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GI II Exam 2. > Lecture 15: Antiviral Pharm for HBV and HCV > Flashcards

Lecture 15: Antiviral Pharm for HBV and HCV Flashcards

1
Q

What are the three NS5A inhibitors used in the treatment of HCV?

A

1) Elbasvir
2) Vepatasvir
3) Ledipasvir

*E.V.L (EVIL to HCV!)

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2
Q

If HBV impairs purine/pyrimidine kinase activity, which drugs will they be resistant to?

Which drug may still be used?

A
  • Resistance to nucleoside analogs (i.e., lamivudine, entecavir, telbivudine)
  • Pt may still be responsive to nucleotide analogs (tenofovir)
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3
Q

Which combo of drugs for 48 weeks has been shown to be effective against HBV infection + HBV/HCV co-infection?

A

PEGylated interferon α-2A or α-2B + Ribavirin

*SYNERGISTICALLY produce more ISGs

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4
Q

What is the nucleoside and nucleotide used in the treatment of HCV?

A
  • Nucleoside = Ribavirin
  • Nucleotide = Sofosbuvir
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5
Q

What was the “classic” treatment for HCV?

Why is it not used as much anymore?

A
  • Ribavirin + PEGylated interferon α
  • Long tx = 24-48 regimen
  • With <50% cure rate
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6
Q

What is an adverse effect associated with using Tenofovir?

A

Nephrotoxicity - proximal renal tubule

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7
Q

What are 2 ways that HBV can become resistant to nucleosides/nucleotides?

A
  • Impaired purine/pyrimidine kinase activity (needed for conversion to active NRTIs)
  • Mutation of DNA polymerase
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8
Q

What are the 4 protease inhibitors used for HCV?

A
  1. Simeprevir (2nd gen.)
  2. Telaprevir (1st gen.)
  3. Boceprevir (1st gen.)
  4. Grazoprevir
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9
Q

Of HBV and HCV which can be cured?

A
  • Only HCV can be cured
  • HBV can only be treated
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10
Q

How do the pharmacokinetics differ between interferon α-2b and PEGylated interferon α-2a/2b?

A
  • Interferon α-2b does not last as long and must be redosed frequently
  • PEGylated interferons last longer w/ less frequent need to redose
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11
Q

Which genotypes of HCV is Sofosbuvir useful against?

A

Disrupts ALL genotypes of HCV

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12
Q

Which nucleoside/nucleotide used for HBV does not have good long-term efficacy due to frequent emergence of drug resistance?

A

Lamivudine (nucleoside)

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13
Q

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?

A
  • Simeprivir + PEGylated interferon α-2a or 2b + Ribavirin
  • Simeprivir + Sofosbuvir ± Ribavirin (chronic genotype 1 infection)
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14
Q

What are the known MOA’s of Ribavirin?

A
  • Interferes w/ synthesis of GTP
  • Inhibits capping of viral mRNA
  • Inhibits the viral RNA-dependent polymerase of certain viruses
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15
Q

What’s a ribavirin free regimen that can be used to treat HCV genotype 1?

A

Ledipasvir (NS5A inhibitor) + Sofosbuvir (nucleotide/NS5A inhibitor)

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16
Q

What is the second gen. protease inhibitor used for HCV?

A

Simeprevir

17
Q

What are the 2 nucleotides used to treat HBV?

A
  1. Tenofovir
  2. Adefovir
18
Q

Which class does the agent for HCV, Sofosbuvir, belong to?

MOA?

A
  • NS5B inhibitor –> Nucelotide analog
  • Inhibts NS5B which is an RNA dependent RNA polymerase needed for HCV replication
19
Q

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….

A
  • Can be taken orally
  • Better tolerated than interferon α
  • Higher response rate
  • CAN be used in pts with decompensated cirrhosis
20
Q

Ribavirin is contraindicated in which 2 groups of patients?

A
  • PREGNANT patients
  • Patients w/ anemia
21
Q

What are 5 pros of using interferons to tx HBV?

A
  • Shorter course (24-48 wks)
  • Good efficacy
  • Decreased HBV DNA
  • Decreased HBeAg
  • Acquired resistance = rare
22
Q

Levels of what in the serum are seen increased with PEGylated interferon α treatment of HBV?

Signal of what?

A
  • ALT
  • Hepatitis ‘flare’ is a sign that seroconversion is progressing = good sign that Tx is working
23
Q

Which nucleotide/nucleoside is the first line HBV infection agent?

Why?

Better choice in pts with what condition?

A
  • 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
24
Q

What are the 3 nucleosides used to treat HBV?

A
  1. Lamivudine
  2. Telbivudine
  3. Entecavir
25
Q

What is needed for nucleosides to become active NRTIs for antiviral effects on HBV?

A
  • Conversion by cellular kinases —> nucleotides
  • Need to be triphosphorylated –> nucleotide triphosphate = ACTIVE antiviral agent
26
Q

What are 4 cons of using interferons to tx HBV?

A
  • Parenteral administration
  • Expensive
  • Side effects (80%) = flu like syndrome w/ fever, HA, chills, myalgia
  • Dangerous in decompensated cirrhosis
27
Q

What is the MOA of the protease inhibitors (Simepravir, Telaprevir, Boceprevir, and Grazoprevir) in treating HCV?

A
  • Block the NS3 CATALYTIC site of the NS3/NS4A interaction
  • Inhibit the translation and processing of viral replication
28
Q

Why is Ribavirin useful when added to a regiment with PEGylated interferon α?

A
  • Potentiates the actions of PEGylated interferons
  • Upregulates interferon stimulated genes (ISGs)
29
Q

What is the MOA of interferons used in treating HBV?

A
  • 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)
30
Q

What should treatment of a patient with co-infection of HBV and HCV be directed at?

A

Directed at predominant virus

31
Q

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?

A
  • Velpatasvir (NS5A inhibitor) + Sofosbuvir (nucleotide/NS5A inhibitor)
  • Elbasvir (NS5A inhibitor) + Grazoprevir (protease inhibitor) = 1x daily!
32
Q

Dose limiting toxicities associated with the use of interferons for tx of HBV?

A
  • Bone marrow suppression
  • Neurotoxicity - behavioral changes
33
Q

What is the first line drug for wild-type HBV and used in pts with resistance to nucleosides?

A

Tenofovir (nucleotide)

34
Q

Interferon α and PEGylated interferon α are contraindicated in?

A

Patients w/ decompensated cirrhosis!!!!

35
Q

What are the 3 interferons used to treat HBV?

A

1) Interferon α-2b
2) PEGylated interferon α-2b
3) PEGylated interferon α-2a

36
Q

What are the indications for use of Interferons in the treatment of HBV?

A
  • 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
37
Q

Nucleosides/nucleotides used for HBV work how (MOA)?

A

- INHIBIT viral reverse transcriptase/DNA polymerase

= NRTI –> Nucleoside/nucleotide Reverse Transcriptase Inhibitor

38
Q

What is the function of interferon stimulated genes (ISGs) in the treatment of HBV?

A
  • Inhibit multiple steps of viral replication
  • Inhibit viral protein synthesis
39
Q

What are the adverse effects experienced by 80-90% of pts taking interferons for HBV?

A
  • Flu-like syndrome = HA, fever, chills, myalgia, malaise
  • Fatigue and mental depression

GI II Exam 2. (8 decks)

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