Hello doctors in the house, kindly help me understand between EMTRICITABINE tenefovir disoproxil fumarate and Tenefovir disoproxil fumarate LAMIVUDINE… which one amongst the two drugs is best suitable for HBV Patients?
Hi @Vera,
Lamivudine (aka 3TC) is an early generation inhibitor of HBV replication which is no longer widely used due to the development of drug resistance in about 30% of individuals.
Emtricitibine (aka FTC) is a mid-generation inhibitor of HIV and HBV replication which is found in approved medications used to treat HIV infection but is not approved for the treatment of HBV infection.
Entecavir (aka ETV) is a later generation inhibitor of HBV replication which is approved for the treatment of HBV infection. Drug resistance to ETV is rare but more common place amongst people who have previously developed drug resistance to 3TC.
Tenofovir disoproxil fumarate (aka TDF) is a prodrug formulation of tenofovir which improves its stability and is a later generation inhibitor of HIV and HBV replication. TDF is approved for the treatment of both HIV and HBV infections. Drug resistance to this medication is very rare.
Tenofovir alafenamide (aka TAF) is a different prodrug of tenofovir which improves its residence in the liver. As such, a lower dose of TAF is requried for equivalent antiviral effect compared to TDF. TAF is recognized to be less likely to cause reduced kidney function and bone demineralization in patients than TDF (although this is an issue in only a minority of patients taking TDF).
ETV, TDF and TAF are considered to the the most suitable for control of HBV infection and associated liver disease.
Best regards,
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Dear Dr. @availlant , my dearest greetings.
Reading your explanation about these medications, I have a question: is there a risk that these current medications, TAF, TDF or Entecavir, will also suffer resistance? What causes this type of resistance? Is it a mutation of the virus or the way the medication works?
Hi @La.sciamachie,
Resistance against these antivirals is incredibly rare, so not much is known about them. ETV resistant viruses are still susceptible to TDF/TAF, so there is generally no clinical issue.
Thomas
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I am always very grateful for your attention, @ThomasTu
Dear @La.sciamachie,
First Thomas’ comments here are important - please be reassured by these.
It is widely understood that all NUC compounds have comparable effects on inhibiting the HBV reverse transcriptase (which is required for the formation of HBV DNA in infectious virus) what is not widely discussed in the field is these these compounds have different abilities to stimulate the innate immune response. This effect appears to be related to the nucleotides these compounds are derived from:
This effect appears to be lamivudine >> entecavir > tenofovir diphosphate (either TDF or TAF).
These have been well described in mechanistic studies and we also see this in clinical practice as ETV and TDF/TDF therapy are also accompanied by higher rates of HBeAg seroconversion and stronger declines in HBV RNA and HBcrAg (which indicate inactivation of cccDNA). A few studies have also shown very slow declines in cccDNA levels in the liver. Stimulation of innate immunity is likely at least a part of these effects. For instance, lamivudine is a cytosine analog and deamination of cytidine to uridine has been shown to led to stimulation of innate immunity by TLR8. Entecavir is a guanosine analog known to activate TLR 7 and tenofovir diphosphate (a adenosine analog) has been shown to stimulate interferon-like responses by stimulating a specific nucleoside receptor (purine p1 receptor). In this case, tenofovir diphosphate is actually a much stronger activator of the purine p1 response than naturally occurring adenosine!
In principle, mutational resistance is possible for all NUCs but the development of resistance is made much more unlikely with these later generation NUCs at least in part because of these additional effects which are not impacted by the generation of new mutations arising during the HBV replication process.
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Thank you very much for your kind attention and explanation, Dr. @availlant .
I really had this fear: that current medications would lose their effectiveness in the face of new mutations. However, your answer reassured me a lot.
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