Protease Inhibitors

Question 1

Protease Inhibitors

PIs

Answer 1

ATV- atazanavir 
DRV- darunavir 
Ritonavir (boosting dose: /r)
FPV- fosamprenavir 
SQV- saquinavir 
IDV- indinavir 
NFV- nelfinavir
TPV- tipranavir 
RTV- ritonavir (full dose)

Prezcobix- darunavir, cobicistat
Evotaz- atazanavir, cobicistat
Kaletra- lopinavir, ritonavir boosting

Combos with PIs was the beginning of highly active antiretroviral therapy (HAART); have had major impact on prolonged lifespan among HIV patients

Now entering their third generation- more potent agents with few acute toxicities; long term toxicities are arising as a concern

Key advance is using boosting- either ritonavir (/r) or the PK booster cobicistat (/c) to increase serum concentrations and half lives of other PIs
Boosting now routine for all PIs

Only current use is HIV
PIs for HCV are different drugs; HIV PIs not active for HCV and vice versa

Question 2

Protease Inhibitors

(PIs) MOA

Answer 2

When proteins are created, some of them are created in long chains that need to be cup up into component parts to work correctly
PIs selectively inhibit HIV protease responsible for this process
Protease is like scissors cutting out shapes from a piece of paper; PIs take away the scissors so the shapes just remain one big piece of paper

Question 3

Protease Inhibitors Adverse Effects

PIs

Answer 3

Cardiovascular
Interact with conventional CV risk factors to increase risk for MI and stroke beyond that from just prolonging lifespan
Atazanavir and darunavir may have lower risk
Manage with usual CV prevention strategies (diet, exercise, drugs)

GI
All pretty hard on GI tract (N/V/D)
Taking with food may somewhat reduce the side effects
Many find them more tolerable with time
Severe cases may require coadministration with antiemetic or anti diarrheals

Hepatotoxicity
Potential exists with entire class
Ranges from asymptomatic transaminase elevations to clinical hepatitis
Risk may be highest with boosted with tipranavir

Metabolic
Adverse effects on lipid profile
Also associated with lipodystrophy (fat accumulation in abdomen, breasts, and neck)

Nephrotoxicity
Renal toxicity in kidneys/ureters has been reported
Most common with now infrequently used indinavir
Reported rarely with atazanavir or fosamprenavir
Adequate fluid intake recommended for prevention

Question 4

Protease Inhibitors

(PIs) Important Facts

Answer 4

More robust to antiviral resistance compared to NNRTIs and INSTIs
Several mutations in target enzyme required for high level resistance
May be slightly less forgiving of poor adherence

Pose tremendous drug interaction challenges
All are substrates of CYP enzymes

Ritonavir originally approved for 400mg BID
Not well tolerated at this dose
Now almost used exclusively as PK booster at a lower dose

Question 5

Protease Inhibitors

(PIs) Good For

Answer 5

Initial HIV: darunavir regimens preferred
Atazanavir and lopinavir are alternative

Resistant: variety of PIs used for salvage regimens

Risk vs benefit: durable viral suppression vs long term effects (especially CV)

Only atazanavir can be used unboosted (only for selected patients)
Every PI regimen should have some kind of PK booster