Lecture 15: Antiviral Pharm for HBV and HCV Flashcards
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 3 nucleosides used to treat HBV?
- Lamivudine
- Telbivudine
- Entecavir
What are the 2 nucleotides used to treat HBV?
- Tenofovir
- Adefovir
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
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
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
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
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 is the function of interferon stimulated genes (ISGs) in the treatment of HBV?
- Inhibit multiple steps of viral replication
- Inhibit viral protein synthesis
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
Interferon α and PEGylated interferon α are contraindicated in?
Patients w/ decompensated cirrhosis!!!!
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
Dose limiting toxicities associated with the use of interferons for tx of HBV?
- Bone marrow suppression
- Neurotoxicity - behavioral changes
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
Nucleosides/nucleotides used for HBV work how (MOA)?
- INHIBIT viral reverse transcriptase/DNA polymerase
= NRTI –> Nucleoside/nucleotide Reverse Transcriptase Inhibitor
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 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
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)
What is the first line drug for wild-type HBV and used in pts with resistance to nucleosides?
Tenofovir (nucleotide)
What is an adverse effect associated with using Tenofovir?
Nephrotoxicity - proximal renal tubule
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
Which nucleoside/nucleotide used for HBV does not have good long-term efficacy due to frequent emergence of drug resistance?
Lamivudine (nucleoside)
Of HBV and HCV which can be cured?
- Only HCV can be cured
- HBV can only be treated
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
Why is Ribavirin useful when added to a regiment with PEGylated interferon α?
- Potentiates the actions of PEGylated interferons
- Upregulates interferon stimulated genes (ISGs)
Ribavirin is contraindicated in which 2 groups of patients?
- PREGNANT patients
- Patients w/ anemia
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 are the 4 protease inhibitors used for HCV?
- Simeprevir (2nd gen.)
- Telaprevir (1st gen.)
- Boceprevir (1st gen.)
- Grazoprevir
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
What is the second gen. protease inhibitor used for HCV?
Simeprevir
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 is the nucleoside and nucleotide used in the treatment of HCV?
- Nucleoside = Ribavirin
- Nucleotide = Sofosbuvir
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
Which genotypes of HCV is Sofosbuvir useful against?
Disrupts ALL genotypes of HCV
What are the three NS5A inhibitors used in the treatment of HCV?
1) Elbasvir
2) Vepatasvir
3) Ledipasvir
*E.V.L (EVIL to HCV!)
What’s a ribavirin free regimen that can be used to treat HCV genotype 1?
Ledipasvir (NS5A inhibitor) + Sofosbuvir (nucleotide/NS5A inhibitor)
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!
What should treatment of a patient with co-infection of HBV and HCV be directed at?
Directed at predominant virus
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
