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."
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.
"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."
Excellent read. Thanks to cajim and steven.
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.