Hep C

Question 1

What are some extrahepatic manifestations of hepatitis C?

Answer 1

Autoantibodies 40-60%
Tpe 2 DM 11 x increase
Essential mixed cryoglobulinaemia 11 x inrease
Membranoproliferative GN 7 x increase
lichen planus 2 x increase
MALT and NHL
keratoconjunctivitis sicca
porphyria cutanea tarda  12 x increase
Thyroid dysfunction
Polyarthritis

Question 2

What proportion of hep C patients have cryoglobulinaemia

Answer 2

commonest cause of cyroglobulinaemia is Hep C (90%)
one third of hep C patients have cryoglobulines but clinical features only in 10-15%
See fatigue, arthralgias, rash, neuropathy, GN
May need long term treatment
Role for direct acting antivirals- hard to treat with interferon as often do not respond

Question 3

Indications for treatment hep C

Answer 3

HCV Ab positive
HCV RNA positive
and absence of contraindications

Question 4

Measures of response to HCV treatment

Answer 4

Virological - loss HCV RNA
Biochemical- normalisation ALT
Histological- reduction in inflammation

Question 5

How to define SVR in hep C treatment?

Answer 5

HCV RNA negative 6 months after end of treatment with interferon, 12 weeks with direct acting antiretrovirals

Question 6

How long until HCV Ab positive?

Answer 6

4-24 weeks

Question 7

Why do we want to treat HCV?

Answer 7

Reduced HCC, liver failure, liver related mortality, and all cause mortality if obtain SVR

Question 8

What are the three targets of the direct acting antivirals?

Answer 8

1. NS 3/4 protease inhibitors. First step after uncoating is translation of the positive sense RNA and translation and polyprotein processing. NS3/4 protease inhibitors interfere with chopping up of polyproteins into protein for virion replication. ONLY WORK ON GENOTYPE 1

eg Simeprevir, Telaprevir, Bocprevir

2. NS5B polymerase inhibitors (can be nucleoside/nucleotide/nonnucleoside) Block RNA replication

eg Sofosbuvir, dasabuvir

Then there is virion assembly in the ER lumen

3. NS5A inhibitors block complex formation/assembly (not release)

eg Daclatasvir, ledipasvir

Question 9

Why did we used to care aboue IL28B CC status?

Answer 9

IL28B non CC used to predict less likely to respond to interferon therapy

Question 10

Which factors predict serious adverse events with peg interf/ribavirin/PI in genotype 1?

Answer 10

Plt less than 100
Albumin under 35

–> if both, 44% chance of dying
Hence can only treat well compensated patients.

This helps you decide which patients to treat. Less toxic if cut out protease inhibitor.

Also know that if Q80K positive, no benefit in adding simeprevir

Question 11

Three common adverse effects with Boceprevir?

Answer 11

Anaemia
Neutropaenia
Dysgeusia

Question 12

Three common adverse effects with Telaprevir?

Answer 12

Rash that can be severe
Anaemia
Anorectal events like haemorrhoids

Question 13

Three common adverse events with Simeprevir

Answer 13

Rash
Photosensitivity
Increased bili and jaundice

Question 14

In genotype 1, if Q80K positive what is the significance

Answer 14

No benefit in adding simeprivir/protease inhibitor to interferon or ribavirin- no benefit in SVR and expensive

Question 15

How does ribavirin work?

Answer 15

ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine, inducing mutations in RNA-dependent replication in RNA viruses

Question 16

Can you dose reduce these new drugs?

Answer 16

No! Induces resistance. All or nothing

Question 17

If in doubt, which combination will work for all genotypes?

Answer 17

Sofosbuvir and daclastasvir

Question 18

What is the mechanism of sofosbuvir?

Answer 18

Nucleos(t)ide NS5B polymerase inhibitor