How to know if Entecavir stopped working

[Aydin1358]

Dear all,
First I have to really thank for all of you who are giving us lots of good information.
I am 33 years old man and I think I have Hep B from birth, because of our family history.
I started taking Entecavir 2 years ago and the reason to start treatment was having 640 milion copy/ml of DNA and ALT more than normal range (almost two times of normal ). So Doctor decided to treat. Almost after a year of taking Entecavir my DNA dropped to 20 copy/ml, but still ALT more than the normal range. Then 6 months later DNA increased to 70 with abnormal ALT and  6 month after that DNA went up to 137 with ALT 70. When I started treatment my Hbeag was positive but after a year it turned to be negative and Hbab get positive.
Now I am a little worried about Entecavir suspecting that maybe virus gets resistance to it because of my DNA increase but doctor telling me that these variations in DNA are ok since it is not too much variations and the most important is that your e-antigen is negative. Yesterday I again tested for DNA test but really I am worried.
Any comments and suggestions will be much appreciated.
Aydin

[stef2011]

you do have resistance, entecavir doesn t work if hbvdna is not und

you must add on tenofovir as soon as possible

[stef2011]

change doctor he said many fantasy things, as regards alt it is best they dont get normal when hbvdna gets und so hbsag goes down faster

[StephenCastlecrag]

I tend to agree with your doctor that the variations in your DNA is not that significant. An order of 1 magnitude (i.e. 10 folds) is usually considered significant. I wonder why your ALT is still elevated - how is your weight?

[stef2011]

hbvdna over 137iu/ml after more than one year is definitly resistance mutants, especially after being und, it is also useless to take an antiviral with such an hbvdna detactable it can only worsen and cumulate mutations fast

[StephenCastlecrag]

I have always been troubled by VBT (virological breakthrough, a 10-fold increase in hbvdna) during treatment. Does it mean it is a GR (genotypic resistance, mutation confirmed by testing)? Apparently VBTs happen quite a bit and not all VBTs are GR. In these cases, the hbvdna goes down again without change of medication.
According to research literature, all VBTs should first be confirmed, i.e. test again in 1-3 month time. Patients will also be asked whether they have been taking the medication faithfully. In the case of high-genetic-barrier-to-resistance drugs like Entecavir and Tenofovir, a genetic test to confirm resistance is the golden standard.

What is a 10-fold increase of "undetectable"? Researchers use the lower limit of detection of 29 iu/ml as the baseline. So a rise from undetectable to > 290 iu/ml is technically a VBT.

As for achieving undetectable viral load by week 24 of treatment to signify a response, some researchers believe in the case of newer NAs such as ENT and TDF, the drugs should be given a longer time because of their high barrier to mutation and because trials showed most patients do achieve a response given time.

So because each person is different, I don't think we can be too arbitrary in deciding VBT and GR. Here, I will put my trust in experienced specialists, after all they have seen more real-life cases.

Just my opinion.

[4est]

I tend to disagree with @StephenCastlecrag (sorry Stephen) because we discuss this variation under treatment.
Usually, without any treatment I tend to agree that some variation are normal, but not under treatment,

@Aydin1358 From what country are you ?  Do you use generic Entecavir or du you change your Entecavir  provider in last year ? (I was thinking that maybe the concentration was not corect or you had a fake Entecavir )

before taking Entecavir, you was a naive patient or you take some other HBV medication (e.g. Lamivudine)?

You say that you have a family vith HBV history, was your mama tretaed with Lamivudine before you where born ? (I was thinking that maybe you had a HVB resistant to Lamivudine from your mama)


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@StephenCastlecrag An order of 1 magnitude (i.e. 10 folds) is usually considered significant - from 100 to 1000 is 1 magnitude from 10000  to 100000 is also  1 magnitude. are this with the same signification ?

[stef2011]

i disagreee too, resistance tests cannot detect mutants until too late because sensibility is too poor (population 25%), etv has also resistance for hbsag mutants but these tests are not available

what is the goal of these studies?keep selling drug and trying to tell patients keep using it?

hbvdna und as soon as possible is the minimum result from these antivirals when there is liver damage, if they dont get this result the antiviral is useless

[StephenCastlecrag]

@StephenCastlecrag An order of 1 magnitude (i.e. 10 folds) is usually considered significant - from 100 to 1000 is 1 magnitude from 10000  to 100000 is also  1 magnitude. are this with the same signification ? Yes.

http://onlinelibrary.wiley.com/doi/10.1002/hep.24318/full
Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice

Virological breakthrough (VBT) is the first manifestation of antiviral drug resistance during nucleos(t)ide analogue (NUC) treatment of chronic hepatitis B (CHB), but not all VBTs are due to drug resistance. This study sought to determine the incidence of VBT and genotypic resistance (GR) in patients with CHB who were receiving NUCs in clinical practice. Records of patients with CHB who were receiving NUCs were reviewed. All patients with VBT were tested for drug resistance mutations. Of 148 patients included, 73% were men and mean age was 44.9 years. During a mean follow-up of 37.5 ± 20.1 months, 39 (26%) patients had at least 1 VBT. Of these 39 patients, 15 (38%) were not confirmed to have VBT on retesting, and 10 of these 15 had no evidence of GR. The cumulative probability of VBT, confirmed VBT, and GR at 5 years was 46.1%, 29.7%, and 33.9%, respectively. In multivariate analysis, failure to achieve undetectable hepatitis B virus (HBV) DNA was the only factor significantly associated with VBT. Among the 10 patients who had VBT but no confirmed VBT or GR and who were maintained on the same medications, serum HBV DNA decreased in all 10, and nine had undetectable HBV DNA at a mean of 6.8 months after the VBT. Four patients had persistently undetectable HBV DNA, six had transient increase in HBV DNA during follow-up, and none had GR. Conclusion: VBT was common in patients with CHB receiving NUCs in clinical practice, but nearly 40% of the VBTs were not related to antiviral drug resistance. Counseling of patients with CHB on medication adherence and confirmation of VBT and/or GR can avoid unnecessary changes in antiviral medications. (HEPATOLOGY 2011;)

[StephenCastlecrag]

The gold standard of resistance is by genetic testing.


"i disagreee too, resistance tests cannot detect mutants until too late because sensibility is too poor (population 25%), etv has also resistance for hbsag mutants but these tests are not available"

By sensitivity, I take it that you mean the % of mutants in the population of wild type is too low?  This may be so. We now know the hbv viruses in our liver are a population consisting of many quasispecies. However, not all mutants will go on to become the dominant type. I am sure the composition of this population of quasispecies will change constantly. In the case of ENT and TDF, mutants need to acquire and hold more than 1 mutation together, exist in many infected cells, in order to become selected to become the dominant type. That is why to confirm ENT or TDF drug resistance, genetic testing is the golden standard.

Hard to see a role for HBsAg mutant in drug resistance, since NAs do not interfere with the production of the surface antigens.

[Aydin1358]

Thank you for all the responses.
I am waiting for my results to get in two weeks.
Should I switch to only Tenefovir or a combination of Entecavir+Tenefovir?
Another question : Why still my Hbeag negative, if my DNA is not undetectable? Does not it mean that I have servoconverted ? Here in Canada I can not easily change my doctor, but he has a good personality and I can discuss with him. Which kind of test I can ask him to do to confirm my resistance to Entecavir?

Thanks again

[Aydin1358]

My ALT never get normal during these two years. Lots of fluctuations.
I do not drink alcohol and I am in pretty good shape. I weigh 76 kg

[Aydin1358]

I am from Canada and I have never changed my Entecavir provider myself . I am getting it from Medicinshop in Canada and do not know whether they have changed their provider or not.
My mom  has never been treated and before I start taking ETV I never had another drug like Lam.

[StephenCastlecrag]

Fatty liver can cause elevated ALT, that is why I ask about your weight. So if you are over-weight, you may try to lose a few kilos to see if it makes a difference to your level of ALT. You can also ask your doctor about the elevated ALT. I hope your doctor is a liver specialist. In Australia, most GPs are not expert at managing Hepatitis B.

[Aydin1358]

I see your point. I will try to eat more healthier and exercise more. I asked him about that but he mostly emphasizes on servo conversion from Hbeag positive to negative. Does not give any comments about ALT. He is infection disease specialist.

[stef2011]

i also had etv failure, hbvdna detactable at less than 20iu/ml after 2 years, researchers added tdf so i am on etv+tdf
liver specialist did not push on tdf but researchers did

plans are to make etv+tdf+peginterferon in sept and maybe discountinue etv if there is big response on hbsag

[stef2011]

as to ast/alt i had never got to normal range but that s better because it means you have immune activity in the liver and hbsag goes down even on antivirals, slowly and after you are hbvdna und for 3 years, but it does go down

if ast/alt stay normal hbsag tends to increase or stay stable

of course fatty liver and bad diet must be excluded first so you know by exclusion it is immune activity

[Aydin1358]

As far as I know my hbvdna measured in copies/ml. which has some conversion factor to convert to iu/ml. But anyway 137 copies/ml means 23 iu/ml which is still detectable.

Do you think it is going to be late if I wait for my next appointment with my doctor which will be in November. Here we have this problem of  long waiting appointments.
How do you manage to have both ETV and TDF. One needs to be on empty stomach and the other with food. So I think you need to take them separately at different times?
Did your DNA went to undetectable after you took ETV+TDF?
Thank you so much and I wish you will have success in Sep and your body will be able to clear the virus.

[stef2011]

i thought it was 137iu/ml, at 23iu/ml you can consider it partial response without resistance

but i dont change my mind because hbvdna in the blood must get to below 0iu/ml since even 0iu/ml in the blood corresponds to plently hbvdna inside the liver, so i am still pro tdf add on

How do you manage to have both ETV and TDF. One needs to be on empty stomach and the other with food. So I think you need to take them separately at different times?

there are many members on his combo here and it is best to take etv and tdf 12hrs apart from eachother
as regards taking etv on empty stomach i stopped this because it is not possible to check every day for empty stomach, after i saw how etv was
useless on me i added tdf and didn t care for empty stomach anymore

my hope is to get rid of these pills as soon as possible by making hbsag low, i dont like taking these chemicals for more than 5 years

[stef2011]

Did your DNA went to undetectable after you took ETV+TDF?

of course it did within 5 days

etv never fully worked from the start i had to add alinia to make hbvdna und and when i stopped alinia hbvdna rebounded to detactable

[stef2011]

and ast/alt got more elevated and this is good because it means immune system got more active

[Aydin1358]

Wow. in 5 days. It shows that how  tdf is powerfull. I wish I had chosen tdf from the start, but that day I was thinking what if tdf does not work and then i will have no option.
Anyway I will keep posted here about my latest results and will try to go on combo as soon as possible.

[calmama]

If you do decide to take etv+tdf combo, try taking ETV first thing in the morning and eat your breakfast an hour or two later.  Take TDF with dinner.

This is what an old member stevenNYer did when I read the older posts.

[Aydin1358]

By the way, My Genotype is D. I was reading in an article ( I will try to find and attach later here) that those with this Genotype showed much chance of clearing hbsag than the other genotypes after 2 years of taking Entecavir. But on the other hand those with D genotype are not good candidate for peginterferon.  Now that I dont respond to entecavir, do you think that still Genotype matters after you get undetactable and want to use peginterferon like you.