Hi,
So I have read, it seems hepb virus seldom becomes resistant to tenofovir, the question is why ?
Lucikly the virus aint that advanced to mutate ?
Br,
Dear @hepb1,
HBV is highly mutable and this process occurs regardless of antiviral therapy. Unlike earlier NUCs, the active metabolite of TDF (tenofovir diphosphate) is a also strong stimulator of innate immunity (and hence inactivation of cccDNA). This has been widely reported in the early characterizations of TDF effects during its development and also for TDF in numerous clinical studies looking at markers of cccDNA activity (HBcrAg and HBV RNA).
So in addition to inhibiting the replication of HBV (which is susceptible to mutational escape just like other NUCs), TDF also inactivates cccDNA and this effect is not susceptible to mutational escape.
Unfortunately, most of the production of HBsAg (in the form of subviral particles or SVP) occurs from chromosomally integrated HBV DNA, which is not impacted by stimulation of innate immunity. This is why HBsAg decline on TDF (and all other NUCs) is negligible. So while effective against the replication of the virus, the production of SVP continues and the immunosuppression of the immune response against HBV infection caused by SVP remains. This is why, even despite its resistance to mutational escape, removal of TDF leads to reactivation of HBV infection and usually fulminant hepatitis.
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What Andrew writes is correct and the innate suppression of cccDNA almost certainly contributes strongly to the failure of tenofovir resistance mutations to arise. However, I think the dual mechanism he highlighted is unlikely to be enough to fully stop development of tenofovir resistance as the shutdown of HBV replication by tenofovir is not complete (low level HBV replication has been detected in well-controlled patients under tenofovir treatment).
Molecularly, this is a mystery to me too, even after working on the viral polymerase that tenofovir targets for over 30 years. If I remember some old data correctly, engineering mutations into HBV polymerase that are analogous to resistance mutations in HIV yields HBV that is tenofovir resistant in cell culture. That says the enzyme can work with the tenofovir resistance mutations in it, yet clinically, resistance is negligible.
The implication is that there is some unknown fitness cost to the virus from those mutations that prevent these variants from evolving. The fitness cost may not even stem from their effects on the polymerase protein. Some possibilities for the loss of fitness include possibly altering a critical fold of the pgRNA, or changing translation or transcription rates that cause misfolding of an RNA, the polymerase, or one of the HBs proteins. There are lots of possibilities, but all of them are really subtle and would be very hard to test.
Sorry not to be able to give a firm answer, but I’m confused by this too!
John.
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But sir, I don’t know why we keep on hearing stories about chronic hbv,yet people are being cured in china on daily basis.
China have achieved 33% cute rates.
This is a virus 
that infected innocent people from childhood…
Chronic hbv have hinder many from achieving their future dreams .
Dear @chigoziekingsley5454,
I think you may be referring to some of the recent studies conducted in China with experimental agents. If this is the case, it is important to note that these studies are conducted in unicorn patients. These are patients with low levels of HBsAg who represent less than 5% of the HBV infected population. We have known for years that in these patients, HBV functional cure is achieved more easily with immunotherapeutic approaches like pegylated interferon. These experimental approaches (siRNA and antisense) also have important immunotherapeutic side effects so also appear to have high rates of HBV functional cure. However, unlike pegIFN, HBV infection slowly rebounds in almost all patients slowly rebound when these experimental therapies are removed. In the majority of patients (with normal levels of HBsAg), we know that these new agents are unable to achieve functional cure.
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3.5 log is pretty average in e negative hepb patients. unicorn patients can be defined as hbsag < 100
We can start treating patients in this group. This will be a good start.
Unicorn patients are < 1000 IU/mL not < 100 IU/mL. Abnormally strong responses to immunotherapy are still observed in patients between 100 and 1000 IU/mL. THis is well documented in the literature. Even so, patients with < 100 IU/mL represent less than 1% of patients worldwide so utility will be very rare. The treatment history of these patients has not been disclosed which is problematic.
Also, it is important to note the there is little to no ASO effect from Bepi. This ASO actually works by stimulating TLR9. This has been clearly demonstrated from clinical studies with GalNAc-Bepi vs Bepi (HBsAg declines are correlated with accumulation in immunoreactive cells in the liver where there is no infection) and from the absence of effect on HBsAg with other ASOs devoid of immunstimulatory activity (ie the abandoned Roche and Aligos ASOs).
Also rebound is almost universally observed in these unicorn patients after removal of Bepi with longer term follow-up > 24 weeks, even with addition of pegIFN (just like siRNA).
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My hbv DNA is 530, I got this from childhood, i haven’t taken any medication for hbv, I leave on healthy lifestyle, how can I participate for the functional cure trial sir, because I really need to clear this from my system.
Till now I don’t know how I got hbv is really really really sad to me.
I don’t sleep around
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Dear @chigoziekingsley5454 ,
Your HBV DNA is very low without therapy so you have partial cure. It would be nice to know what your most recent liver function tests were.
While your wish for functional cure is understandable, your long term prognosis in the absence of therapy is excellent.
The best thing to do is keep watch on clinicaltrials.gov for new HBV trials and see if one of these is recruiting patients from a location that makes sense for you.
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Hello @availlant, I’m one of those patient, my viral load has been undetectable for the 5 years I have unknown i have it. Few months ago, it was detected at 12 IU but with F2 and elevated AST and normal ALT. Everything else is okay. The repeated LF tests indicated elevated ALT but this time normal AST. Was more confused. The doctor is now recommending I start meds and already sent out order for them. I live in a small town in US. I feel like something should be done differently or at least look at different options before being put on permanent meds. What would be your honest advice here in my case please? Is immunotherapy an option for me as well?
Dear @MMal_jr ,
Have you had your HBsAg evaluated by a quantitative assay? This would be important in assessing the potential for pegIFN.
Not yet, maybe I should be considering that in my next blood work.
But would I be eligible even with F2?
Dear @MMal_jr ,
PegIFN is only contraindicated in decompensated cirrhosis. If you started pegIFN therapy, you would certainly need to take suppressive NUC therapy at the same time.
So taking TDF is advised in my case right now? My Dr suggested I should start TDF even with low viral loads since F2 is detected and AST, ALT a bit high though not above normal.
I’m also seeing some swelling beneath my right rib, especially when I have eaten large meal, no apparent pain. I did Fibroscan last week and haven’t got the results yet. It’s making me bit restless and maybe headache in nervous since these are all new developments. The scan never took this long
Any suggestions on diet? Especially fats and cooking oil?
Dear @MMal_jr ,
Can you please provide more details?
Actual ALT / AST results?
What was the basis for the diagnosis of fibrosis? Imaging? Fibroscan? If so what were these results?
Was there any finding of fat accumulation in the liver (steatosis)?