Anti-Viral Hepatitis Agents

Question 1

Hep C

Answer 1

Only curable one

Question 2

Hep C Infection Cure does not prevent against

Answer 2

reinfection

Question 3

Why can Hep C be cured?

Answer 3

Virus does no integrate into human genome

Question 4

Epclusa

Answer 4

SOF + Velpatasvir

Question 5

Mavyret

Answer 5

Glecaprevir (GLE) + Pibrentasvir (PIB)

Question 6

Vosevi

Answer 6

SOF + VEL+ Voxilaprevir (VOX)

Question 7

NS3/4A protease

Answer 7

-PREVIR

Targeting HCV Protein Processing

Question 8

NS3/4A protease

Names

Answer 8

• Glecaprevir
• Grazoprevir
• Paritaprevir
• Simeprevir
• Voxilaprevir

Question 9

NS5B Polymerase

Answer 9

-BUVIR

Targeting HCV Replication

Question 10

NS5B Polymerase

Names

Answer 10

• Sofosbuvir

- Dasabuvir

Question 11

NS5A

Answer 11

-ASVIR

Targeting HCV Replication

Question 12

NS5A

Names

Answer 12

• Pibrentasvir

- Velpatasvir

Question 13

HCV NS3/4A Protease

Answer 13

• NS4A critical for activity of NS3 serine protease (HCV protease)
• early work to identify inhibitors focused on optimizing SUBSTRATE-BASED INHIBITORS

Question 14

Modern NS3/4A Protease Inhibitors

Answer 14

• Voxilaprevir (VOX)
• Glecaprevir (GLE)
• both active against NS3/4A IN ALL HCV GENOTYPES

only 2 FDA approved for HCV

Question 15

Voxilprevir

VOX

Answer 15

NS3/4A Protease Inhibitor

Question 16

Glecaprevir

GLE

Answer 16

NS3/4A Protease Inhibitor

Question 17

HCV NS5A Inhibitors

Answer 17

• bind to DIMERIZED DOMAIN I and prevent RNA from binding, disrupting replication
• ** 1st gen LOW BARRIER TO DEVOLOPMENT OF RESISTANT VARIANTS ***

Question 18

NS5A

Answer 18

• protein with virus induced MEMBRANE VESICLES
• DIMER
• plays important role in VIRAL RNA REPLICATION

Question 19

2nd Gen NS5A Inhibitors

Answer 19

• Velpatasvir
• Pibrentasvir
• PANGENOTYPIC
• IMPROVED RESISTANCE BARRIER

Question 20

Velpatasvir

Answer 20

2nd Gen NS5A Inhibitors

Question 21

Pibrentasvir

Answer 21

2nd Gen NS5A Inhibitors

Question 22

NS5B RNA-Dependent RNA Polymerase (RdRp) Nucelos(t)ide Inhibitors

Answer 22

• Sofosbuvir
• – TROJAN HORSE
• add first P to overcome rate limiting step (which is adding the first P)
• mask/protect drug with other groups in order to promote entry with P

Question 23

NS5B RdRp

Answer 23

• catalyzes RNA synthesis
• nucleotide binding site conserved across all genotypes
• Challenge
• – identificying inhibitors
• – NEED 3P INORDER TO BE ACTIVE; can’t get into cell with 3P

Question 24

Sofosbuvir

Answer 24

NS5B RNA-Dependent RNA Polymerase (RdRp) Nucelos(t)ide Inhibitors

• – TROJAN HORSE
• add first P to overcome rate limiting step (which is adding the first P)
• mask/protect drug with other groups in order to promote entry with P

Question 25

Allosteric Inhibitors of NS5B Polymerase

Answer 25

- Dasabuvir (not as effective as Sofosbuvir)

Question 26

Recommended Regimens for HCV Therapy

Answer 26

- Sofosbuvir/velpatasvir 12 week - Sofobuvir/velpatasvir/voxilaprevir RESCUE THERAPY - Glecaprevir/pibrentasvir 8 week *** DONT NEED TO TEST FOR GENOTYPE ***

Question 27

HCV cures are associated with a _____ reduction in HCC risk

Answer 27

79%

Question 28

HBV

Answer 28

- DNA virus - integrates into human genome - 7 known viral genotypes - -- relaxed circular dsDNA - no cure yet

Question 29

Key HBV Markers

Answer 29

- NTCP: membrane receptor | - cccDNA: main template for RNA

Question 30

First-line Agents for Treating HBV

Answer 30

- Entecavir - TAF - TDF

Question 31

TDF

Answer 31

- Tenofovir disproxil fumarate

Question 32

TAF

Answer 32

- Tenofovir Alafenamide

Question 33

Entecavir

Answer 33

- nucleoside reverse transcriptase inhibitor (NRTI) - COMPETITIVELY inhibits all 3 functions of HBV DNA polymerase: - -- BASE PRIMING - -- REVERSE TRANSCRIPTION - -- SYNTHESIS OF + STRAND * ** HIGH BARRIER TO RESISTANCE ***

Question 34

Entecavir | Pharmacokinetics

Answer 34

- orally active - t1/2 > 5 days - renal elimination

Question 35

Entecavir Common Side Effects Severe Side Effects

Answer 35

Common - headache, fatigue, dizziness, nausea, high blood sugar, decreased kidney function Severe - LACTIC ACIDOSIS - liver issues

Question 36

Tenofovir (TFV)

Answer 36

- ADENOSINE NUCLEOTIDE ANALOG - phosphorylated in situ to active TENOFOVIR DISPHOSPHATE (TFV-DP) - -- triphosphate analog - inhibits HIV and HBV RNA-dependent DNA polymerases (RT) - LOW BIOAVAILABILITY

Question 37

TFV Prodrugs | TDF & TAF

Answer 37

- prodrug increases cell permeability and oral bioavailability - nucleotide analog RT inhibitor for both HIV and HBV * ** TAF REDUCES OFF-TARGET EXPOSURE OF TDF, particularly to the kidney and bone ***

Question 38

TAF Mechanism of Action

Answer 38

- passively enters cell - CARBOXYPEPTIDASE CATHEPSIN A (CatA) hydrolyzes TAF - -- TAF -> TFV - key intermediate formed (alanine) - alanine releases TFV - TFV phosphorylated into pharmacologically active metabolite TFV-DP

Question 39

TAF novel prodrug

Answer 39

- goes right into liver cell - no need to adjust for bioavailability (you do with TDF) TAF > TDF

Question 40

Important things to note with HBV

Answer 40

- when to START treatment - when to STOP treatment - lifelong therapy?

Question 41

Bulevirtide | Myrcludex B

Answer 41

- HepD - ENTRY INHIBITOR - active against both HBV and HDV - block infection in cell via entry