Lecture 5 - HCV

Question 1

SVR

Answer 1

sustained virologic response = cure

undetectable RNA 12 weeks post treatment

Question 2

Ribavirin

Answer 2

guanosine analog that is phosphorylated intracellularly by host cell enzymes
blocks capping of viral mRNA inhibiting viral RNA dependent polymerase

PO
prodrug
can be used in combination with interferon

Question 3

What toxicity is associated with ribavirin?

Answer 3

hemolytic anemia in 10-20% of pts

this is because this drug looks like a nucleotide (guanisine) so it’s not super selective for the virus over us

Question 4

How long are pts on ribavirin?

Answer 4

forever

so they are forever at risk for hemolytic anemia

Question 5

Interfons

Answer 5

SC or IM administration
cytokines that bind to their favorite interferon receptors
increases the immune response –you want the immune system to ramp up and attack the virus

SE: flu like sxs (BAD)

Question 6

What are the cellular effects of interferon?

Answer 6

after binding to membrane receptor:

• increase major histocompatibility complex antigens
• induces intracellular signals leading to inhibition of viral penetration/translation/transcription/protein processing/maturation/and release
• increase phagocytic activity of macrophages
• increase proliferation and survival of cytotoxic T cells

Question 7

What are the contraindications of interferon?

Answer 7

hepatic decompensation 
autoimmune disease 
history of cardiac arrhythmia 
severe depression 
pregnancy (can cause abortion)

Question 8

What is the BBW for new “direct acting” HCV agents such as protease inhibitors, polymerase inhibitors, NS5A inhibitors?

Answer 8

HBV reactivation in HCV/HBV coinfection

Question 9

Which HCV drugs attack structural proteins directly?

Answer 9

Ribavirin is the only one that attacks the capsid/envelope directly

Question 10

Simeprevir

Answer 10

PO
HCV protease inhibitor
targets NS3/4A protease

good against HCV genotype 1

first of the new generation of drugs

doesn’t need Peg/RBV

24-48 week therapy

Question 11

What are the toxicities of simeprevir?

Answer 11

rash 
photosensitivity 
elevated bilirubin/uric acid 
DO NOT use in pregnancy 
P-glycoprotein transporter/CYP3A4 inhibitors/substrates = Rx-Rx interactions (rousuvastatin/atorvastatin)

Question 12

Sofosbuvir

Answer 12

PO prodrug –activated by phosphorylation
one of the most effective drugs for HCV

RNA dependent NS5B RNA polymerase inhibitor (pangentoypic)

good against HCV genotype 1-6 and those resistant to protease inhibitors

Question 13

How long are patients on sofosbuvir?

Answer 13

12 weeks (plus peg/ribavarin) = 90% SVR

Question 14

What is the standard first line treatment for HCV?

Answer 14

Sofosbuvir with ledipasvir, RBV, or Peg

Question 15

What are the toxicities for Sofosbuvir?

Answer 15

well tolerated

not to be used in renal pts - renal toxicity

Question 16

Ledipasvir

Answer 16

NS5A protein inhibitor

blocks replication via preventing RNA binding to polymerase
inhibits viral assembly andrelease

approved for HCV genotype 1

only available in combo with Sofosbuvir (harvoni)
no PegIFN or RBV needed

Question 17

Harvoni

Answer 17

sofosbuvir + ledipasvir