Flashcards in Antiretrovirals: PIs, INSTI, CCR5 Antagonist, Fusion Inhibitor Deck (29):
Moving on to the Protease Inhibitors (PIs) --- Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir. What is the MOA?
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
What is important toxicity common to all approved protease inhibitors?
Potential for metabolic drug interactions
Most inhibit CYP3A4 at clinically achieved concentrations, although the magnitude of inhibition varies
It is common practice to combine HIV protease inhibitors with that?
--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
The use of protease inhibitors has lead to what general disorders?
Carbohydrate and Lipid Metabolism
hyperglycemia, insulin resistance and hyperlipidemia in addition to altered body fat distribution (buffalo hump, gynecomastia, and truncal obesity)
Lets go through each protease inhibitor and name their adverse effect and drug interactions. First is Atazanavir
Benign Hyperbilirubinemia, Rash, PR interval prolongation, nephrolithiasis
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)
Second is darunavir
Avoid in patients with sulfur allergy
Third is Indinaivr
asymptomatic elevation of indirect bilirubin, nephrolithiasis, cholelithiasis, rash and blurred vision
Fourth is Lopinavir
generally well tolerated, headache, asthenia, pancreatitis
Fifth is Nelfinavir
Generally well tolerated, diarrhea, nausea, and flatulence are common
Metabolized by several CYP enzymes (3A4 and 2C19)
Moving on to the next class of HIV drugs are the Integrase Strand Transfer Inhibitor (INSTI) --- Dolutegravir, Elvitegravir, Raltegravir. What are some features?
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
What are some features of Raltegravir?
Eliminated by glucuronidation mediated by the uridine diphosphate (UDP)- glucuronosyltransferase (UGT) 1A1 enzymes
Induces of UGT1A1 enzymes (rifampin) can reduce the concentration of raltegravir.
What are features of Dolutegravir?
Metabolized by UGT1A1 but has some contribution from CYP3A4, therefore drug drug interactions are more common than with raltegravir.
What are features of Elvitegravir?
Metabolized primarily by CYP3A4 enzymes
--CYP3A induces or inhibitors may alter active concentrations of this drug
--requires enhancing with a pharmacokinetic enhancer
INSTIs are generally well tolerated, but what are some rare but severe effects?
Increase in creatine phosphokinases, myopathy, rhabdomyolysis and systemic hypersensitivity reactions
Favorable effect on lipid profile so quite popular drug
Next HIV drug is a CCR5 antagonist called Maraviroc. What is the MOA for this drug?
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
What is the interaction with other drugs and Maraviroc?
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
What are AE of Maraviroc?
Pyrexia, Rash, Cough, Musculoskeletal symptoms, abdominal pain and postural dizziness
Hepatotoxicity can occur
Next HIV drug is a Fusion Inhibitor, Enfuvirtide. What is the MOA?
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
What are the adverse effects of Enfuvirtide?
Local injection site reactions with mild or moderate pain, erythema, induration, nodules and cysts
No drug drug interactions
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?
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
What are features of Cobicistat?
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
All HIV infected pregnant women should receive combination antiretroviral therapy during pregnancy to prevent?
Progression of their own disease and to reduce the risk of perinatal transmission
What HIV drugs should not be used during pregnancy?
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
Three or more active drugs should be used for occupational exposures. Explain the treatment process
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
What is the preferred regiment for occupational post exposure prophylaxis?
Raltegravir + Tenofovir + Emtricitabine
What vaccines are recommended for all HIV infected patients?
Live vaccines can be administered to HIV positive patients with a CD4 cell count over 200 (MMR and varicella)
What is the current recommendations for treatment regiments in naive patients?
2x NRTI + INSTI
2x NRTI + PI
What are the two INSTI based regimens?
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