Lecture 15: Antiviral Pharm for HBV and HCV Flashcards
What are the three NS5A inhibitors used in the treatment of HCV?
1) Elbasvir
2) Vepatasvir
3) Ledipasvir
*E.V.L (EVIL to HCV!)
If HBV impairs purine/pyrimidine kinase activity, which drugs will they be resistant to?
Which drug may still be used?
- Resistance to nucleoside analogs (i.e., lamivudine, entecavir, telbivudine)
- Pt may still be responsive to nucleotide analogs (tenofovir)
Which combo of drugs for 48 weeks has been shown to be effective against HBV infection + HBV/HCV co-infection?
PEGylated interferon α-2A or α-2B + Ribavirin
*SYNERGISTICALLY produce more ISGs
What is the nucleoside and nucleotide used in the treatment of HCV?
- Nucleoside = Ribavirin
- Nucleotide = Sofosbuvir
What was the “classic” treatment for HCV?
Why is it not used as much anymore?
- Ribavirin + PEGylated interferon α
- Long tx = 24-48 regimen
- With <50% cure rate
What is an adverse effect associated with using Tenofovir?
Nephrotoxicity - proximal renal tubule
What are 2 ways that HBV can become resistant to nucleosides/nucleotides?
- Impaired purine/pyrimidine kinase activity (needed for conversion to active NRTIs)
- Mutation of DNA polymerase
What are the 4 protease inhibitors used for HCV?
- Simeprevir (2nd gen.)
- Telaprevir (1st gen.)
- Boceprevir (1st gen.)
- Grazoprevir
Of HBV and HCV which can be cured?
- Only HCV can be cured
- HBV can only be treated
How do the pharmacokinetics differ between interferon α-2b and PEGylated interferon α-2a/2b?
- Interferon α-2b does not last as long and must be redosed frequently
- PEGylated interferons last longer w/ less frequent need to redose
Which genotypes of HCV is Sofosbuvir useful against?
Disrupts ALL genotypes of HCV
Which nucleoside/nucleotide used for HBV does not have good long-term efficacy due to frequent emergence of drug resistance?
Lamivudine (nucleoside)
What are the 2 different combos in which Simeprivir (2nd gen.) can be used for HCV infection?
Which is specifically for chronic genotype 1 infection?
- Simeprivir + PEGylated interferon α-2a or 2b + Ribavirin
- Simeprivir + Sofosbuvir ± Ribavirin (chronic genotype 1 infection)
What are the known MOA’s of Ribavirin?
- Interferes w/ synthesis of GTP
- Inhibits capping of viral mRNA
- Inhibits the viral RNA-dependent polymerase of certain viruses
What’s a ribavirin free regimen that can be used to treat HCV genotype 1?
Ledipasvir (NS5A inhibitor) + Sofosbuvir (nucleotide/NS5A inhibitor)
What is the second gen. protease inhibitor used for HCV?
Simeprevir
What are the 2 nucleotides used to treat HBV?
- Tenofovir
- Adefovir
Which class does the agent for HCV, Sofosbuvir, belong to?
MOA?
- NS5B inhibitor –> Nucelotide analog
- Inhibts NS5B which is an RNA dependent RNA polymerase needed for HCV replication
What are some of the pros associated with using nucleosides/nucleotides in treating HBV as compared to interferons?
i.e., route of administration, response, state of pt disease….
- Can be taken orally
- Better tolerated than interferon α
- Higher response rate
- CAN be used in pts with decompensated cirrhosis
Ribavirin is contraindicated in which 2 groups of patients?
- PREGNANT patients
- Patients w/ anemia
What are 5 pros of using interferons to tx HBV?
- Shorter course (24-48 wks)
- Good efficacy
- Decreased HBV DNA
- Decreased HBeAg
- Acquired resistance = rare
Levels of what in the serum are seen increased with PEGylated interferon α treatment of HBV?
Signal of what?
- ALT
- Hepatitis ‘flare’ is a sign that seroconversion is progressing = good sign that Tx is working
Which nucleotide/nucleoside is the first line HBV infection agent?
Why?
Better choice in pts with what condition?
- Entecavir (nucleoside)
- Potent antiviral activity and low rate of resistance
- Limited side effects, and better choice than adefovir or tenofovir in pts w/ renal insufficiency
What are the 3 nucleosides used to treat HBV?
- Lamivudine
- Telbivudine
- Entecavir
What is needed for nucleosides to become active NRTIs for antiviral effects on HBV?
- Conversion by cellular kinases —> nucleotides
- Need to be triphosphorylated –> nucleotide triphosphate = ACTIVE antiviral agent
What are 4 cons of using interferons to tx HBV?
- Parenteral administration
- Expensive
- Side effects (80%) = flu like syndrome w/ fever, HA, chills, myalgia
- Dangerous in decompensated cirrhosis
What is the MOA of the protease inhibitors (Simepravir, Telaprevir, Boceprevir, and Grazoprevir) in treating HCV?
- Block the NS3 CATALYTIC site of the NS3/NS4A interaction
- Inhibit the translation and processing of viral replication
Why is Ribavirin useful when added to a regiment with PEGylated interferon α?
- Potentiates the actions of PEGylated interferons
- Upregulates interferon stimulated genes (ISGs)
What is the MOA of interferons used in treating HBV?
- Bind type 1 interferon receptor and activate JAK1 and TYK2 –> phosphorylate of intracellar domains
- Dimerization of STAT1 and STAT2 –> translocate to nucleus and activate transcription is interferon stimulated genes (ISGs)
What should treatment of a patient with co-infection of HBV and HCV be directed at?
Directed at predominant virus
What are 2 ribavirin free regimens which can be use to treat HCV genotypes 1, 2, and 3?
Which of these regimens can be given once daily?
- Velpatasvir (NS5A inhibitor) + Sofosbuvir (nucleotide/NS5A inhibitor)
- Elbasvir (NS5A inhibitor) + Grazoprevir (protease inhibitor) = 1x daily!
Dose limiting toxicities associated with the use of interferons for tx of HBV?
- Bone marrow suppression
- Neurotoxicity - behavioral changes
What is the first line drug for wild-type HBV and used in pts with resistance to nucleosides?
Tenofovir (nucleotide)
Interferon α and PEGylated interferon α are contraindicated in?
Patients w/ decompensated cirrhosis!!!!
What are the 3 interferons used to treat HBV?
1) Interferon α-2b
2) PEGylated interferon α-2b
3) PEGylated interferon α-2a
What are the indications for use of Interferons in the treatment of HBV?
- Primarily used in pts w/ well compensated liver dz
- Pt who does not want to be on long-term treatment
- Pt plans to be pregnant within the next 2-3 years
Nucleosides/nucleotides used for HBV work how (MOA)?
- INHIBIT viral reverse transcriptase/DNA polymerase
= NRTI –> Nucleoside/nucleotide Reverse Transcriptase Inhibitor
What is the function of interferon stimulated genes (ISGs) in the treatment of HBV?
- Inhibit multiple steps of viral replication
- Inhibit viral protein synthesis
What are the adverse effects experienced by 80-90% of pts taking interferons for HBV?
- Flu-like syndrome = HA, fever, chills, myalgia, malaise
- Fatigue and mental depression
