Lecture 21: HIV Pharmacology (Exam 2) Flashcards
What are 4 common drugs used as NTRIs? (E, L, A, T)
emtricitabine, lamivudine, abacavir, tenofovir
What are 3 common drugs used as INSTIs? (R, D, B)
raltegravir, doltegravir, bictelgravir
- all end with “-gravir”
What are 2 common drugs used as Protease Inhibitors? (A and D)
azatanavir /c and darunavir /c
What are 5 common drugs used as NNRTIs? (N, E, E, R, D)
nevirapine, efavirenz, etravirine, rilpivirine, doravirine
What is the normal drug combination for achieving viral suppression via ART?
- generally 3 active drugs are given from 2+ drug classes (usually 2 NRTIs as therapy BACKBONE)
- viral load reduction below limits of assay detection usually occurs in first 12-24 weeks of therapy
What are 5 predictors of virologic ART success?
- low baseline viremia, high potency of ARV regime, tolerability, convenience, and excellent adherence to regime
What is the MOA of NRTIs? (Nucleoside Reverse Transcriptase Inhibitors)
What can NTRIs potentially inhibit in human cells that is NOT viral related?
- binds to the viral DNA chain being synthesized, competes for base pair addition, and causes termination of the product
- terminate elongation because they LACK 3’-OH group (must be PHOSPHORYLATED to work)
- some mitochondrial DNA polymerases are inhibited by NTRIs, but most human ones have low affinity
What nucleotide does each NRTI mimic? (6)
Thymidine
Cytidine
Guanosine
Adenosine
T: Zidovudine (AZT) –> first NRTI used
- and stavudine
C - emtricitabine/lamivudine
G - abacavir
A - tenofovir
What are 3 toxicities commonly associated with NRTIs? (LAS, PN, P)
Lactic Acidosis Syndrome, Peripheral Neuropathy, Pancreatitis
- all due to mitochondrial toxicity
Zidovudine and Stavudine:
Clinical Applications and Toxicities
- NRTIs (S-PHASE specific; thymidine mimic)
T: inhibits HIV-1/2 and HTLV-1/2 (only IV NRTI avail.)
- bone supp, skeletal muscle myopathy, heap. steat
S: inhibits HIV-1/2
- Peripheral neuropathy, fat wasting (why we no use)
- also lactic acidosis/hepatic steatosis
Emtricitabine and Lamivudine:
What are they, what are their clinical applications, and what are their toxicities?
What other drug are they normally given with?
- NRTIs (cytidine mimic) that are coformulated with Tenofovir; low barriers to resistance if monotherapy and long half-lives; excreted unchanged in urine
CA: used to treat HIV-1/2 and HBV
T: not very toxic, though prolonged Emtricitabine use causes hyperpigmentation in the palms and soles of African Americans
- lamivudine and doltegravir are given to treat naive pts.
Abacavir:
What is it, what is its clinical application, and what are its toxicities?
Who should it NOT be given to? (2)
- NTRI (guanosine mimic) that should NOT given to HLA-B*5701 genotype pts. or pts with coronary artery disease
CA: treats HIV but does NOT treat HBV
T: potentially fatal hypersensitivity syndrome (HLA) and causes hyperlipidemia/cardiovascular events (CAD)
Tenofovir Disoproxil Fumarate and Alafenamide:
What are they, what are their clinical applications, and what are their toxicities?
NRTI (adenosine mimic) with POOR bioavailability; long half-lives and excreted unchanged in urine
CA: HIV and HBV
T: TDF has higher chance of nephrotoxicity w/acute tubular necrosis (Fanconi Syndrome) and dec. bone mineral density than TAF (due to lower plasma conc.)
What is the MOA of INSTIs? (Integrase Strand Transfer Inhibitors)
How are they incorporated into the ARV regime?
- prevent formation of covalent bonds between viral and host DNA (“Strand Transfer” blockage)
- are primary “+1” active agent recommended for treatment of NAIVE HIV patients
Raltegravir
What is it, what is its clinical application, and what are its toxicities?
INSTI that blocks strand transfer; eliminated in urine unchanged
CA: HIV and Naive pt. treatments
- resistance due to integrase mutations
T: little clinical toxicity but can cause Immune Reconstitution Syndrome
Dolutegravir and Bictegravir:
What are they, what are their clinical applications, and what are their toxicities?
INSTIs that block strand transfer and viral DNA integration into human DNA
CA: HIV and Naive pt. treatments
- resistance due to integrase mutations
- has HIGH GENETIC BARRIER to resistance though
T: D - (immune reconstitution syndrome; avoid in pregnancy) and B - generally well tolerated but only available as fixed-dose single tablet regimen
Which INSTI is metabolized by CYP3A4 and needs to be boosted if given? What is it normally given with?
ELVITEGRAVIR
- given with cobicistat, emtiricitabine, and TDF/TAF
What is the MOA of Protease Inhibitors?
- frequently second-line “+1” active agents
- peptide-like chemicals that competitively inhibit activity of viral ASPARTYL PROTEASE by cleaving N-terminal side of Pro residues
- prevents proteolytic cleavage of HIV gag and pol precursor peptides needed to generate reverse transcriptase, protease, and integrase
How are Protease Inhibitors cleared by body and how do they interact with other drugs metabolism?
- highly protein bound in plasma and mainly cleared by hepatic clearance
- metabolized by CYP3A4 –> all inhibit metabolism of other drugs (RITONAVIR is most potent inhibitor with a low dose able to BOOST other agents)
- all are substances for P-glycoproteins (MDR1)
Saquinavir and Indinavir:
What are they, what are their clinical applications, and what are their toxicities?
Saquinavir (first protease inhibitor) and Indinavir are protease inhibitors with poor bioavailability
CA: inhibits HIV-1/2 (Saquinavir - not widely used anymore due to pill burden)
T: S (lipodystrophy - long term) and I (crystaluria and renal stones)
Darunavir:
What is it, what are its clinical applications, and what are its toxicities?
- non-peptide protease inhibitor (first choice PI when boosted)
CA: inhibits HIV-1/2 (mainly HIV-1 treatment)
T: rash and hypersensitivity (its a sulfa drug), immune reconstitution syndrome, fat redistribution syndrome
Atazanavir:
What is it, what are its clinical applications, and what are its toxicities?
- protease inhibitors (first choice PI when boosted)
CA: inhibits HIV-1/2 (also for naive patients)
T: unconjugated hyperbilirubinemia NOT associated with hepatitis, immune reconstitution syndrome, fat redistribution, hypersensitivity
Iopinavir:
What is it, what are its clinical applications, and what are its toxicities?
- protease inhibitor only available in form boosted with ritonavir
CA: inhibits HIV-1/2 (often works when other PI regimes fail, also for naive patients)
T: increases triglycerides and cholesterol
Ritonavir and Cobicistat:
What are they, what are their clinical applications, and what are their toxicities?
both are used to BLOCK CYP3A4 (Ritonavir is a protease inhibitor though) used to boost levels of protease inhibitors
CA: boost plasma drug levels (cobicistat for Azatanavir and Darunavir)
T: flushing, rash, GI, CYP3A4 effects on other drugs
What is the MOA of NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)?
When are they used and what are they NOT good for?
- inhibitor that binds to REVERSE TRANSCRIPTASE and denatures it so that the enzyme cannot produce viral DNA (binds in p66 subunit hydrophobic pocket)
- act as NON-COMPETITIVE ANTAGONISTS
- now THIRD-line “+1” active agents
- only active against HIV-1 because HIV-2 has instrinsic resistance to NNRTI
What can cause resistance to NNRTIs?
- single amino acid substitution in binding pocket
ex: single exposure to nevirapine in absence of other drugs causes resistance in 1/3 of HIV infected peoples
Nevirapine:
What is it, what are its clinical applications, and what are its toxicities?
What is a special consideration women should be aware of when taking it?
- NNRTI preventing viral DNA generation; induces CYP3A4 (use alternative forms of birth control)
CA: HIV-1 infection in adults and children
T: rash and itching
Efavirenz:
What is it, what are its clinical applications, and what are its toxicities?
What is a special consideration women should be aware of when taking it?
- NNRTI preventing viral DNA generation (first NNRTI approved); induces CYP3A4 (use alternate birth control)
CA: HIV-1 infection in adults and children
- do NOT add to failing regimen
- co-formulated w/emtricitabine/tenofovir
T: CNS toxicity and psychiatric side effect (few discontinue)
- WAS considered teratogenic (not anymore)
Etravirine:
What is it, what are its clinical applications, and what are its toxicities?
- NNRTI used to prevent viral DNA generation; induces CYP3A4
CA: HIV-1; works after mutations that disrupt other NNRTI activity
T: fat redistribution, immune reconstitution syndrome, Stevens-Johnson Syndrome
Rilpivirine and Doravirine:
What are they, what are their clinical applications, and what are their toxicities?
- NNRTIs that prevent viral DNA generation; both metabolized by CYP3A4 (Doravirine not impacted by ACID-REDUCING agents)
CA: naive patients with HIV-1 infection
T: R (fat redistribution, CNS, Endo in kids) and D (low incidence of typical problems, immune reconstitution syndrome)
Which NNRTI is considered that new “best in class”?
Doravirine
- still 3rd choice among +1 treatments
Enfuvirtide (T-20):
What is it, what are its clinical applications, and what is its major toxicity?
How must it be administered?
- HIV fusion inhibitor derived from gp41 part of HIV; inhibits CD4 infection as well as cell-cell transmission
CA: only for TREATMENT-EXPERIENCED adults
- NOT active against HIV-2
- very expensive; LAST RESORT drug
T: injection site reactions (MUST BE ADMINISTERED PARENTERALLY)
Maraviroc:
What is it, what are its clinical applications, and what is its toxicity?
When is it used?
- chemokine receptor antagonist that blocks GP120 binding to CCR5 co-receptor (blocks CCR5-trophic HIV entry into cells)
CA: for ART combos against HIV that likes CCR5, but NOT active against CXCR4 or mixed tropic HIV viruses
- expensive phenotypic test required to see tropism
T: generally well tolerated, though it is ORALLY active and a CYP3A4 substrate; also adjust renal dose due to renal elimination
used seldomly and is not recommended as initial therapy
ART and Preventing Sexual Transmission
- maintaining plasma HIV RNA levels of < 200 copies/mL prevents sexual transmission
- use alternate prevention for first 6 months of treatment and until levels are < 200 copies/mL
- MUST MAINTAIN HIGH LEVELS OF ART ADHERENCE; are still vulnerable to other STIs
ART and Treatment Failure
- drug-resistance testing while patient is taking failing regimen or < 4 weeks after discontinuation
- new regimen should include at least 2, if not 3, fully active agents
DO NOT ADD SINGLE antiretroviral agent to failing regimen
ART and Child-Bearing Potential/Pregnancy
What drug has been shown to cause neural tube defects in infants born to mothers on ART?
- pregnancy test should be performed for those of childbearing age PRIOR to ART initiation
- inc. risk of neural tube defects in infants born to mothers taking DOLUTEGRAVIR
- focus to maintain viral load below limit of detection to reduce risk of transmission to fetus/newborn
