HIV Pharmacology Flashcards by Madelaine Hess

achieving viral suppression currently requires the use of combination ARV regimens that generally include…

3 active drugs from 2+ drug classes

usually 2 NRTIs + INSTI

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ART typically begins with what as the backbone of therapy?

2 NRTIs (nucleoside reverse transcriptase inhibitor)

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what must occur for NRTIs to provide substrate for enzymes?

NRTI must enter the cells and become phosphorylated

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how do NRTIs exert their effects?

inhibiting incorporation of native nucleotides

2. terminating elongation of nascent proviral DNA (lacks 3’-OH group)

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what human polymerase is inhibited by some NRTIs?

human mitochondrial DNA polymerase (“y”)

human DNA polymerase a and B have low affinity for these drugs

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what four NRTIs have lower affinity for human mitochondrial DNA polymerase y?

emtricitabine
lamivudine
abacavir
tenofovir

these are the most commonly used NRTIs now

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where does the NRTI bind to terminate production?

to the DNA chain

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what is the black box warning on all NRTIs?

lactic acidosis syndrome

d/t mitochondrial toxicity

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what are the toxicities of NRTIs?

black box - lactic acidosis syndrome
peripheral neuropathy
pancreatitis
anemia
myopathy

1-3 d/t mitochondrial toxicity, 4 d/t granulocytopenia

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NRTI - interferes w/ thymidine incorporation

S-phase specific (why?)

only NRTI available IV; t1/2 is 3-4 hours

loss of limb fat, bone marrow suppression, skeletal muscle myopathy, hepatic steatosis (among others)

zidovudine / AZT

s-phase specific b/c thymidine kinase is specific to that phase of the cell cycle

inhibits HIV-1, HIV-2, HTLV-1 and HTLV-2; approved for inhibiting transmission from mom to baby

other common complaints: [malaise, myalgia, anorexia, insomnia]

fever, HA, nausea

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NRTI - interferes w/ thymidine incorporation

S-phase specific (why?)

excreted in urine; t1/2 3.5 hours; absorbed well, penetrates well (CSF)

most common serious toxicity is peripheral neuropathy, NRTI most strongly associated with lipodystrophy/fat wasting; lactic acidosis and hepatic steatosis associated

stavudine / d4T

s-phase specific b/c thymidine kinase is specific to that phase of the cell cycle

inhibits HIV-1 and HIV-2 only (AZT is in the same class, inhibits HTLV as well)

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NRTI - interferes w/ cytosine incorporation

low barrier to resistance if monotherapy; active against HBV; co-formulation w/ tenofovir provides superior combination

t1/2 39 hours; excreted in urine

one of the least toxic agents; prolonged used can lead to hyperpigmentation (palms and soles) in AAs

emtricitabine / FTC

approved for HIV-1 and HIV-2

common SE: [cough]

fever, infection, HA, N/D, rash, nasal symptoms

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NRTI - interferes w/ cytidine incorporation

low barrier to resistance if monotherapy; active against HBV; co-formulated w/ tenofovir

t1/2 12-18 hours; excreted in urine; rapid and extensive absorption

one of the least toxic agents

lamivudine / 3TC

lamivudine + dolutegravir is approved for treatment of naive patients w/ low HIV copy numbers in plasma

common SE: [neutropenia, infections of ENT, MSK pain]

fever, HA, fatigue, N/D, rash, nasal symptoms

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NRTI - the only guanosine analog

should not be given to patient w/ HLA-B*5701 genotype d/t toxicity (potentially fatal hypersensitivity syndrome)

t1/2 21 hours; not a CYP substrate, renal elimination; rapid and extensive absorption

avoid in pts w/ CAD

abacavir / ABC

not effective against HBV

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lamivudine + what drug?

is approved for treatment of naive patients w/ low HIV copy numbers in plasma

dolutegravir

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what patients should not receive abacavir, and why?

describe the presentation of a patient w/ the unique toxicity

HLA-B*5701 genotype – potentially fatal hypersensitivity syndrome

w/in 6 days - 6 weeks…

fever
abdominal pain/GI distress
mild maculopapular rash
malaise, fatigue

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which NRTIs are nucleoTIDE reverse transcriptase inhibitors?

tenofovir disproxil fumarate / TDF

tenofovir alafendamide / TAF

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NtideRTI - adenosine analog; selectively toxic

approved for HBV; co-formulated w/ emtricitabine – superior combination to other NRTIs

resistance to drug d/t single substitution in RT (K65R) - seldom

t1/2 10-50 hours; excreted in urine

nephrotoxicity w/ ATN –> Fanconi (what GFR is ideal?)
decreased bone mineral density; GI upset

tenofovir disoproxil fumarate / TDF

GFR <60

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what NRTI is associated w/ Fanconi syndrome?

tenofovir disoproxil fumarate / TDF

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a patient w/ RT K65R mutation will develop resistance to what NRTIs?

tenofovir disproxil fumarate / TDF

tenofovir alafenamide / TAF

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NRTI - adenosine analog

active against HIV-1, HIV-2, and HTLV-1 but supplanted by less toxic drugs d/t peripheral neuropathy pancreatitis, and hepatic steatosis

didanosine

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NtideRTI - adenosine analog; selectively toxic

approved for HBV; co-formulated w/ emtricitabine – superior combination to NRTIs

resistance to drug d/t single substitution in RT (K65R) - seldom

t1/2 10-50 hours; excreted in urine; lower doses administered (compared to other adenosine analog) leading to lower plasma concentrations but higher intracellular concentrations

less renal and bone toxicity than other adenosine analog

tenofovir alafenamide / TAF

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what drug class is the primary +1 active agent for treatment of HIV patients?

INSTIs

integrase strand transfer inhibitors

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what is the “-gravir” suffix for?

Study These Flashcards

INSTIs

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA) resistance develops d/t mutations in integrase t1/2 9 hours; excreted in urine and feces immune reconstitution syndrome; severe skin hypersensitivity; myopathy/rhabdomyolysis

raltegravir

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA) resistance develops d/t mutations in integrase, but has high genetic barrier to resistance t1/2 14 hours; primary metabolism is glucuronidation by UGT1A1 before renal excretion immune reconstitution syndrome; severe skin hypersensitivity; increase in liver enzymes; avoid in pregnancy (NT defects)

dolutegravir * *combination w/ abacavir and lamivudine -- Triumeq * *combination w/ rilpivirine -- Juluca ((CYP3A4 metabolism after UGT1A1 like other INSTIs..??))

what drug class is preferred for treatment of naive patients?

INSTIs

INSTI - metabolized by CYP3A4 and needs to be boosted

elvitegravir cobicistat + emtricitabine + [tenofovir alafendamide] -- Genvoya cobicistat + emtricitabine + [tenofovir disproxil fumarate] -- Stribild

INSTI - prevents strand transfer (formation of covalent bonds b/w viral and host DNA) resistance develops d/t mutations in integrase, but has high genetic barrier to resistance t1/2 16-23 hours; more readily absorbed than other INSTIs; glucuronidation by UGT1A1 and metabolized by CYP3A4, fewer DDIs b/c only affected by potent dual inhibitors of both enzymes; 1/3 excreted in urine, 2/3 excreted in feces only available as fixed dose single tablet regimen

bictegravir regimen: bictegravir + emtricitabine + tenofovir alafenamide -- Biktarvy SE: HA, D, insomnia

what are the frequent second-line +1 active agents?

protease inhibitors (PIs)

PIs are peptide-like chemicals that [non/competitively?] inhibit activity of...?

PIs competitively inhibit activity of virus aspartyl protease (homodimer) *human aspartyl proteases are monomers -- renin, pepsin, cathepsin D, etc -- not inhibited by PIs

PIs prevent proteolytic cleavage of HIV...

gag and pol precursor peptides | needed to generate RT, protease, and integrase; and various structural polypeptides of capsid

do PIs penetrate the CSF well?

no -- they are highly protein-bound (in the plasma)

PI - first one, high pill burdern t1/2 1-2 hours, poor bioavailability

saquinavir HIV-1 and HIV-2 SE: NVD; lipodystrophy (long-term)

PI - early t1/2 1.8 hours w/ SE: crystaluria/renal stones

indinavir for HIV-1 and HIV-2 no longer recommended, frequent exam question b/c of SE

PI - non-peptidic PI used off-label of post-exposure prophylaxis, current first-line choice when boosted t1/2 15 hours when boosted; 80% fecal excretion w/ 40% unchanged SE: sulfa drug so some rash, hypersensitivity; increases trigs and cholesterol, fat redistribution syndrome, immune reconstitution syndrome

darunavir HIV-1 > HIV-2 metabolized by CYP3A4 (like the entire class..?)

PI - current first-choice when boosted (w/ ritonavir, cobicistat) used in treatment of naive patients; use in treatment-experienced patients guided by PI resistance substitutions t1/2 7-9 hours but doubles when boosted; mostly excreted in feces w/ 20% unchanged SE: elevated bili, unconjugated hyperbilirubinemia not associated w/ hepatitis; fat redistribution, hypersensitivity, immune reconstitution syndrome, increased serum cholesterol, NVD, fever, cough

atazanavir HIV-1 and HIV-2

PI - only available in boosted form (w/ ritonavir) often works after failure of other PI-containing regimens t1/2 5-6 hours

lopinavir (boosted = Lop/r) *no longer go-to drug, supplanted by darunavir and azatanavir

what are the two PI CYP3A4 inhibitors?

ritonavir and cobicistat *not interchangeable

PI - only used to inhibit CYP3A4 / booster t1/2 3-5 hours SE: flushing, rash, GI upset

ritonavir

CYP3A4 inhibitor / booster -- not a PI t1/2 3-5 hours; primarily excreted in feces

cobicistat

is cobicistat a PI?

no, just a CYP3A4 inhibitor

which CYP3A4 inhibitor is excreted in feces?

cobicistat

what is the third line +1 active agent?

NNRTIs non-nucleoside reverse transcriptase inhibitors

NNTRI binds to and causes denaturation of...

reverse transcriptase

where do NNRTIs bind?

hydrophobic pocket in p6 subunit of HIV RT

are NNRTIs competitive or non-competitive antagonists?

non-competitive binding in hydrophobic pocket of HIV RT p66 subunit causes a conformational change in the enzyme

do NNRTIs require phosphorylation for activation?

are NNRTIs active against HIV-1, HIV-2, or both?

HIV-1; HIV-2 is intrinsically resistant to NNRTIs

single exposure to this NNRTI in the absence of other drugs causes resistance in 1/3 of HIV-infected people

nevirapine single substitution (K103N) in hydrophobic pocket of HIV RT p66 subunit confers resistance

NNRTI can be used in children (combination) t1/2 25-30 hours induces CYP3A4, reduces levels of OCP SE: rash, itching

nevirapine K103N renders ineffective; needs to be used in combination otherwise 1/3 patients develop resistance

NNRTI should not be added to failing regimen; co-formulation w/ emtricitabine and tenofovir helps maintain this as early selection in class; can be used in children (combination) t1/2 40-50 hours (first NNRTI for 1x/daily dosing) induces CYP3A4; reduces levels OCP SE: CNS toxicity/psychiatric; questions about teratogenicity

efavirenz other SE: dizziness, impaired concentration, vivid dreams but subside w/in a few weeks; rash, but also resolves K103N mutation renders infeffective

NNRTI approved for treatment-naive patients; less resistant to mutation than other NNRTIs t1/2 50 hours, metabolized by CYP3A4; 85% excreted in feces w/ 25% unchanged SE (children, adolescents > adults): CNS depression, HA, drowsiness; nausea; decreased cortisol; fat redistribution, immune reconstitution syndrome

rilpivirine **not susceptible to K103N mutation like nevirapine and efavirenz

NNRTI -- newest and best in class, but still in 3rd line class of +1 treatment options treatment-naive patients; switching patients on stable effective regimen to this drug novel resistance mutations t1/2 15 hours, metabolized by CYP3A4, less drug interactions than other NNRTIs; available individually or co-formulated w/ lamivudine and tenofovir

doravirine works when resistance to efavirenz or rilpivirine if pt resistant to doravirine, efavirenz or rilpivirine will work SE: low incidence of CV, CNS, GI, skin adverse effects -- better than other NNRTIs; potential for immune reconstitution syndrome

which entry blocker drug targets HIV fusion inhibitor?

enfuvirtide / T-20 T-20 peptides prevent conformational change --> prevent hairpin structure --> fusion prevented and entry blocked

entry blocker - 36 aa peptide from viral gp41 part that fuses w/ cell membrane inhibits formation of 6-helix bundle (critical for membrane fusion); inhibits infection of CD4+ by free virus particle; inhibits cell-cell transmission only treatment-experienced patients w/ viral replication expensive, administered parenterally

enfuvirtide / T-20 not active against HIV-2, only HIV-1 unique mechanism -- retains retains activity against viruses resistant to other drug classes; only resistant w/ gp41 mutation only HIV drug administered parenterally and happens 2x/daily

which entry blocker drug targets CCR5?

maraviroc gp120 anchors HIV to target cell via CD4; CCR5 stabilizes the complex, allowing gp41-mediated fusion of virus membrane w/ host membrane maraviroc binds to CCR5 to prevent gp120 binding, fusion, and entry

entry blocker - chemokine receptor antagonist, blocks binding of gp120 to CCR5 co-receptor essential, but expensive, phenotypic test required to determine tropism t1/2 10.6 hours; CYP3A4 substrate; renal elimination SE: cold-like symptoms, dizziness, GI upset seldom used

maraviroc approved for use in ART combinations for HIV caused by CCR5 (R5) trophic virus; not active against CXCR4 (X4) or mixed trophic viruses resistance d/t: shift from CCR5 to CXCR4 tropism or mutation in V3 loop of gp120 retains activity against viruses that have become resistant to other classes d/t unique MOA

HIV Pharmacology Flashcards

(58 cards)