HCV therapies Flashcards
Why is IFN treatment no longer preferred?
Long term IFN-based treatment didn’t halt progression of chronic HCV in patients not responding to initial treatment.
What is SVR (sustained virological response)
Negative by PCR at 12 weeks after cessation of therapy.
What are some IFN based regimes for HCV treatment?
IFN-alpha activates IFN mediated antiviral responses or pegylated IFN-alpha (conjugated w/albumin)
Ribavirin
What base analogue is Ribavirin?
Guanosine
What is the MOA of ribavirin?
Incoprorated into RNA by NS5B, it is mutagenic.
What are the problems of IFN based HCV treatment
Response rate varies with genotype
Relapse
Side effects: neutrophil, platelt, Hg reduction.
Side effect of ribavirin
Anaemia
What are direct-acting antivirals (DAAs)
Small molecules that interfere with function of viral protein by direct binding
What do DAAs target in HCV life cycle
Translation and polyprotein process
What HCV proteins are DAA targets
NS4A, NS4B, NS3, NS5A and NS5B
What’s the issue with single DAAs
Resistance quickly occurs
How does resistance develop against DAAs
NS5B is error-prone, DAA probvides selection pressure
What species type within a cell is HCV?
Quasi-species
What is a quasi species (HCV)
Many genomes infect one cell
What do -previrs inhibit
HCV protease, NS3/4A
Generations of -previrs, example and info
First gen: Telaprevir/Boceprevir: Potent but low barrier to resistance and cross-resistance. Specific to genotype 1.
Second gen: SImeprevir: Potent and effective against 1st generation resistance. Some genotypes but not 3.
Third gen: Glecaprevir and Voxaliprevir: Potent against all genotypes and some resistance mutants, they are fluorinated and improve potency and physicochemical properties.
NS3/4A blocks induction of what IFN expression
Beta
What do -asvirs inhibit
NS5A
Potency of -asvirs
Highly potent
What is the MOA of -asvirs
Uncertain, mapped to amphipathic helix. Conformational change of oligomer NS5A
The two generations of -asvirs
First gen like Daclatasvir has low barrier to resistance.
Second gen compounds have better resistance profile and activity against 1st generation resistance variants.
What do -buvirs inhibit
NS5B RNA polymerase
