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SBL Final > Pharmacology of HIV > Flashcards

Pharmacology of HIV Flashcards

1
Q

achieving viral suppression currently requires what?

A

the use of combination ARV regimens that generally include 3 active drugs from more than 2 drug classes

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2
Q

after initiation of effective ARV, viral load reduction to below limits of assay detection usually occurs when?

A

within the first 12-24 weeks of therapy

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3
Q

5 predictors of virologic success include?

A

low baseline viremia, high potency of the ARV regimen, tolerability of the regimen, convenience of the regimen, and excellent adherence to the regimen

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4
Q

ART typically begins with what?

A

2 nucleoside reverse transcriptase inhibitors (NRTI) as the backbone of therapy

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5
Q

once the viral RNA is inside the cell, what happens?

A

it is reverse transcribed into DNA by reverse transcriptase

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6
Q

what is the general MOA of nucleoside reverse transcriptase inhibitors?

A

they compete for base pair addition to the growing chain and the process of adding one of them on lead to DNA chain termination; NRTIs exhibit their effects by inhibiting incorporation of native nucleotides and by terminating elongation of nascent proviral DNA

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7
Q

the NRTI must enter the cells and what in order to provide substrate for the enzymes?

A

they must become phosphorylated

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8
Q

the selective toxicity of NRTIs depend on what?

A

depend on their ability to inhibit HIV reverse transcriptase without inhibiting host cell DNA polymerase

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9
Q

human DNA polymerases alpha and beta have low affinity for NRTIs, however, human mitochondrial DNA polymerase (gamma) is inhibited by some NRTI; which NRTIs have a lower affinity for DNA polymerase gamma? (4)

A

emtricitabine, lamivudine, abacavir, and tenofovir

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10
Q

what are the NRTIs that are now most used?

A

emtricitabine, lamivudine, abacavir, and tenofovir

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11
Q

what are 5 toxicities commonly associated with NRTI use?

A

lactic acidosis syndrome, peripheral neuropathy, pancreatitis, anemia, myopathy

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12
Q

what is the mechanism of action of zidovudine (AZT)?

A

it is a nucleoside reverse transcriptase inhibitor that interferes with thymidine incorporation

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13
Q

what was the first antiretroviral drug discovered?

A

zidovudine (AZT)

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14
Q

zidovudine is the most potent in what cells? and why?

A

most potent in active cells since thymidine kinase is an S-phase specific enzyme

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15
Q

what are the clinical applications of zidovudine (AZT)?

A

it inhibits HIV-1, HIV-2, HTLV-1, and HTLV-2

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16
Q

what is the t1/2 of zidovudine (AZT)?

A

3-4 hours

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17
Q

what is the only NRTI that is available as an IV?

A

zidovudine (AZT)

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18
Q

what are 3 atypical adverse effects of zidovudine (AZT)?

A

bone marrow suppression, skeletal muscle myopathy, and hepatic steatosis

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19
Q

what is stavudine (d4T)?

A

a nucleoside reverse transcriptase inhibitor that interferes with thymidine incorporation rarely used now because of its toxicities

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20
Q

what are the clinical applications of stavudine (d4T)?

A

it inhibits HIV-1 and HIV-2

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21
Q

what are the toxicities associated with stavudine (d4T)?

A

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

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22
Q

what is the MOA of emtricitabine (FTC)?

A

it is a nucleoside reverse transcriptase inhibitor that interferes with cytosine incorporation

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23
Q

what are the clinical applications of emtricitabine (FTC)?

A

HIV-1 and HIV-2

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24
Q

when should emtricitabine (FTC) not be used?

A

should not be used for HBV unless TAF or TDF are also administered

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25
Q

what is the current NRTI of choice and why?

A

emtricitabine (FTC) and lamivudine (3TC)–> it has a long intracellular half-life (39 hours and 12-18 hours respectively)

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26
Q

what is one of the least toxic antiretroviral agents?

A

emtricitabine (FTC)

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27
Q

what does prolonged use of emtricitabine (FTC) lead to?

A

hyperpigmentation of skin, especially in palms and soles–> more common in african americans

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28
Q

What is lamivudine (3TC)’s MOA?

A

it is a nucleoside reverse transcriptase inhibitor that interferes with cytidine incorporation

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29
Q

what are the clinical applications of lamivudine (3TC)?

A

HIV-1 and HIV-2

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30
Q

what should lamivudine not be used for?

A

HBV

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31
Q

how would you treat a naive patient with low HIV copy numbers in plasma?

A

dual agent combination of lamivudine and dolutegravir

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32
Q

what are the toxicities associated with lamivudine (3TC)?

A

it is one of the least toxic antiretroviral agents–> no significant adverse effects but some minor ones

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33
Q

what is the MOA of abacavir (ABC)?

A

it is a nucleoside reverse transcriptase inhibitor–> it is the only guanosine analog

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34
Q

what are the clinical applications of abacavir (ABC)?

A

HIV infection in combination with other drugs

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35
Q

when should abacavir (ABC) not be given?

A

should not be given to a patient with HLA-B*5701 genotype due to toxicity–> hypersensitivity

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36
Q

is abacavir (ABC) effective against HBV?

A

no

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37
Q

what are the toxicities associated with abacavir (ABC)?

A

it has a unique/ potentially fatal hypersensitivity syndrome ; also at risk for hyperlipidemia and cardiovascular events so should also be avoided in patients with CAD

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38
Q

what is the mechanism of action of tenofovir disoproxil fumarate (TDF)?

A

it is a nucleotide reverse transcriptase inhibitor- adenosine analog; only nucleotide used–> the parent compound has a very poor bioaavailability

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39
Q

what are the clinical applications for tenofovir disoproxil fumarate (TDF)?

A

HIV and HBV

40
Q

resistance to tenofovir disoproxil fumarate (TDF) is due to what?

A

a single substitution in reverse transcriptase (K65R)

41
Q

what are the atypical adverse effects associated with tenofovir disoproxil fumarate (TDF)?

A

nephrotoxicity with acute tubular necrosis leading to Fanconi syndrome; also see decreased bone mineral density

42
Q

what is didanosine?

A

an adenosine analog active against HIV-1 HIV-2 and HTLV-1

43
Q

what is the MOA of tenofovir alafenamide (TAF)?

A

it is a nucleoside reverse transcriptase inhibitor adenosine analog; only the nucleotide is used–> parent compound has very poor bioavailability

44
Q

what are the toxicities associated with tenofovir alafenamide (TAF)?

A

it is generally very well tolerated with few adverse effects; there is less renal and bone toxicity than seen in TDF bc plasma concentration is lower; it causes the most weight gain among all of the NRTIs, but less than the INSTIs

45
Q

which combination of NRTIs is arguably superior to other combinations?

A

emtricitabine and tenofovir

46
Q

what are INSTIs?

A

integrase strand transfer inhibitors- they are the primary +1 active agents now recommended for treatment of naive HIV patients

47
Q

what was the first developed INSTI?

A

raltegravir

48
Q

all INSTI drugs end in what?

A

-gravir

49
Q

What is the MOA of raltegravir?

A

it prevents the formation of covalent bonds between the viral and host DNA–> a process known as strand transfer

50
Q

what are the effects of raltegravir?

A

it blocks strand transfer (which is normally what allows viral DNA to remain in host for prolonged periods of inactivity); it lowers the plasma viral RNA faster than NNRTI efavirenz

51
Q

what are the clinical applications of raltegravir?

A

it is approved for ART combinations; now preferred for treatment-naive patients

52
Q

how does resistance towards raltegravir develop?

A

due to mutations in integrase

53
Q

what is a major con of raltegravir?

A

it is not available in the single table co-formulations that decrease pill burder

54
Q

what toxicities can be seen with raltegravir?

A

immune reconstitution syndrome

55
Q

what is the MOA of dolutegravir?

A

it prevents formation of covalent bonds between viral and host DNA–> which is a process known as strand transfer

56
Q

what is the effect of dolutegravir?

A

it blocks chromosomal integration of viral DNA

57
Q

can resistance develop against dolutegravir?

A

yes- due to mutations in integrase, but it has a high genetic barrier to resistance

58
Q

what is the 1st choice of treatments for naive HIV patients?

A

dolutegravir and 3TC combination

59
Q

what are the toxicities associated with dolutegravir?

A

there has been a recent recognition of significant weight gain in some; should also avoid if pregnant as there is evidence of neural tube defects

60
Q

what is elvitegravir?

A

it is an INSTI that is metabolized by CYP3A4 and needs to be boosted–> will likely contribute to a reduction in its use over the next few years

61
Q

what is the MOA of bictegravir?

A

it prevents the formation of covalent bonds between viral and host DNA–> process known as strand transfer

62
Q

what are the effects of bictegravir?

A

it blocks chromosomal integration of viral DNA (i.e. it blocks HIV integrase)

63
Q

can resistance develop against bictegravir?

A

yes- due to mutations in integrase, but has a high genetic barrier to resistance

64
Q

what is special about the pharmacokinetics of bictegravir?

A

it is more soluble/readily absorbed than any other INSTI

65
Q

how is bictegravir available?

A

only available as a fixed-dose 1x/day single tablet regimen of BIC/TAF/FTC

66
Q

what are the toxicities associated with bictegravir?

A

generally well tolerated, but new reports show that is also causes weight gain

67
Q

why is there a weight gain associated with INSTIs?

A

the combination with HIV and DTG or RAL led to effects in adipose tissue including: increased adipogenesis, increased ECM production, decreased adiponectin, and increased insulin resistance

68
Q

what is important to note about protease inhibitors?

A

they are no frequent second-line +1 active agents

69
Q

what is the general MOA of protease inhibitors?

A

they competitively inhibit activity of virus aspartyl protease; they prevent proteolytic cleavage of HIV gag and pol precursor peptides

70
Q

what is the cleavage of HIV gag and pol precurosr peptides needed for?

A

to generate reverse transcriptase, protease, and integrase and various structural polypeptides of the capsid needed for the metamorphosis of HIV particles into their mature infectious form

71
Q

protease inhibitors are cleared how?

A

mainly by hepatic clearance (via oxidation); metabolized primarily by CYP3A4–> all inhibit metabolism of other drugs

72
Q

what is by far the most potent protease inhibitor?

A

ritonavir

73
Q

protease inhibitors are all substrates for what?

A

P-glycoprotein (PGP)–> so they can influence/ be influenced by other drugs transported via this mechanism

74
Q

the speed of resistance development of protease inhibitors is?

A

intermediate- between NNRTI (fast) and NRTI (slow)

75
Q

what was the first protease inhibitor discovered?

A

saquinavir

76
Q

what are the clinical applications of saquinavir?

A

it inhibits both HIV-1 and HIV-2; it is not longer widely used in developed world due to pill burden

77
Q

what are the pharmacokinetics like of saquinavir?

A

poor bioavailability

78
Q

what are the toxicities associated with saquinavir?

A

GI distress, nausea, vomiting, diarrhea; long term–> lipodystrophy

79
Q

what was an early protease inhibitor that is no longer recommended due to its atypical toxicities? and what was this toxicity?

A

indinavir; unique crystalluria/renal stones

80
Q

what are the clinical applications of Darunavir (DRV)?

A

inhibits both HIV-1 and HIV-2, but it is indicated for HIV-1 treatment

81
Q

what is a current protease inhibitor of choice when boosted?

A

darunavir (DRV)

82
Q

what are the toxicities associated with darunavir (DRV)?

A

it’s a sulfa drug- so some rash or hypersensitivity; hyperlipidemia, and increased cardiovascular risk

83
Q

what is the MOA of atazanavir (ATV)?

A

it is an azapeptide protease inhibitor, a current first choice PI when boosted

84
Q

what are the clinical applications of atazanavir (ATV)?

A

inhibits both HIV-1 and HIV-2; treatment naive patients; use in treatment-experienced patients guided by protease inhibitor resistance substitutions

85
Q

what are some toxicities associated with atazanavir (ATV)?

A

jaundice, unconjugated hyperbilirubinemia, cholelithiasis, nephrolithiasis; PR prolongation

86
Q

what is the MOA of lopinavir?

A

it is a protease inhibitor only available in form boosted with ritonavir (Lop/r)

87
Q

what are the clinical applications of lopinavir?

A

inhibits both HIV-1 and HIV-2; often works after failure of other PI-containing regimens

88
Q

boosted lopinavir was a go-to drug choice for a few years in the past, but no longer- it has been supplanted by what two drugs?

A

darunavir and atazanavir

89
Q

what is the MOA of ritonavir?

A

it is a protease inhibitor but used only to block CYP3A4

90
Q

what is the effect of ritonavir?

A

it boosts levels of other more potent protease inhibitors

91
Q

what are the clinical applications of ritonavir?

A

to boost plasma levels of other drugs

92
Q

what are the pharmacokinetics of ritonavir?

A

it is a potent CYP3A4 inhibitor

93
Q

what is the MOA of cobicistat?

A

it is a CYP3A4 inhibitor

94
Q

what is the effect of cobicistat?

A

it is used to boost levels of protease inhibitors

95
Q

what are the clinical applications of cobicistat?

A

used to boost plasma levels of azatanavir and darunavir; not considered a replacement for ritonavir in instances where ritonavir is used

SBL Final (21 decks)

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