Antiretrovirals: PIs, INSTI, CCR5 Antagonist, Fusion Inhibitor

Question 1

Moving on to the Protease Inhibitors (PIs) — Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir. What is the MOA?

Answer 1

Competitively inhibit the action of the virus aspartyl protease

• -prevent proteolytic cleavage of HIV gag and pol polyproteins that include essential structural and enzymatic components of the virus
• -prevents metamorphosis of HIV particles into their mature infectious form

Question 2

What is important toxicity common to all approved protease inhibitors?

Answer 2

Potential for metabolic drug interactions

Most inhibit CYP3A4 at clinically achieved concentrations, although the magnitude of inhibition varies

Question 3

It is common practice to combine HIV protease inhibitors with that?

Answer 3

Pharmacokinetic enhancer

• -results in enhanced pharmacokinetic profile of HIV protease inhibitors
• -this results in improved oral bioavailability and a longer elimination half life
• -therefore reduce both drug doses and dosing frequency

Question 4

The use of protease inhibitors has lead to what general disorders?

Answer 4

Carbohydrate and Lipid Metabolism
AE:
hyperglycemia, insulin resistance and hyperlipidemia in addition to altered body fat distribution (buffalo hump, gynecomastia, and truncal obesity)

Question 5

Lets go through each protease inhibitor and name their adverse effect and drug interactions. First is Atazanavir

Answer 5

AE:
Benign Hyperbilirubinemia, Rash, PR interval prolongation, nephrolithiasis
Drug Interactions:
Concurrent use of drugs that increase gastric pH, such as PPIs, H2 blockers, and antacids may decrease absorption of atazanavir (needs an acidic environment to be absorbed)

Question 6

Second is darunavir

Answer 6

AE: 
rash 
Drug Interaction: 
Inhibits CYP3A4
Avoid in patients with sulfur allergy

Question 7

Third is Indinaivr

Answer 7

AE:
asymptomatic elevation of indirect bilirubin, nephrolithiasis, cholelithiasis, rash and blurred vision
Drug Interaction:
Inhibits CYP3A4

Question 8

Fourth is Lopinavir

Answer 8

AE:
generally well tolerated, headache, asthenia, pancreatitis
Drug Interactions:
Inhibits CYP3A4

Question 9

Fifth is Nelfinavir

Answer 9

AE:
Generally well tolerated, diarrhea, nausea, and flatulence are common
Drug Interaction:
Metabolized by several CYP enzymes (3A4 and 2C19)

Question 10

Moving on to the next class of HIV drugs are the Integrase Strand Transfer Inhibitor (INSTI) — Dolutegravir, Elvitegravir, Raltegravir. What are some features?

Answer 10

HIV-1 integrase catalyzes the process that results in viral DNA insertion into the host genome.
–these drugs block the enzyme activity, preventing viral DNA from integrating with cellular DNA

Question 11

What are some features of Raltegravir?

Answer 11

Eliminated by glucuronidation mediated by the uridine diphosphate (UDP)- glucuronosyltransferase (UGT) 1A1 enzymes
Induces of UGT1A1 enzymes (rifampin) can reduce the concentration of raltegravir.

Question 12

What are features of Dolutegravir?

Answer 12

Metabolized by UGT1A1 but has some contribution from CYP3A4, therefore drug drug interactions are more common than with raltegravir.

Question 13

What are features of Elvitegravir?

Answer 13

Metabolized primarily by CYP3A4 enzymes

• -CYP3A induces or inhibitors may alter active concentrations of this drug
• -requires enhancing with a pharmacokinetic enhancer

Question 14

INSTIs are generally well tolerated, but what are some rare but severe effects?

Answer 14

Increase in creatine phosphokinases, myopathy, rhabdomyolysis and systemic hypersensitivity reactions
Favorable effect on lipid profile so quite popular drug

Question 15

Next HIV drug is a CCR5 antagonist called Maraviroc. What is the MOA for this drug?

Answer 15

Bind to the CCR5 co receptor, preventing entry of CCR5 tropic viruses into CD4 host cells
–used for tx naive and tx experienced adults with CCR5 tropic strains

Question 16

What is the interaction with other drugs and Maraviroc?

Answer 16

Substrate of CYP3A4 enzymes and P-glycoprotein
–concentrations of maraviroc can be significantly increased in the presence of strong CYP3A4 inhibitors are reduced when combined with CYP3A4 inducers

Question 17

What are AE of Maraviroc?

Answer 17

Pyrexia, Rash, Cough, Musculoskeletal symptoms, abdominal pain and postural dizziness
Hepatotoxicity can occur

Question 18

Next HIV drug is a Fusion Inhibitor, Enfuvirtide. What is the MOA?

Answer 18

After HIV binds to the host cell surface, a conformational change occurs in the transmembrane glycoprotein subunit (gp41) of the viral envelope, facilitating fusion of the viral and host cell membranes and entry of the virus into the cell

• -Enfuvirtide binds to gp41 and prevents the conformational change
• -indicated for treatment experienced patients with ongoing HIV replication despite therapy

Question 19

What are the adverse effects of Enfuvirtide?

Answer 19

Local injection site reactions with mild or moderate pain, erythema, induration, nodules and cysts
No drug drug interactions

Question 20

The last set of HIV drugs are Pharmacokinetic Enhancers – Ritonavir and Cobicistat. They are used solely to enhance pharmacokinetic profiles of some anti-retroviral drugs. What are features of Ritonavir?

Answer 20

Inhibitor of CYP3A4

• -when given in low doses in combo with any other protease inhibitor it will increase the plasma concentration of the protease inhibitor (therefore lower or less frequent dosing with greater tolerability)
• -always used with protease inhibitors and never used alone

Question 21

What are features of Cobicistat?

Answer 21

Inhibitor of CYP3A4 and used in the same capacity as ritonavir (Enhance antiretrovirals that are metabolized by that enzyme)
No anti retroviral activity on its own
Used in combo with INSTI elvitegravir but can be used in combo with darunavir and atazanavir

Question 22

All HIV infected pregnant women should receive combination antiretroviral therapy during pregnancy to prevent?

Answer 22

Progression of their own disease and to reduce the risk of perinatal transmission

Question 23

What HIV drugs should not be used during pregnancy?

Answer 23

Efavirenz (ESp during first trimester)
Risk of neural tube defects is restricted to the first 5-6 weeks of pregnancy, so women who present for antenatal care after this time and are already taking efavirenz and have optimal viral suppression can stay on it.
Nevirapine should be avoided in women with CD4 counts greater than 250 due to hepatotoxicity

Question 24

Three or more active drugs should be used for occupational exposures. Explain the treatment process

Answer 24

Tx should be started within 72h of exposure and continued for 4 weeks
Follow up HIV testing is recommended for at least 4-6 months after the exposure

Question 25

What is the preferred regiment for occupational post exposure prophylaxis?

Answer 25

Raltegravir + Tenofovir + Emtricitabine

Question 26

What vaccines are recommended for all HIV infected patients?

Answer 26

S. pneuoniae 
Hep A 
Hep b
Influenza 
Live vaccines can be administered to HIV positive patients with a CD4 cell count over 200 (MMR and varicella)

Question 27

What is the current recommendations for treatment regiments in naive patients?

Answer 27

2x NRTI + INSTI

2x NRTI + PI

Question 28

What are the two INSTI based regimens?

Answer 28

1) Raltegravir + tenofovir + Emtricitabine
2) Dolutegravir + Tenofovir + Emtricitabine
- -these regimens will be highly effective and have few adverse effects and no significant CYP3A4 associated drug interactions

Question 29

What is the PI based regimen?

Answer 29

Darunavir (+ ritonavir) + tenofovir + emtricitabine