALT elevation due to some other cause.
A liver biopsy showed moderate portal inflammation. The patient had a METAVIR stage of F2. There was an A2 grade of inflammation.
Which would you do?
1. Start lamivudine
2. Start adefovir
3. Start interferon
4. Start lamivudine and adefovir
5. No treatment, monitor patient
Dr. Perrillo (OC): In this instance, we chose lamivudine therapy because it's more potent actually than adefovir. And it is also significantly cheaper. Lamivudine mono therapy costs about $150.00 US dollars per month. Whereas with adefovir, it's about $550 to $600.00. So there was a consideration of financial cost. We also felt that if the patient developed lamivudine resistance, we could roll the patient over to adefovir therapy at that time.... In fact, many authorities tend to go with this approach.
The patient was started on lamivudine, 100 mg daily. Liver function tests and HBV serology were monitored every three months. Twelve months after beginning lamivudine therapy, the following test results were obtained:
Laboratory Results
ALT: 32 U/L
HbeAg: positive
HBV DNA: undectable
Dr. Perillo (VO): This is a graph of the patient's course during the first 12 months. Notice the very prompt fall in HBV DNA. And the decremental change in ALT. However, E-antigen remained positive throughout this period.
Which would you do now?
1. Continue lamivudine
2. Stop lamivudine, treat with adefovir
3. Continue lamivudine, add adefovir
Dr. Perrillo (OC): Lamivudine was continued because at the time, at the 12 month interval, there was no indication that the patient had become resistant to lamivudine. HBV DNA remained suppressed and ALT level remained normal.
The patient continued on lamivudine 100 mg/d. Eighteen months after lamivudine had been initiated, the laboratory reported the following results:
Laboratory Results
ALT: 80 U/L
HBeAg: positive
HBV DNA: 3 x105 copies/mL
Which would you do now?
1. Continue lamivudine
2. Stop lamivudine, treat with adefovir
3. Continue lamivudine, add adefovir
Dr. Perrillo (OC): We switched to adefovir mono therapy because we did not yet have the data at hand to suggest that there would be an ALT flair when that is done. And the patient preferred to be on one drug instead of two drugs.... Combination of adefovir and lamivudine therapy would have been as effective and probably would have prevented the ALT flair that happened when lamivudine was discontinued.
Dr. Perrillo (OC) to (VO): This graph depicts the course of the patient after adefovir was added and lamivudine was discontinued. Notice that we can easily detect the YMDD mutunt form of Hepatitis B, that is the lamivudine resistant form, which accounted for the secondary increase in HBV DNA and ALT. The patient does convert the E-antigen several months after starting adefovir. But perhaps because the lamivudine was discontinued, you see a further slight increment in HBV DNA even though adefovir is already being administered. And a secondary flair in ALT.
Dr. Perrillo (VO to OC): Many authorities would probably continue the lamivudine therapy when adding adefovir, to prevent such a flair. In one study, where adefovir mono therapy was used, it was found that 37% of patients exhibited an ALT flair after lamivudine was discontinued.
Dr. Perrillo (OC to VO): Nonetheless, adefovir has had striking benefit in this patient, resulting in a fall in HBV DNA levels, to nondetectable limits and an eventual resolution of the ALT abnormality.
Ten months after initiation of adefovir therapy, the laboratory reported the following results:
HbeAg: negative
Anti-Hbe: positive
HBV DNA: undetectable
ALT: within normal limits
Would you recommend stopping adefovir?
1. Yes
2. No
Dr. Perrillo (OC): We would like to think that time limited therapies can be effective if providing durable suppression of the virus. But in many cases, that's simply not possible.... In this instance, it would be reasonable with an F 2 stage of fibrosis to consider doing that. You have to have that E-antigen seroconversion for awhile. Several months, three months at the very minimum before you can successfully withdrawal the therapy. If E-antigen seroconversion has occurred more recently than that and you have stopped the therapy, there's a higher rate that you're going to have what we call reactivated Hepatitis B. And conversion once again, from anti-E, to E-antigen. It's very important that you consider following the patient at three month intervals, or perhaps even shorter intervals if you're very concerned about reactivated Hepatitis B. This allows us some safety margin to appreciate early reoccurrences so that you can treat the patient again. We would suspect that with adefovir having a very low resistance profile in this present case, that if you added adefovir therapy again after stopping it, it would be effective.
During a routine screening, a 53-year-old Vietnamese woman was found to have abnormal ALT and AST. A physical examination did not reveal signs of chronic liver disease.
Laboratory Results:
HbsAg: positive
HbeAg: positive
HBV DNA: 3 x 106 copies/mL
ALT: 180 U/L
Bilirubin: within normal limits
Albumin: within normal limits
Would you recommend a liver biopsy?
1. Yes
2. No
Dr. Perillo (OC): This is obviously a case in which there is ongoing viral replication and it's what we would call E-antigen positive chronic Hepatitis B.... And that's why liver biopsy is so important because it really shows changes consistent with chronic Hepatitis B. Otherwise, if you did not have a biopsy, it's possible that this individual does have ALT elevation due to some other cause.
A liver biopsy showed moderate portal inflammation. The patient had a METAVIR stage of F2. There was an A2 grade of inflammation.
Which would you do?
1. Start lamivudine
2. Start adefovir
3. Start interferon
4. Start lamivudine and adefovir
5. No treatment, monitor patient
Dr. Perrillo (OC): In this instance, we chose lamivudine therapy because it's more potent actually than adefovir. And it is also significantly cheaper. Lamivudine mono therapy costs about $150.00 US dollars per month. Whereas with adefovir, it's about $550 to $600.00. So there was a consideration of financial cost. We also felt that if the patient developed lamivudine resistance, we could roll the patient over to adefovir therapy at that time.... In fact, many authorities tend to go with this approach.
The patient was started on lamivudine, 100 mg daily. Liver function tests and HBV serology were monitored every three months. Twelve months after beginning lamivudine therapy, the following test results were obtained:
Laboratory Results
ALT: 32 U/L
HbeAg: positive
HBV DNA: undectable
Dr. Perillo (VO): This is a graph of the patient's course during the first 12 months. Notice the very prompt fall in HBV DNA. And the decremental change in ALT. However, E-antigen remained positive throughout this period.
Which would you do now?
1. Continue lamivudine
2. Stop lamivudine, treat with adefovir
3. Continue lamivudine, add adefovir
Dr. Perrillo (OC): Lamivudine was continued because at the time, at the 12 month interval, there was no indication that the patient had become resistant to lamivudine. HBV DNA remained suppressed and ALT level remained normal.
The patient continued on lamivudine 100 mg/d. Eighteen months after lamivudine had been initiated, the laboratory reported the following results:
Laboratory Results
ALT: 80 U/L
HBeAg: positive
HBV DNA: 3 x105 copies/mL
Which would you do now?
1. Continue lamivudine
2. Stop lamivudine, treat with adefovir
3. Continue lamivudine, add adefovir
Dr. Perrillo (OC): We switched to adefovir mono therapy because we did not yet have the data at hand to suggest that there would be an ALT flair when that is done. And the patient preferred to be on one drug instead of two drugs.... Combination of adefovir and lamivudine therapy would have been as effective and probably would have prevented the ALT flair that happened when lamivudine was discontinued.
Dr. Perrillo (OC) to (VO): This graph depicts the course of the patient after adefovir was added and lamivudine was discontinued. Notice that we can easily detect the YMDD mutunt form of Hepatitis B, that is the lamivudine resistant form, which accounted for the secondary increase in HBV DNA and ALT. The patient does convert the E-antigen several months after starting adefovir. But perhaps because the lamivudine was discontinued, you see a further slight increment in HBV DNA even though adefovir is already being administered. And a secondary flair in ALT.
Dr. Perrillo (VO to OC): Many authorities would probably continue the lamivudine therapy when adding adefovir, to prevent such a flair. In one study, where adefovir mono therapy was used, it was found that 37% of patients exhibited an ALT flair after lamivudine was discontinued.
Dr. Perrillo (OC to VO): Nonetheless, adefovir has had striking benefit in this patient, resulting in a fall in HBV DNA levels, to nondetectable limits and an eventual resolution of the ALT abnormality.
Ten months after initiation of adefovir therapy, the laboratory reported the following results:
HbeAg: negative
Anti-Hbe: positive
HBV DNA: undetectable
ALT: within normal limits
Would you recommend stopping adefovir?
1. Yes
2. No
Dr. Perrillo (OC): We would like to think that time limited therapies can be effective if providing durable suppression of the virus. But in many cases, that's simply not possible.... In this instance, it would be reasonable with an F 2 stage of fibrosis to consider doing that. You have to have that E-antigen seroconversion for awhile. Several months, three months at the very minimum before you can successfully withdrawal the therapy. If E-antigen seroconversion has occurred more recently than that and you have stopped the therapy, there's a higher rate that you're going to have what we call reactivated Hepatitis B. And conversion once again, from anti-E, to E-antigen. It's very important that you consider following the patient at three month intervals, or perhaps even shorter intervals if you're very concerned about reactivated Hepatitis B. This allows us some safety margin to appreciate early reoccurrences so that you can treat the patient again. We would suspect that with adefovir having a very low resistance profile in this present case, that if you added adefovir therapy again after stopping it, it would be effective.
Lamivudine was discontinued. The patient was started on tenofovir 300 mg/d. On tenofovir, his HBV DNA became suppressed again. The patient continued to be clinically compensated.
Laboratory Results:
HBV DNA 0.017 pg/mL
AST: 35 U/L
ALT: 57 U/L
After 11 months of tenofovir therapy, adefovir became available. Tenofovir was discontinued, and adefovir treatment was begun. After six months of adefovir treatment, the lab reported the following test results:
HBV DNA: 352 pg/ml
AST: 61 U/L
ALT: 34 U/L
Which would you do now?
1. Discontinue adefovir, restart tenofovir
2. Discontinue adefovir, restart lamivudine
3. Continue adefovir, add lamivudine
In this case, the attending physician chose tenofovir, because it had been effective for this patient in the past.
Dr. Wright (OC): Adefovir resistance at one year is zero. And it's only with the availability of long term data at two years and three years, that we are beginning to see or observe or hear about very low levels of adefovir resistance....I didn't use dual therapy from the get go because we had guidance from trials of compensated Hepatitis B patients that you could switch to adefovir and you would have the same viral suppression as if you maintained lamivudine and adefovir. So it didn't seem that we should give him an unnecessary drug such as lamivudine.
Adefovir was discontinued and tenofovir was restarted. On tenofovir HBV DNA decreased to .107 pg/mL and then to 0.004 pg/mL. Which would you do now?
1. No change in therapy
2. Add lamivudine
Dr. Wright (OC): I began lamivudine again because I was concerned that if he developed tenofovir resistance, that he could decompensate further.... Whether or not one continues with lamivudine is somewhat controversial.... In the patient who has the potential for decompensation in the setting of resistance, I am increasingly continuing patients on both lamivudine and adefovir or tenofovir because I'm concerned that if they develop resistance in the setting of partially compensated or decompensated liver disease, that resistance can result in worsening of their clinical outcomes. And we know that lamivudine resistant variants are adefovir and tenofovir sensitive and conversely that adefovir resistant variants are lamivudine sensitive. I want to stress however, that the development of adefovir resistance is very low and only about four percent at three years in clinically compensated patients, we don't know if that's also true in decompensated patients. But to my mind, in these patients with advanced liver disease, you should err on the side of over treating rather than under treating because the consequences if they do fail therapy are much greater.
Dr. Wright (OC to VO): Change in the HBV DNA level over time is shown in this slide. You can see that when the patient was started on the lamivudine, he had approximately a 2-log reduction in HBV DNA. But that was gradually lost over time with a rise in HBV DNA levels close to his pre-treatment values. This is when he was switched to tenofovir with marked suppression of HBV DNA. When he was switched to adefovir following FDA approval of adefovir, HBV DNA levels rose again and these fell when tenofovir was reinstituted. Lamivudine was added to tenofovir and in the combination lamivudine/tenofovir, he has remained Hepatitis B virally suppressed.
Dr. Wright (VO): This slide shows changes of serum ALT in association with changes in HBV DNA seen on the prior slide. And lamivudine therapy initially was associated with improvement in serum ALT and AST. When lamivudine resistance developed, this improvement was lost, but tenofovir actually resulted not just in suppression of DNA, but also improvement in serum ALT shown between 27 and 52 months of therapy. Adefovir was shown with a slight loss of ALT benefit, but this loss was now improved when tenofovir was reinstituted and then when lamivudine was added to the regimen.
Dr. Wright (VO to OC): The time course over which we have observed him now is several years. And the natural history of Hepatitis B is still to progress. Not all patients will have clinical improvement despite viral suppression.... In follow up the patient continues to be virally suppressed on lamivudine and tenofovir, however, he's had progressive ascites with temporal muscle wasting, progressive hepatic disfunction.
Conclusion and Summary: On recent testing, the patient's serum albumin was 1.8. His bilirubin was 3.5, and his INR was 2. He was referred for consideration of liver transplantation. He is currently waiting liver transplantation with a MELD score of 14.
Laboratory Results:
HBV DNA 0.017 pg/mL
AST: 35 U/L
ALT: 57 U/L
After 11 months of tenofovir therapy, adefovir became available. Tenofovir was discontinued, and adefovir treatment was begun. After six months of adefovir treatment, the lab reported the following test results:
HBV DNA: 352 pg/ml
AST: 61 U/L
ALT: 34 U/L
Which would you do now?
1. Discontinue adefovir, restart tenofovir
2. Discontinue adefovir, restart lamivudine
3. Continue adefovir, add lamivudine
In this case, the attending physician chose tenofovir, because it had been effective for this patient in the past.
Dr. Wright (OC): Adefovir resistance at one year is zero. And it's only with the availability of long term data at two years and three years, that we are beginning to see or observe or hear about very low levels of adefovir resistance....I didn't use dual therapy from the get go because we had guidance from trials of compensated Hepatitis B patients that you could switch to adefovir and you would have the same viral suppression as if you maintained lamivudine and adefovir. So it didn't seem that we should give him an unnecessary drug such as lamivudine.
Adefovir was discontinued and tenofovir was restarted. On tenofovir HBV DNA decreased to .107 pg/mL and then to 0.004 pg/mL. Which would you do now?
1. No change in therapy
2. Add lamivudine
Dr. Wright (OC): I began lamivudine again because I was concerned that if he developed tenofovir resistance, that he could decompensate further.... Whether or not one continues with lamivudine is somewhat controversial.... In the patient who has the potential for decompensation in the setting of resistance, I am increasingly continuing patients on both lamivudine and adefovir or tenofovir because I'm concerned that if they develop resistance in the setting of partially compensated or decompensated liver disease, that resistance can result in worsening of their clinical outcomes. And we know that lamivudine resistant variants are adefovir and tenofovir sensitive and conversely that adefovir resistant variants are lamivudine sensitive. I want to stress however, that the development of adefovir resistance is very low and only about four percent at three years in clinically compensated patients, we don't know if that's also true in decompensated patients. But to my mind, in these patients with advanced liver disease, you should err on the side of over treating rather than under treating because the consequences if they do fail therapy are much greater.
Dr. Wright (OC to VO): Change in the HBV DNA level over time is shown in this slide. You can see that when the patient was started on the lamivudine, he had approximately a 2-log reduction in HBV DNA. But that was gradually lost over time with a rise in HBV DNA levels close to his pre-treatment values. This is when he was switched to tenofovir with marked suppression of HBV DNA. When he was switched to adefovir following FDA approval of adefovir, HBV DNA levels rose again and these fell when tenofovir was reinstituted. Lamivudine was added to tenofovir and in the combination lamivudine/tenofovir, he has remained Hepatitis B virally suppressed.
Dr. Wright (VO): This slide shows changes of serum ALT in association with changes in HBV DNA seen on the prior slide. And lamivudine therapy initially was associated with improvement in serum ALT and AST. When lamivudine resistance developed, this improvement was lost, but tenofovir actually resulted not just in suppression of DNA, but also improvement in serum ALT shown between 27 and 52 months of therapy. Adefovir was shown with a slight loss of ALT benefit, but this loss was now improved when tenofovir was reinstituted and then when lamivudine was added to the regimen.
Dr. Wright (VO to OC): The time course over which we have observed him now is several years. And the natural history of Hepatitis B is still to progress. Not all patients will have clinical improvement despite viral suppression.... In follow up the patient continues to be virally suppressed on lamivudine and tenofovir, however, he's had progressive ascites with temporal muscle wasting, progressive hepatic disfunction.
Conclusion and Summary: On recent testing, the patient's serum albumin was 1.8. His bilirubin was 3.5, and his INR was 2. He was referred for consideration of liver transplantation. He is currently waiting liver transplantation with a MELD score of 14.
S301 Case 2, 53yo man diagnosed with hepatitis B in 1990, by Teresa L. Wright.
A 53-year-old man was diagnosed with hepatitis B in 1990. At the time of diagnosis, he was working full time as a gardner. He had no history of injection drug use. He had had multiple sexual partners with unprotected sex. His physical examination was within normal limits. The patient was clinically compensated with normal serum bilirubin, serum albumin, and a normal INR.
Laboratory Results:
CBC: normal
Platelet count: 147k/cmm
Alpha protein: normal
Alkaline phosphate: normal
Serum transaminases 69 U/L
ALT: 122 U/L
HBV DNA: unavailable
HbsAg, HbeAg positive
Anti-HCV, anti-HDV negative
HIV negative
A liver biopsy demonstrated moderate inflammation with cirrhosis. The only treatment available was interferon. Treatment was not initiated. He was recommended to have a serial ultrasound and alphatine protein levels at various intervals of a year to screen for hepatocellular carcinoma.
In 1998, the patient came to the liver clinic. He had been followed at another medical center for eight years. He now had a marked increase in fatigue and was no longer able to work. Physical examination revealed temporal muscle wasting and increased vascular markings on the abdominal wall. There were no ascites or encephalopthy. Serum bilirubin and albumin had risen.
Laboratory Results
Serum bilirubin: 1.4 mb/dl
AST: 369 U/L
ALT: 619 U/L
INR: 1.2
Platelet count: 100k/cmm
HbeAg positive
HBV DNA 1411pg/ml
Which would you do?
1. Order ultrasound of liver
2. Order CT scan of liver
3. Neither
Dr. Wright: These patients are clearly at risk with Hepatitis B cirrhosis of developing liver cancer and that risk may be life long as high as 10 to 15 percent. The way we screen these patients however is controversial because our current screening tests are not very sensitive. Even at high resolution CT scans can miss lesions that are one centimeter in diameter and ultrasounds are probably less sensitive.... Increasingly, we're performing CT scans to screen for hepatocellular carcinoma, although CT scans are more expensive than performing ultrasounds and they also carry within a low risk of radiation of nephrotoxicity from the intravenous contrast.
The CT scan showed no evidence of ascites or focal mass. Would you order an endoscopy?
1. Yes
2. No
In this case, the attending physician ordered an endoscopy. It showed moderately-sized esophageal varices. Would you begin treatment with beta blockers at this time?
1. Yes
2. No
Dr. Wright (OC): The endospy was performed as we do in all our patients now with biopsy proven cirrhosis and certainly in our patients who have evidence of hepatic decompensation because if you document the presence of moderate size esophageal varices, you should begin patients on beta blockers to reduce the risk of bleeding from esophageal varices.
Beta blocker therapy was started. Lamivudine and interferon were the only therapies available for treating hepatitis B. In addition to beta blocker therapy, which would you do?
1. Begin lamivudine
2. Begin interferon
3. No additional therapy
Dr. Wright (OC): Lamivudine was begun in 1998 and this was shortly after FDA approval of lamivudine when we had increasing information that lamivudine could suppress Hepatitis B replication in the setting of significant liver disease. It wasn't begun earlier because it was not yet FDA approved for that indication.
The patient was started on lamivudine 100 mg/dy and beta blockers. He was seen every three months in the liver clinic. Twelve months later, in 1999, he was less fatigued and was able to work part time.
Laboratory Results:
AST: 37 U/L
ALT: 45 U/L
Total bilirubin: 1.4 mg/dL
INR: 1.2
Platelet count: 85k/cmm
HBV DNA suppressed at 12 pg/mL
HbeAg positive
The patient continued to be followed every three months in the liver clinic. He was maintained on lamivudine 100 mg/dy. HBV DNA levels remained detectable. Over time, HBV DNA levels slightly increased to 29 pg/mL and then to 44 pg/mL.
In 2001, three years after starting lamivudine, the following test results were obtained:
Laboratory Results:
HBV DNA 675 pg/mL
INR: 1.1
AST: 256
ALT: 378
HbeAg positive
Which would you do now?
1. Discontinue lamivudine, begin adefovir
2. Discontinue lamivudine, begin tenofovir
Dr. Wright (OC): When the patient developed lamivudine resistance, we were concerned that he was clinically decompensating and worsening and we would have begun him on adefovir because the trials of adefovir were then being performed and data were becoming available that this drug could suppress Hepatitis B, but it was not approved for use. So we gave the patient tenofovir which is very similar to adefovir, and that was already available because it is indicated for the management of HIV infection. Had adefovir been available rather than tenofovir, I would have given the FDA approved drug at that time.
A 53-year-old man was diagnosed with hepatitis B in 1990. At the time of diagnosis, he was working full time as a gardner. He had no history of injection drug use. He had had multiple sexual partners with unprotected sex. His physical examination was within normal limits. The patient was clinically compensated with normal serum bilirubin, serum albumin, and a normal INR.
Laboratory Results:
CBC: normal
Platelet count: 147k/cmm
Alpha protein: normal
Alkaline phosphate: normal
Serum transaminases 69 U/L
ALT: 122 U/L
HBV DNA: unavailable
HbsAg, HbeAg positive
Anti-HCV, anti-HDV negative
HIV negative
A liver biopsy demonstrated moderate inflammation with cirrhosis. The only treatment available was interferon. Treatment was not initiated. He was recommended to have a serial ultrasound and alphatine protein levels at various intervals of a year to screen for hepatocellular carcinoma.
In 1998, the patient came to the liver clinic. He had been followed at another medical center for eight years. He now had a marked increase in fatigue and was no longer able to work. Physical examination revealed temporal muscle wasting and increased vascular markings on the abdominal wall. There were no ascites or encephalopthy. Serum bilirubin and albumin had risen.
Laboratory Results
Serum bilirubin: 1.4 mb/dl
AST: 369 U/L
ALT: 619 U/L
INR: 1.2
Platelet count: 100k/cmm
HbeAg positive
HBV DNA 1411pg/ml
Which would you do?
1. Order ultrasound of liver
2. Order CT scan of liver
3. Neither
Dr. Wright: These patients are clearly at risk with Hepatitis B cirrhosis of developing liver cancer and that risk may be life long as high as 10 to 15 percent. The way we screen these patients however is controversial because our current screening tests are not very sensitive. Even at high resolution CT scans can miss lesions that are one centimeter in diameter and ultrasounds are probably less sensitive.... Increasingly, we're performing CT scans to screen for hepatocellular carcinoma, although CT scans are more expensive than performing ultrasounds and they also carry within a low risk of radiation of nephrotoxicity from the intravenous contrast.
The CT scan showed no evidence of ascites or focal mass. Would you order an endoscopy?
1. Yes
2. No
In this case, the attending physician ordered an endoscopy. It showed moderately-sized esophageal varices. Would you begin treatment with beta blockers at this time?
1. Yes
2. No
Dr. Wright (OC): The endospy was performed as we do in all our patients now with biopsy proven cirrhosis and certainly in our patients who have evidence of hepatic decompensation because if you document the presence of moderate size esophageal varices, you should begin patients on beta blockers to reduce the risk of bleeding from esophageal varices.
Beta blocker therapy was started. Lamivudine and interferon were the only therapies available for treating hepatitis B. In addition to beta blocker therapy, which would you do?
1. Begin lamivudine
2. Begin interferon
3. No additional therapy
Dr. Wright (OC): Lamivudine was begun in 1998 and this was shortly after FDA approval of lamivudine when we had increasing information that lamivudine could suppress Hepatitis B replication in the setting of significant liver disease. It wasn't begun earlier because it was not yet FDA approved for that indication.
The patient was started on lamivudine 100 mg/dy and beta blockers. He was seen every three months in the liver clinic. Twelve months later, in 1999, he was less fatigued and was able to work part time.
Laboratory Results:
AST: 37 U/L
ALT: 45 U/L
Total bilirubin: 1.4 mg/dL
INR: 1.2
Platelet count: 85k/cmm
HBV DNA suppressed at 12 pg/mL
HbeAg positive
The patient continued to be followed every three months in the liver clinic. He was maintained on lamivudine 100 mg/dy. HBV DNA levels remained detectable. Over time, HBV DNA levels slightly increased to 29 pg/mL and then to 44 pg/mL.
In 2001, three years after starting lamivudine, the following test results were obtained:
Laboratory Results:
HBV DNA 675 pg/mL
INR: 1.1
AST: 256
ALT: 378
HbeAg positive
Which would you do now?
1. Discontinue lamivudine, begin adefovir
2. Discontinue lamivudine, begin tenofovir
Dr. Wright (OC): When the patient developed lamivudine resistance, we were concerned that he was clinically decompensating and worsening and we would have begun him on adefovir because the trials of adefovir were then being performed and data were becoming available that this drug could suppress Hepatitis B, but it was not approved for use. So we gave the patient tenofovir which is very similar to adefovir, and that was already available because it is indicated for the management of HIV infection. Had adefovir been available rather than tenofovir, I would have given the FDA approved drug at that time.
Conclusion and Summary: This patient had been diagnosed with HbeAg positive chronic hepatitis B. Before treatment, his ALT was four times the upper limit of normal. He had moderate elevation of HBV DNA and histological evidence of moderate chronic liver disease. In the absence of therapy, his likelihood of progression to fibrosis would have been between 20% and 30%. He responded well to nucleoside analog therapy, achieving HbeAg seroconversion by six months and reduction in HBV DNA to a level of 103 copies/mL. After treatment was discontinued, the patient was monitored monthly for six months. His ALT remained normal, and he maintained seroconversion. His HBV DNA level remained at 103 copies/mL, indicating that he had a sustained status as an inactive carrier. Thereafter, he was checked twice yearly. At the second-year visit, HBsAg was undetectable and he had acquired anit-HBs. Thus, after two years, he had achieved a Hepatitis B surface antigen seroconversion. His HbeAg/HbsAg seroconversion was sustained throughout five years of regular monitoring.
S201 Case One: 32yo man with abnormal liver tests, no history of acute hepatitis, by Jules L. Dienstag
During routine medical evaluation, a 32-year-old unmarried man was found to have abnormal liver tests. A thorough history failed to identify a clinically recognized, past episode of acute hepatitis. The patient had never received a blood transfusion. He had not used injection drugs. He had had unprotected sexual encounters with multiple partners over several years. On physical examination, he had no signs of chronic liver disease. On receiving the following results from the laboratory, the primary care physician referred him to a liver specialist.
Laboratory Results:
ALT: 175
AST: 145 IU
Bilirubin: Normal
Alkaline phosphatase: Normal
Albumin: Normal
Globulin: Normal
CBC: Normal
Prothrombin: Normal
HbsAg reactive
IgG anti-HBc reactive
HbeAg reactive
HBV DNA 1.5 x 107 copies/ml
Six months after his initial visit to his primary care physician, the patient presented to the liver specialist. Subsequent testing showed no substantive changes since the initial lab work. A liver biopsy showed moderately active hepatitis with a necroinflammatory histologic activity index score of 10/18 and a fibrosis score of 3/6.
Which would you do at this time?
1. No treatment, monitor patient
2. Begin treatment with antiviral therapy]
Dr. Dienstag (OC): We generally in somebody with this level of inflammatory activity, do consider monitoring them for at least for several months to see if they're in the process of improving spontaneously.
Dr. Dienstag (OC to VO): We were quite satisfied that this was chronic liver disease rather than acute hepatitis B.... This is a patient with E-antigen positivity. A modest level of HBV DNA and an elevated ALT.... He had IGG antibody to the core, indicating that this was almost certainly a chronic rather than an acute infection.... And he had a sustained period of ALT elevation without any viralogic move.... Between the time that he was referred to us and the time that he started with his primary physican, more than six months had elapsed.
Dr. Dienstag (VO to OC): In clinical trials patients with this type of chronic hepatitis B monitored for a year had a progression of fibrosis somewhere in the vicinity of 20 to 30 percent of cases. And we thought that he should be treated with antiviral therapy.
Which therapy would you choose?
1. Interferon
2. Lamivudine
3. Adefovir
Dr. Dienstag (OC): This is a case that many of my esteemed colleagues would treat with interferon. This is exactly the features of a likely success with interferon therapy. The interesting phenomenon however is that these are exactly the features of someone who will respond to nucleoside or nucleotide analog therapy. And given the choice between interferon therapy and nucleoside analog therapy, many of our patients select the simpler oral drug without side effects to the more challenging interferon course of therapy.
The patient chose oral therapy. Which would you recommend?
1. Lamivudine
2. Adefovir
Dr. Dienstag (OC): We chose lamivudine over adefovir primarily because at the time we treated this patient adefovir wasn't available. But even now I would probably choose lamivudine in this case because lamivudine is probably a little bit more potent. And a little bit more likely to achieve an E-antigen sero conversion than adefovir during the course of therapy. For example if you look at the subgroup of patients in registration trials who had ALT levels greater than five times the upper limit of normal, the E-antigen sero conversion rate was about 50 to 60 percent with lamivudine where it was only about 20 percent with adefovir.
Lamivudine was begun at 100 mg/dy and treatment was extended for a full year. During the early weeks of therapy, the patient's ALT rose transiently, peaking at 275 iu/Ml during the fifth week and falling to normal by the tenth week. His hepatitis B DNA level fell from 1.5 x 107 to 103, representing a 4-log drop. By the fifth month, his E-antigen was undetectable. Anti-Hbe became detectable during the sixth month. The patient did not experience lamivudine resistance and tolerated the drug well with no side effects. Treatment continued for the rest of the year, during which there were no substantive changes in laboratory values.
Which would you do now?
1. Continue lamivudine
2. Continue lamivudine and add adefovir
3. Discontinue lamivudine and treat with interferon
4. Discontinue therapy and monitor patient
The attending physician decided to discontinue therapy.
Dr. Dienstag (OC): How to stop therapy is a very good question. In fact it's so much easier to start these drugs, than it is to stop them.... Really no one has been able to define precisely how long a patient should be treated after a seroconversion. And in the absence of therapy, what some authorities recommend is at least six months after an E-antigen seroconversion.... In clinical trials with lamivudine, an E-antigen seroconversion was associated with a high likelihood of maintaining that response So in a sense, we think of E-antigen seroconversion as a therapeutic signal that we're able to stop therapy and we're able to stop therapy in perhaps 60 to 80 percent of patients.... After a seroconversion achieved during the first year of therapy, treatment can be discontinued.... But it's very important to monitor patients monthly during the immediate post-treatment phase, to look for and respond to reactivations that can sometimes be quite severe.
During routine medical evaluation, a 32-year-old unmarried man was found to have abnormal liver tests. A thorough history failed to identify a clinically recognized, past episode of acute hepatitis. The patient had never received a blood transfusion. He had not used injection drugs. He had had unprotected sexual encounters with multiple partners over several years. On physical examination, he had no signs of chronic liver disease. On receiving the following results from the laboratory, the primary care physician referred him to a liver specialist.
Laboratory Results:
ALT: 175
AST: 145 IU
Bilirubin: Normal
Alkaline phosphatase: Normal
Albumin: Normal
Globulin: Normal
CBC: Normal
Prothrombin: Normal
HbsAg reactive
IgG anti-HBc reactive
HbeAg reactive
HBV DNA 1.5 x 107 copies/ml
Six months after his initial visit to his primary care physician, the patient presented to the liver specialist. Subsequent testing showed no substantive changes since the initial lab work. A liver biopsy showed moderately active hepatitis with a necroinflammatory histologic activity index score of 10/18 and a fibrosis score of 3/6.
Which would you do at this time?
1. No treatment, monitor patient
2. Begin treatment with antiviral therapy]
Dr. Dienstag (OC): We generally in somebody with this level of inflammatory activity, do consider monitoring them for at least for several months to see if they're in the process of improving spontaneously.
Dr. Dienstag (OC to VO): We were quite satisfied that this was chronic liver disease rather than acute hepatitis B.... This is a patient with E-antigen positivity. A modest level of HBV DNA and an elevated ALT.... He had IGG antibody to the core, indicating that this was almost certainly a chronic rather than an acute infection.... And he had a sustained period of ALT elevation without any viralogic move.... Between the time that he was referred to us and the time that he started with his primary physican, more than six months had elapsed.
Dr. Dienstag (VO to OC): In clinical trials patients with this type of chronic hepatitis B monitored for a year had a progression of fibrosis somewhere in the vicinity of 20 to 30 percent of cases. And we thought that he should be treated with antiviral therapy.
Which therapy would you choose?
1. Interferon
2. Lamivudine
3. Adefovir
Dr. Dienstag (OC): This is a case that many of my esteemed colleagues would treat with interferon. This is exactly the features of a likely success with interferon therapy. The interesting phenomenon however is that these are exactly the features of someone who will respond to nucleoside or nucleotide analog therapy. And given the choice between interferon therapy and nucleoside analog therapy, many of our patients select the simpler oral drug without side effects to the more challenging interferon course of therapy.
The patient chose oral therapy. Which would you recommend?
1. Lamivudine
2. Adefovir
Dr. Dienstag (OC): We chose lamivudine over adefovir primarily because at the time we treated this patient adefovir wasn't available. But even now I would probably choose lamivudine in this case because lamivudine is probably a little bit more potent. And a little bit more likely to achieve an E-antigen sero conversion than adefovir during the course of therapy. For example if you look at the subgroup of patients in registration trials who had ALT levels greater than five times the upper limit of normal, the E-antigen sero conversion rate was about 50 to 60 percent with lamivudine where it was only about 20 percent with adefovir.
Lamivudine was begun at 100 mg/dy and treatment was extended for a full year. During the early weeks of therapy, the patient's ALT rose transiently, peaking at 275 iu/Ml during the fifth week and falling to normal by the tenth week. His hepatitis B DNA level fell from 1.5 x 107 to 103, representing a 4-log drop. By the fifth month, his E-antigen was undetectable. Anti-Hbe became detectable during the sixth month. The patient did not experience lamivudine resistance and tolerated the drug well with no side effects. Treatment continued for the rest of the year, during which there were no substantive changes in laboratory values.
Which would you do now?
1. Continue lamivudine
2. Continue lamivudine and add adefovir
3. Discontinue lamivudine and treat with interferon
4. Discontinue therapy and monitor patient
The attending physician decided to discontinue therapy.
Dr. Dienstag (OC): How to stop therapy is a very good question. In fact it's so much easier to start these drugs, than it is to stop them.... Really no one has been able to define precisely how long a patient should be treated after a seroconversion. And in the absence of therapy, what some authorities recommend is at least six months after an E-antigen seroconversion.... In clinical trials with lamivudine, an E-antigen seroconversion was associated with a high likelihood of maintaining that response So in a sense, we think of E-antigen seroconversion as a therapeutic signal that we're able to stop therapy and we're able to stop therapy in perhaps 60 to 80 percent of patients.... After a seroconversion achieved during the first year of therapy, treatment can be discontinued.... But it's very important to monitor patients monthly during the immediate post-treatment phase, to look for and respond to reactivations that can sometimes be quite severe.
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