Pharm of HIV/AIDS Flashcards
What does ART typically being with as the backbone of therapy?
2 NRTIs (Nucleoside Reverse Transcriptase Inhibitors)
How do NRTIs provide substrate for the enzymes?
Must enter the cell and become phosphorylated
NRTI exert their effects by?
Inhibiting incorporation of native nucleotides and by terminating elongation of proviral DNA
What do NRTIs selective toxicity depend on?
Ability to inhibit HIV reverse transcriptase without inhibiting host cell DNA polymerase
Which human DNA polymerase is inhibited by some NRTI?
The human mitochondrial DNA polymerase (γ)
Which NRTI have the lowest affinity for DNA polymerase γ?
1) Emtricitabine
2) Lamivudine
3) Abacavir
4) Tenofovir
Which nucleotide does the NRTI zidovudine (AZT) and stavudine (d4T) compete with?
Which does emtricitabine and Lamivudine compete with?
Which does abacavir compete with?
Which does tenofovir compete with?
1) Thymidine
2) Cytidine
3) Guanosine
4) Adenosine
What mitochondrial toxicities can NRTIs cause?
1) Lactic acidosis syndrome
2) Peripheral neuropathy
3) Pancreatitis
Which NRTI is the most potent in active cells since thymidine kinase is an S Phase specific enzyme?
Zidovudine
What are the clinical applications of zidovudine besides inhibiting HIV-1 and HIV-2?
Inhibits HTLV-1 and HTLV-2
What NRTI similarly interferes with thymidine incorporation like AZT but is rarely used now because of its toxicities?
Stavudine
What are potential toxicities of stavudine?
1) Peripheral neuropathy
2) Lipodystrophy/fat wasting
3) Lactic acidosis
Bone marrow suppression, skeletal muscle myopathy, and hepatic steatosis are all potential toxicities of?
Zidovudine
The NRTI with the most common serious toxicity of peripheral neuropathy along with being the most strongly associated with lipodystrophy/fat wasting is?
Stavudine
Which NRTIs MOA is to interfere with cytosine incorporation?
Emtricitabine (FTC) and Lamivudine (3TC)
Both emtricitabine and lamivudine have a low barrier to resistance if?
Besides HIV what are they also active against?
They are co-formulated with what other drug?
How are their half-lives compared to other NRTIs?
1) Used in monotherapy
2) HBV
3) Tenofovir
4) Long
What are potential toxicities of emtricitabine and lamivudine?
They are one of the least toxic ART agents but prolonged use of emtricitabine could lead to hyperpigmentation of palms and soles
What NRTI is the only guanosine analog?
Abacavir (ABC)
Abacavir should not be given to patients with what genotype due to a potentially fatal hypersensitivity syndrome?
Also, it is not effective against what virus?
1) HLA-B*5701
2) HBV
Which NRTIs are analogs to adenosine?
1) Tenofovir disoproxil fumarate (TDF)
2) Tenofovir alafenamide (TAF)
How do the tenofovir drugs differ from other NRTIs?
They are nucleotide-RTI not nucleoside-RTI
What other virus are TDF and TAF approved for?
HBV
Which tenofovir has less renal and bone toxicity because plasma concentrations are lower?
Tenofovir alafenamide
What is the best combination of NRTI therapy?
Emtricitabine and tenofovir
Why aren’t emtricitabine and lamivudine combined?
Why aren’t tenofovir disoproxil fumarate and tenofovir alafenamide combined?
1) Both cysteine analogs
2) Both prodrug formulations of the same active agent
What is now recommended for use in treatment of naïve patients unless the HIV load is high?
lamivudine in combination with dolutegravir
Integrase Strand Transfer Inhibitors are the primary “+1” active agents now recommended
for?
Treatment of naïve HIV patients
All INSTI drugs names end with?
-gravir
What is the MOA of the INSTI drugs raltegravir, dolutegravir, and bictegravir?
Blocks strand transfer, which is the process that prevents formation of covalent bonds between viral and host DNA
Resistance can develop in INSTI drugs due to mutations in?
However which INSTI drugs have high genetic barrier to resistance?
1) Integrase
2) Dolutegravir and bictegravir
While INSTI drugs are generally well tolerated which one should you avoid in pregnancy since there is evidence of increased neural tube defects?
Dolutegravir
Which INSTI drugs is primary metabolized by UGR1A1 glucuronidation?
Which is glucuronidated by UGT1A1 and metabolized by CYP3A4?
1) Dolutegravir
2) Bictegravir
Which INSTI drug is only available as a fixed dose single tablet regimen?
Bictegravir
What are now frequent second-line “+1” active agents?
Protease Inhibitors
Protease inhibitors are peptide-like chemicals that?
Competitively inhibit activity of virus aspartyl protease
Virus aspartyl protease cleaves the N-terminal side of?
Proline residues
Protease inhibitors prevent proteolytic cleavage of what HIV precursor peptides?
These peptides are needed to generate?
1) gag and pol
2) Reverse transcriptase, protease, and integrase
Why are protease inhibitors unable to enter the CSF?
They are highly protein bound
Protease inhibitors are metabolized primarily by?
How do they affect the metabolism of other drugs?
1) CYP3A4
2) Inhibit
What is by far the most potent CYP3A4 inhibitor making it the reason a low dose of it is able to ”boost” other agents?
ritonavir
All protease inhibitors are substrates for?
P-glycoprotein (MDR1)
While no longer in use, which protease inhibitor causes unique crystalluria/renal stones?
indinavir
Which protease inhibitor is a sulfa drug so it causes some rash and hypersensitivity reactions?
darunavir
Which protease inhibitor causes unconjugated hyperbilirubinemia not associated with hepatitis?
atazanavir
Darunavir and atazanavir are both current PI of first choice when boosted with?
Why must they be boosted?
1) Ritonavir or cobicistat
2) Because they are metabolized by CYP3A4
Although it has been replaced by darunavir and atazanavir, what PI often worked after failure of other PI-containing regimens?
Lopinavir
Which CYP3A4 inhibitor is also a protease inhibitor but its only function is to block CYP3A4?
What is just a CYP3A4 inhibitor?
1) ritonavir
2) cobicistat
What is the MOA of the ritonavir and cobicistat?
Boost levels of protease inhibitors
What are the third line “+1” agents?
What are their MOA?
1) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
2) Prevents generation of DNA from viral RNA in host cells
What does NNRTI bind to?
Therefore, NNRTI function as what type of antagonist?
1) Hydrophobic pocket in p66 subunit of HIV reverse transcriptase
2) Non-competitive
NNRTI is only active against which HIV subtype?
Why is it not active against the other type?
1) HIV-1
2) HIV-2 is intrinsically resistant
What type of substitution in the pocket of HIV reverse transcriptase can cause drug resistance?
A single exposure to what drug in the absence of other drugs causes resistance in 1/3 of HIV infected patients?
1) Single aa substitution
2) nevirapine
Which NNRTI induces CYP3A4?
It reduces the level of what form of birth control?
1) nevirapine, efavirenz, etravirine
2) Oral contraceptives
Which NNRTI is co-formulated with emtricitabine and tenofovir?
efavirenz
Which NNRTI is unique in that it still works after mutations that disrupt activity of other NNRTI?
This feature made it approved for which HIV-1 patients?
1) etravirine
2) Treatment-experienced patients
Which NNRTI most significant adverse effect is CNS toxicity/ psychiatric side effects but they typically resolve in a few weeks?
efavirenz
Which NNRTI is not susceptible to common mutations that renders efavirenz and nevirapine ineffective?
What is this mutation?
1) rilpivirine
2) K103N
Which NNRTI are metabolized by CYP3A4?
1) rilpivirine
2) doravirine
Which NNRTI differs from other NNRTI in that it works when there is resistance to efavirenz or rilpivirine?
This drug is also unlike other drugs that are metabolized by CYP3A4 in that it isn’t impacted by?
1) doravirine
2) acid reducing agent
Which NNRTI has adverse effects more common in children and adolescents such as depression, decreased cortisol, and nasuea?
rilpivirine
What HIV fusion inhibitor is a 36 aa peptide derived from viral gp41 part that fuses with cell membrane?
enfuvirtide (aka T-20)
Enfuvirtide inhibits the formation of a 6-helix bundle that is critical for?`
Membrane fusion
Which HIV subtype is enfuvirtide not active against?
It is the only HIV drug that is administered?
1) HIV-2
2) Parenterally
What HIV entry blocker is a chemokine receptor antagonist that blocks binding of GP120 to CCR5 coreceptor?
maraviroc
What is maraviroc approved for use?
What is it not active against?
1) HIV caused by CCR5 trophic virus
2) CXCR4 or mixed trophic viruses
With ART, maintaining a plasma HIV RNA of how many copies/mL or lower prevents sexual transmission of HIV to their partners and reduces risk of transmission to the fetus and newborn during pregnancy?
Less than 200 copies/mL
