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 Iām confused by this too!
John.
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