Direct Hepatitis C Agents

Question 1

Direct Acting Anti-hepatitis C Agents

Answer 1

Agents: protease inhibitors: simeprevir, paritaprevir, grazoprevir, boceprevir, telaprevir

NS5A inhibitors: daclatasvir, elbasvir, ledipasvir, ombitasvir

NS5B (polymerase) inhibitors: sofosbuvir

Non-nucleoside polymerase inhibitors: dasabuvir

Combinations: paritaprevir/ombitasvir/ritonavir; grazoprevir/elbasvir/ledipasvir/sofosbuvir

HCV treatment has unfolded over the last 5 years; began in 2011 with two serine protease inhibitors (boceprevir/telaprevir) but they are now obsolete

Regimens include multiple agents with different MOA; usually duration only 3-4 months with cure rates 80-100%
Old regimens included ribavirin plus interferons

Price can be $1000 per day

Question 2

Direct Acting Anti-hepatitis C Agents MOA

Answer 2

Along with ribavirin, these agents are DAAs- direct acting antivirals; interferons have indirect effects

Some inhibit professes
NS-non structural-5B: inhibit RNA polymerases
NS5A- not clear

Question 3

Direct Acting Anti-hepatitis C Agents Spectrum

Answer 3

At least 6 HCV genotypes that cause infection in humans
DAAs differ in activity against each

Genotype 1 (comes as 1a and 1b) is most prevalent in US
Protease inhibitors potent against these (simeprevir and paritaprevir limited activity against other genotypes)

NS5A/B inhibitors have broad spectrum against various genotypes

Ritonavir is coformulated as a PK booster

Question 4

Direct Acting Anti-hepatitis C Agents Adverse Effects

Answer 4

Most agents well tolerated with mild toxicities: N/V/fatigue

Simeprevir
Photosensitivity: limit sun exposure/wear sunscreen
Transient elevations in bilirubin (do not appear to be associated with significant hepatotoxicity)

Sofosbuvir
Rarely associated with symptomatic episodes of bradycardia (almost all cases occurred in patients on amiodarone)

Elbasvir/grazoprevir and ombitasvir/paritaprevir/ritonavir
Associated with hepatic decompensation (particularly those with pre-existing cirrhosis)
Closely monitor ALT (interrupt treatment for substantial asymptomatic elevations- greater than 10 fold ULN or lower elevations that are associated with symptoms of hepatitis- jaundice, abdominal pain, N/V)

Question 5

Direct Acting Anti-hepatitis C Agents Important Facts

Answer 5

Lots of drug interactions
High prevalence of HIV-HCV coinfection so many interactions with antiretrovirals

Recommended with food
Simeprevir
Ombitasvir/paritaprevir/ritonavir
Dasabuvir

Presence of gastric acidity important for absorption of ledipasvir
Avoid acid suppressing agents or carefully time their administration

For some genotypes or patients (cirrhotic), addition of ribavirin or pegylated interferon to DAAs still recommended

Resistance does develop and seems to correlate with failure to eradicate HCV
Genetic barrier for resistance emergence is lowest with dasabuvir, NS5A inhibitors, and simeprevir; higher with other protease inhibitors and sofosbuvir

Testing for resistance mutations only in selected patients (prior exposure to DAAs and some with cirrhosis)