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SBL Final > Pharmacology of HIV > Flashcards

Pharmacology of HIV Flashcards

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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
what is the current NRTI of choice and why?
emtricitabine (FTC) and lamivudine (3TC)--> it has a long intracellular half-life (39 hours and 12-18 hours respectively)
26
what is one of the least toxic antiretroviral agents?
emtricitabine (FTC)
27
what does prolonged use of emtricitabine (FTC) lead to?
hyperpigmentation of skin, especially in palms and soles--> more common in african americans
28
What is lamivudine (3TC)'s MOA?
it is a nucleoside reverse transcriptase inhibitor that interferes with cytidine incorporation
29
what are the clinical applications of lamivudine (3TC)?
HIV-1 and HIV-2
30
what should lamivudine not be used for?
HBV
31
how would you treat a naive patient with low HIV copy numbers in plasma?
dual agent combination of lamivudine and dolutegravir
32
what are the toxicities associated with lamivudine (3TC)?
it is one of the least toxic antiretroviral agents--> no significant adverse effects but some minor ones
33
what is the MOA of abacavir (ABC)?
it is a nucleoside reverse transcriptase inhibitor--> it is the only guanosine analog
34
what are the clinical applications of abacavir (ABC)?
HIV infection in combination with other drugs
35
when should abacavir (ABC) not be given?
should not be given to a patient with HLA-B*5701 genotype due to toxicity--> hypersensitivity
36
is abacavir (ABC) effective against HBV?
no
37
what are the toxicities associated with abacavir (ABC)?
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
38
what is the mechanism of action of tenofovir disoproxil fumarate (TDF)?
it is a nucleotide reverse transcriptase inhibitor- adenosine analog; only nucleotide used--> the parent compound has a very poor bioaavailability
39
what are the clinical applications for tenofovir disoproxil fumarate (TDF)?
HIV and HBV
40
resistance to tenofovir disoproxil fumarate (TDF) is due to what?
a single substitution in reverse transcriptase (K65R)
41
what are the atypical adverse effects associated with tenofovir disoproxil fumarate (TDF)?
nephrotoxicity with acute tubular necrosis leading to Fanconi syndrome; also see decreased bone mineral density
42
what is didanosine?
an adenosine analog active against HIV-1 HIV-2 and HTLV-1
43
what is the MOA of tenofovir alafenamide (TAF)?
it is a nucleoside reverse transcriptase inhibitor adenosine analog; only the nucleotide is used--> parent compound has very poor bioavailability
44
what are the toxicities associated with tenofovir alafenamide (TAF)?
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
which combination of NRTIs is arguably superior to other combinations?
emtricitabine and tenofovir
46
what are INSTIs?
integrase strand transfer inhibitors- they are the primary +1 active agents now recommended for treatment of naive HIV patients
47
what was the first developed INSTI?
raltegravir
48
all INSTI drugs end in what?
-gravir
49
What is the MOA of raltegravir?
it prevents the formation of covalent bonds between the viral and host DNA--> a process known as strand transfer
50
what are the effects of raltegravir?
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
what are the clinical applications of raltegravir?
it is approved for ART combinations; now preferred for treatment-naive patients
52
how does resistance towards raltegravir develop?
due to mutations in integrase
53
what is a major con of raltegravir?
it is not available in the single table co-formulations that decrease pill burder
54
what toxicities can be seen with raltegravir?
immune reconstitution syndrome
55
what is the MOA of dolutegravir?
it prevents formation of covalent bonds between viral and host DNA--> which is a process known as strand transfer
56
what is the effect of dolutegravir?
it blocks chromosomal integration of viral DNA
57
can resistance develop against dolutegravir?
yes- due to mutations in integrase, but it has a high genetic barrier to resistance
58
what is the 1st choice of treatments for naive HIV patients?
dolutegravir and 3TC combination
59
what are the toxicities associated with dolutegravir?
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
what is elvitegravir?
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
what is the MOA of bictegravir?
it prevents the formation of covalent bonds between viral and host DNA--> process known as strand transfer
62
what are the effects of bictegravir?
it blocks chromosomal integration of viral DNA (i.e. it blocks HIV integrase)
63
can resistance develop against bictegravir?
yes- due to mutations in integrase, but has a high genetic barrier to resistance
64
what is special about the pharmacokinetics of bictegravir?
it is more soluble/readily absorbed than any other INSTI
65
how is bictegravir available?
only available as a fixed-dose 1x/day single tablet regimen of BIC/TAF/FTC
66
what are the toxicities associated with bictegravir?
generally well tolerated, but new reports show that is also causes weight gain
67
why is there a weight gain associated with INSTIs?
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
what is important to note about protease inhibitors?
they are no frequent second-line +1 active agents
69
what is the general MOA of protease inhibitors?
they competitively inhibit activity of virus aspartyl protease; they prevent proteolytic cleavage of HIV gag and pol precursor peptides
70
what is the cleavage of HIV gag and pol precurosr peptides needed for?
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
protease inhibitors are cleared how?
mainly by hepatic clearance (via oxidation); metabolized primarily by CYP3A4--> all inhibit metabolism of other drugs
72
what is by far the most potent protease inhibitor?
ritonavir
73
protease inhibitors are all substrates for what?
P-glycoprotein (PGP)--> so they can influence/ be influenced by other drugs transported via this mechanism
74
the speed of resistance development of protease inhibitors is?
intermediate- between NNRTI (fast) and NRTI (slow)
75
what was the first protease inhibitor discovered?
saquinavir
76
what are the clinical applications of saquinavir?
it inhibits both HIV-1 and HIV-2; it is not longer widely used in developed world due to pill burden
77
what are the pharmacokinetics like of saquinavir?
poor bioavailability
78
what are the toxicities associated with saquinavir?
GI distress, nausea, vomiting, diarrhea; long term--> lipodystrophy
79
what was an early protease inhibitor that is no longer recommended due to its atypical toxicities? and what was this toxicity?
indinavir; unique crystalluria/renal stones
80
what are the clinical applications of Darunavir (DRV)?
inhibits both HIV-1 and HIV-2, but it is indicated for HIV-1 treatment
81
what is a current protease inhibitor of choice when boosted?
darunavir (DRV)
82
what are the toxicities associated with darunavir (DRV)?
it's a sulfa drug- so some rash or hypersensitivity; hyperlipidemia, and increased cardiovascular risk
83
what is the MOA of atazanavir (ATV)?
it is an azapeptide protease inhibitor, a current first choice PI when boosted
84
what are the clinical applications of atazanavir (ATV)?
inhibits both HIV-1 and HIV-2; treatment naive patients; use in treatment-experienced patients guided by protease inhibitor resistance substitutions
85
what are some toxicities associated with atazanavir (ATV)?
jaundice, unconjugated hyperbilirubinemia, cholelithiasis, nephrolithiasis; PR prolongation
86
what is the MOA of lopinavir?
it is a protease inhibitor only available in form boosted with ritonavir (Lop/r)
87
what are the clinical applications of lopinavir?
inhibits both HIV-1 and HIV-2; often works after failure of other PI-containing regimens
88
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?
darunavir and atazanavir
89
what is the MOA of ritonavir?
it is a protease inhibitor but used only to block CYP3A4
90
what is the effect of ritonavir?
it boosts levels of other more potent protease inhibitors
91
what are the clinical applications of ritonavir?
to boost plasma levels of other drugs
92
what are the pharmacokinetics of ritonavir?
it is a potent CYP3A4 inhibitor
93
what is the MOA of cobicistat?
it is a CYP3A4 inhibitor
94
what is the effect of cobicistat?
it is used to boost levels of protease inhibitors
95
what are the clinical applications of cobicistat?
used to boost plasma levels of azatanavir and darunavir; not considered a replacement for ritonavir in instances where ritonavir is used

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