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How to know if Entecavir stopped working
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How to know if Entecavir stopped working

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
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Avatar_m_tn

the facts are:
etv failure and partial response in ur case

resistance can be confimed by test only and even if negative it is not sure you have no resistance, test sensibility is poor

why keep entecavir if:
tenofovir is more potent
tenofovir is safer on cancerogenesis
tenofovir has no resistnce
tenofovir costs 50% less than etv or more

this is not to promote tdf use but it is definitely better especially in ur case, i d make add on 6 months and then stop etv
54 Comments Post a Comment
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Avatar_m_tn

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

you must add on tenofovir as soon as possible
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Avatar_m_tn

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
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Avatar_m_tn
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?
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Avatar_m_tn

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
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Avatar_m_tn
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.
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Avatar_m_tn
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 ?
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Avatar_m_tn

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

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Avatar_m_tn
@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;)
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Avatar_m_tn
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.
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Avatar_m_tn
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
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Avatar_m_tn
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
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Avatar_m_tn
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.
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Avatar_m_tn
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.
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Avatar_m_tn
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.
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Avatar_m_tn

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
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Avatar_m_tn

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
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Avatar_m_tn
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.
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Avatar_m_tn
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
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Avatar_m_tn
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

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Avatar_m_tn

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

i think you should not worry too much about geno d and other stuff, you can do same as i did follwoing studyforhope and pisa researchers indications:

add on tdf to etv for 6 months then keep combo if affordable for you and no sides or just stop etv and just keep tdf

etv+tdf is very potent on hbvdna, you wont be dna detacable on this
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Avatar_m_tn
Can you please explain what is your plan after being on ETV+TDF combo? How long after being in this combo, you are going to have Pegint? Are you going to discontinue ETV+TDF while being on Pegint? Then how long you will be on Pegint?  
Thank you so much
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Avatar_m_tn
Can you please explain what is your plan after being on ETV+TDF combo?

keep it as long as hbsag is detected, i cannot stop antivirals since my liver was severely damaged, maybe we will stop etv when intf is added

How long after being in this combo, you are going to have Pegint?

2,8 years on etv and about 9 months on tdf

Are you going to discontinue ETV+TDF while being on Pegint?

absolutely not, maybe etv if hbsag goes down fast

Then how long you will be on Pegint?  

it depends on hbsag response but not less than 2 years
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Avatar_m_tn
I was also reading your other very useful comments in other threads regarding Vitamin D and E. What I am afraid of is the interaction between drugs? Should I also take vitamin D while on ETV or ETV+TDF and later Pegint.
How about vitamin E?
Thanks
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Avatar_m_tn

vitamins are food, you are taking them already when you eat.

there is no interaction with antivirals at all, just remember to take etv on empty stomach 2 hrs before and 2 hrs after
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Avatar_m_tn
Finally I got my DNA HBV result of 106 week being on Baraclude. I have asked my doctor to have an early meeting to discuss about adding tdf .

Week         DNA          ALT       AST
1             19301802 103   48
12                3994          30         22
30                 192          63         34
45                  60          63         44
74                  21         148         59
77                  41          85     40
91                 137         101         47
107             85          75     32

Do you think I have already developed resistance based on my last results which shows decrease in DNA value ( iu/ml). I saw some studies and my doctor told me also on phone that some people are very slow to response and it may not necessary to switch or add another drug.

http://www.ncbi.nlm.nih.gov/pubmed/21563196

But the question is that am I partial response? Or what if I develop resistance (or may already developed). It is very tough and I really do not want to make a risk and continue on ETV.

Thanks
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Avatar_m_tn

the facts are:
etv failure and partial response in ur case

resistance can be confimed by test only and even if negative it is not sure you have no resistance, test sensibility is poor

why keep entecavir if:
tenofovir is more potent
tenofovir is safer on cancerogenesis
tenofovir has no resistnce
tenofovir costs 50% less than etv or more

this is not to promote tdf use but it is definitely better especially in ur case, i d make add on 6 months and then stop etv
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Avatar_m_tn
You guys don't think for folks with elevated ALT it is better to start doing Pegasys?

If he developed resistance to ETV then he will for sure develop resistance to Tenofovir. They just have not being treating long enough people with HBV, All the data mostly is coming from HIV/HBV infected folks.

Folks over at UCLA Aids center (good doctors there btw) seem to think Truvada is the safest bet to avoid all resistance period.

But I think guys the answer for us is not so much just suppressing the virus but immune system recovery/stimulant..  which Interferon, Imiquimod, Zadaxin, and GcMaf are..

I am reading now about GcMaf that Stefano takes.. This is very promising route to go.

Then Murclydex and Rep9AC protease inhibitors - should do much better then nucs.

So I think this is what the researchers should be focusing on and doctors. Rather then doing antivirals for long. If you worry about resistance take Truvada, Three drugs that will really suppress HBV.
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Avatar_m_tn
Man you sure beat me I had 500,000,000 HBV DNA boy did that made tired. I am with you there brother :( these kinda viral loads are just dangerous.

If your ALT is abnormal why won't they give you Pegasys.. Elevated ALT + viral load = immune system is fighting..
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Avatar_m_tn
What about your HbsAG quantity.  This is so important nowadays.  NOt just DNA.  
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Avatar_m_tn
Folks over at UCLA Aids center (good doctors there btw) seem to think Truvada is the safest bet to avoid all resistance period.

truvada is just marketing for patent, tdf is the first to lose patent and truvada the last.
tenofovir has no resistance for hbv because even if there is resistance to tdf the high dose 300mg makes tdf work anyway...so etv resistance wont make any difference to response to tdf.
etv resistance is a problem because hbv can become cytopatic with some mutations, at that point having hbvdn und makes no differece to damage
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Avatar_m_tn
As far as I read answers of stef and studyforhop from other threads, in order to start Pegint you better to be undetectable for awhile, then need to also measure Hbs ag and monitor to see that decreasing. I have asked my doctor about the availability of this test in Canada and have not yet get answer from him. If not available here, Stef has already found another solution by sending it to india.
Thanks guys for your big support by helping each other.
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Avatar_m_tn
Please explain hbvdn , never heard of it
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Avatar_m_tn

hbvdna und makes no difference if the hbsag has mutated to forms cytopatic, liver will be damaged anyway with hbvdna und, ast/alt normal

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Avatar_m_tn
That is just great. Why give us antivirals in the first place to create super viruses.
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Avatar_m_tn
It seems I am becoming resistant for ETV too. I am still waiting the answer from my doctor after my last blood test....
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Avatar_m_tn
So, I got the answer. He said that there is no reason to panic when the viremy is one month little higher. He said, we will see another result after this month and then we will take a decission. It is little stressing but I still trust him, so, I will see. However, he said that my temporary viremy 1500 UI/ml is very small, no reason to be scared.
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Avatar_m_tn
how long have you been on ETV? if more than a year and 1500 IU/Ml, it signals that maybe ETV not working well. In 24 weeks you should be less than 24 IU/Ml in order to say that ETV works
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Avatar_m_tn
Today i got my results regarding vitamin d.
My vitamin d total is 12.30 nmol/L. seems soooo low/ is'nt it?
I was reading your previous posts regarding this, and as far as i understood, i need start taking 1000 Iu per day of vitamin d pills? Am i right? My doctor told me start with 2000 IU?
which form and brand of vitamin d you suggest?
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Avatar_m_tn
12.30 nmol/L

extremely low but convert to ng/ml which is the correct unit for vit d.for optimum health and immune system you need 60-90ng/ml (normal range 50-100ng/ml)

2000iu is nothing it wont work if vit d is low due to chronic infections, you need at least 10.000iu daily and then recheck in 4 weeks to see if it has increased or not.you need both vit25oh and calcium test to see if everything is working correctly

which form and brand of vitamin d you suggest?
only vit d3 which is the natural form, puritans is ok because they make 5000iu pills and 10.000iu pills and very cheap
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Avatar_m_tn
Finally after lots of discussions with my doctor, he agreed to prescribe TDF. From today I am going to TDF+ETV combo. I have to pay for TDF out of my pocket which is expensive almost 610 $. But ETV is covered. Lets see how much difference this combo will make.  
I just need Hbsag measurements and need to discuss with my Dr. where we can do it in Canada. not knowing this, I will have no idea when should I start Interferon. I just hope that since my ALT was always high, my hbsag has lowered considerably. we will see.
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Avatar_m_tn
Hi everybody:

After being on ETV+TDF combo for 2 months, my HBV DNA reduced to 30 from 70.
Now after 6 months, the number has reduced to 13 iu/ml. My ALT is also 1.5 times of the normal still.
I did Hbsag test and turned out to be 14000 IU

What do you think now. Can I stop taking Entecavir now safely and go only with TDF. I can not afford to have both at the same time.

Regards,
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Avatar_m_tn
it would be best to wait for hbvdna und, you are close to it maybe one more month

hbsag doesn t matter now
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Avatar_m_tn
Thanks Stef;

I am wondering why my hbvdna goes down so slow.
Now almost 3 years on ETV with the last 6 month of  added TDF.  
I have already taken ETV one and half more month than the date of blood test that showed 13 IU/ml.
What may possibility happen if I stop taking ETV? Can I start taking it later if I see any rise again in my hbvdna?

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Avatar_m_tn
You will likely see a small rise in hbv dna when switching to tdf only. These two antivirals have a mildly additive effect when taken together. It is possible that you have some partially adaptive mutation in your hbv genome that explains the less than perfect response. If you have to pay for tdf yourself it would be advisable to buy it from india via internet ordering, you can save more than 70%. i dont have the website handy, but you will find it if you look long enough. I think one of the indian names for tenofovir is tenvir. The indian pharmaceuticals are of the highest quality, you do not need to worry.
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Avatar_m_tn
Thanks for the information regarding Indian drug. I will try it.
So my understanding is that you suggest taking both for sure. What if I only discontinue taking ETV for 6 month starting now and see if hbvdna rises, I again back to combo. Is it possible that these mutations going to increase and make TDF not to work properly? Or TDF still will be effective with no resistance issue if I only take that?

Do you also suggest me taking Heptech products to avoid possibility of having fibrosis due to having higher ALT than normal (1.5 times than normal always)

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Avatar_m_tn
You can try tdf only without risk of loosing ground when switching back to combo in say six month after thorough testing.  
You should have a fibrioscan to determine your livers fibrosis status. Heptec holds the realistic promise of protecting the liver from fibrosis progression, but it is overpriced.
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Avatar_m_tn
This is a very good news that staying only with TDF would not hurt and would not make things worse. I will try going off combo and see what happens. Hopefully will not need to go back to combo, but will monitor my situation closely, in case I need to go back to combo.

What will determine going back to combo? If I still detectable even very low after 6 months of combo, does it

I will also consider fibroscan soon.

Thanks a lot,


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Avatar_m_tn
if your vl on tdf goes above 150 iu i would go back to combo and stay there.

With your hbsag of 14000, the liver is densely infected, better stay on the safe side. The fibroscan will guide you re additional efforts, like heptech or intensely healthy lifestyle measures.
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Avatar_m_tn
indian brand for entecavir  is entica from ranbaxy company and costs 80 indian rupee which is around one and half doller. i dont know for tenofovir but i will find out and share.
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Avatar_m_tn

After being on ETV+TDF combo for 6 months, I discontinued ETV and went alone with TDF. Now after being 7 months on mono TDF,
Tests show that my HBV DNA is less than detectable amount of 20 iu/ml. I think TDF doing pretty good job in terms of suppressing HBV DNA.

However, my blood test still shows that my ALT is in the high normal range and fluctuating between 60 to 80. I am getting worried about this.

I have not been able to find fibroscan and will continue to find one soon. What are the possible reasons for this elevated ALT?
Does ultrasound or MRI can help me in identifying fatty liver?

I have noticed from my results an increase in ferritin levels as well. Not too much, but a bit higher than the upper normal range.

BMI=25.68.  
HDL=29.6 and LDL 106, with total Cholostrol of 168.5, if you think these data will help in identifying the reason for having higher ALT.

Thanks,

  

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