Lecture 15: Antiviral Pharm for HBV and HCV

Question 1

What are the 3 interferons used to treat HBV?

Answer 1

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

Question 2

What are the 3 nucleosides used to treat HBV?

Answer 2

1. Lamivudine
2. Telbivudine
3. Entecavir

Question 3

What are the 2 nucleotides used to treat HBV?

Answer 3

1. Tenofovir
2. Adefovir

Question 4

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

Answer 4

• 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

Question 5

What are 5 pros of using interferons to tx HBV?

Answer 5

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

Question 6

What are 4 cons of using interferons to tx HBV?

Answer 6

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

Question 7

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

Answer 7

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

Question 8

What is the MOA of interferons used in treating HBV?

Answer 8

• 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)

Question 9

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

Answer 9

• Inhibit multiple steps of viral replication
• Inhibit viral protein synthesis

Question 10

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

Signal of what?

Answer 10

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

Question 11

Interferon α and PEGylated interferon α are contraindicated in?

Answer 11

Patients w/ decompensated cirrhosis!!!!

Question 12

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

Answer 12

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

Question 13

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

Answer 13

• Bone marrow suppression
• Neurotoxicity - behavioral changes

Question 14

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….

Answer 14

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

Question 15

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

Answer 15

- INHIBIT viral reverse transcriptase/DNA polymerase

= NRTI –> Nucleoside/nucleotide Reverse Transcriptase Inhibitor

Question 16

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

Answer 16

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

Question 17

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

Answer 17

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

Question 18

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

Which drug may still be used?

Answer 18

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

Question 19

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

Answer 19

Tenofovir (nucleotide)

Question 20

What is an adverse effect associated with using Tenofovir?

Answer 20

Nephrotoxicity - proximal renal tubule

Question 21

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

Why?

Better choice in pts with what condition?

Answer 21

• 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

Question 22

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

Answer 22

Lamivudine (nucleoside)

Question 23

Of HBV and HCV which can be cured?

Answer 23

• Only HCV can be cured
• HBV can only be treated

Question 24

What are the known MOA’s of Ribavirin?

Answer 24

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

Question 25

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

Answer 25

- **Potentiates** the actions of PEGylated interferons - Upregulates interferon stimulated genes **(ISGs)**

Question 26

Ribavirin is contraindicated in which 2 groups of patients?

Answer 26

- **PREGNANT** patients - Patients w/ **anemia**

Question 27

What was the "classic" treatment for HCV? Why is it not used as much anymore?

Answer 27

- **Ribavirin** + **PEGylated interferon** α - Long tx = **24-48 regimen** - With **\<50% cure rate**

Question 28

What are the 4 protease inhibitors used for HCV?

Answer 28

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

Question 29

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

Answer 29

- **Block** the **NS3 CATALYTIC site** of the **NS3/NS4A interaction** - Inhibit the translation and processing of viral replication

Question 30

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

Answer 30

Simeprevir

Question 31

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?

Answer 31

- **Simeprivir** + **PEGylated interferon α-2a or 2b** + **Ribavirin** - **Simeprivir** + **Sofosbuvir** **±** Ribavirin (**chronic genotype 1 infection)**

Question 32

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

Answer 32

- Nucleo**side** = **R****ibavirin** - Nucleo**tide** = **S****ofosbuvir**

Question 33

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

Answer 33

- NS5B inhibitor --\> Nucelo**tide** analog - **Inhibts** **NS5B** which is an **RNA dependent RNA polymerase** needed for HCV replication

Question 34

Which genotypes of HCV is Sofosbuvir useful against?

Answer 34

Disrupts **ALL** genotypes of HCV

Question 35

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

Answer 35

1) **E**lbasvir 2) **V**epatasvir 3) **L**edipasvir \***E.V.L (EVIL** to HCV!)

Question 36

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

Answer 36

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

Question 37

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?

Answer 37

- **Velpatasvir** (NS5A inhibitor) + **Sofosbuvir** (nucleo**tide/**NS5A inhibitor) - **Elbasvir** (NS5A inhibitor) + **Grazoprevir** (protease inhibitor) = **1x daily!**

Question 38

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

Answer 38

Directed at **predominant virus**

Question 39

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

Answer 39

**PEGylated interferon α-**2A **or** α-2B + **Ribavirin** **\*SYNERGISTICALLY** produce **more ISGs**