Dr. Stahelin HIV Flashcards

1
Q

Genetic barrier of resistance

A

the number of mutations in an antiretroviral therapeutic target that are required to confer a clinically meaningful loss of susceptibility to that drug

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2
Q

Maraviroc

A
  • HIV entry inhibitor
  • selective human CCR5 antagonist. Binds to CCR5 on human cells and causes a conformational change that prevents gp120 binding.
  • Has no effect on cell surface levels on CCR5 or on CCR5 signaling
  • can only be used in patients with HIV strains that utilize CCR5
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3
Q

Enfuviritide

A
  • Fusion inhibitor
  • binds to HIV GP41 and blocks GP41 conformation change needed for fusion.
  • 36 amino acid peptide that inhibits fusion of virus membrane with cell membrane
  • only active against HIV-1
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4
Q

NRTI

A
  • are nucleoside analogs that lack the 3’ OH (sometimes called false nucleotides)
  • 2 effects: competitive inhibitor of RT and DNA chain terminator to inhibit elongation. They do this by blocking endogenous nucleotides from being formed.
  • interfere with 1st and 2nd strand DNA synthesis
  • active against HIV-1 and HIV-2
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5
Q

NNRTI

A
  • bind directly to site on RT- hydrophobic pocket near the catalytic site but distinct from that of NRTIs. This binding affects the flexibility of enzyme NNRTIs DO NOT COMPETE with nucleotides for binding (non-competitive inhibitors)
  • block RNA and DNA-dependent DNA polymerase activities
  • blocks polymerization
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6
Q

Integrase inhibitors

A

inhibits the insertion of HIV DNA into the human genome by blocking the strand transfer step.

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7
Q

Protease inhibitors

A

Protease inhibitors are transition state mimetics that can be peptidomimetic (unable to be cleaved) or non-peptide mimetic that work by binding to proteolytic enzymes and blocking their ability allow maturation of the budding HIV particle.

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8
Q

How NRTIs are activated metabolically before enzyme inhibitor can occur

A

all NRTIs must be activated by cellular kinases to triphosphate forms (or equivalent) to be picked up by DNA polymerases. They compete with endogenous nucleotides for DNA polymerase.

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9
Q

structural differences of endogenous nucleosides and nucleoside analogs used in NRTIs

A

Nucleosides contain a 3’ OH group on the sugar backbone. NRTIs lack a 3’ OH is replaced with sulfur, double bond, no additional group, or like tenofovir acyclic structure. And can have additional moieties/functional groups in the nucleotide group such as fluorine or tricyclic ring.

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10
Q

Activation of Tenofovir and differences in structure compared to other NRTIs and how this effects half life.

A

-tenofovir disoproxilfumarate (TDF) is a pro-drug that is converted into tenofovir (TFV). It is an acyclic nucleoside phosphonate analog of adenosine that requires 2 phosphorylation steps instead of 3. Its phosphonate group cannot be cleaved by cellular esterases making it catabolically stable and causing a longer intracellular half-life.

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11
Q

TAF advantages over TDF

A
  • lower plasma concentrations
  • increased accumulation in lymphocytes
  • fewer side effects
  • better accumulation in lymph nodes and higher intracellular concentrations
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12
Q

Why tenofovir and emtricitabine are preferred NRTIs for initial ART

A
  • TFV has a long intracellular half-life
  • once-daily dosing
  • equivalent efficacy to other NRTI combinations
  • less fat maldistribution
  • different resistant mutation profiles
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13
Q

Hypersensitivity reaction caused by Abacavir

A
  • potentially fatal hypersensitivity reaction
  • symptoms: malaise, dizziness, headache, GI disturbances
  • highly associated with HLA-B*507 allele, and testing for this polymorphism is recommended before initiating treatment with abacavir
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14
Q

Resistance to RT inhibitors

A
  • Discriminatory and excision mutations
  • mutations are mainly near the RT active site but can occur at more distant locations
  • mutations can either help RT to distinguish between normal dNTPs or NRTIs or promote the removal of NRTIs after they’ve been incorporated into the growing chain.
  • individual NRTIs have a low barrier of resistance
  • some mutations confer resistance to a subset of NRTIs but make RT more susceptible to inhibition of others, this is why NRTIs are preferred in combination to take advantage of this phenomena
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15
Q

NNRTI mechanism of action

A

bind on RT at the hydrophobic pocket near the catalytic site and this binding affect the flexibility of RT and the catalytic site, thus preventing the uptake of endogenous nucleosides. NNRTIs do NOT compete with nucleotides for binding (non-competitive inhibitors)

  • do not have to be phosphorylated like NRTIs
  • block RNA and DNA-dependent polymerase activities
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16
Q

Difference of Ertavirine and Rilviripine to first-generation NNRTIs

A

Etravirine and Rilviriprine are second generation NNRTIs that are diaryl-pyrimidine-based molecule and was designed to be inherently flexible. Can bind to multiple orientations and binds to mutant strains that are resistant to other NNRTIs`

17
Q

Resistance to NNRTIs

A

a single mutation in the binding site - cannot cross-resistance to other RT inhibitors

18
Q

Raltegravir, Dolutegravir, Elvitegrvair

A
  • integrase inhibitor
  • integrase uses divalent metal ions to catalyze insertion to host DNA, which is coordinated by 3 amino acids in the active site. Raltegravir chelates both metal ions and stabilizes enzyme-DNA complex to block strand transfer
19
Q

Integrase resistance

A
  • caused by primary mutations that reduce INI susceptibility. Secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness.
  • low genetic barrier (dolutegravir higher genetic barrier)
  • extensive but incomplete cross-resistance (dolutegravir less affected)
20
Q

Non-cleavable bonds in atazanavir and darunavir

A

the hydroxyl group in the middle

21
Q

How does the structure of tipranavir, a non-peptidomimetic protease inhibitor differ from other protease inhibitors?

A

its structure retains activity against proteases in highly treated patients, including those resistant to drauvanir.

22
Q

Resistance to protease inhibitors

A
  • the highest genetic barrier of all ART
  • most mutations occur in or near the substrate cleft of the protease. Some can occur at distant sites and act indirectly
  • multiple mutations are usually needed to confer a high level of resistance.
  • DRV retains activity against most PI-resistant mutant proteases
23
Q

How do darunavir and atazanavir differ from other protease inhibitors with regards to PI resistance mutations?

A
  • DRV retains activity against most PI-resistant mutant proteases
  • ATV has a different resistant mutation profile. confers resistance to ATV but increases susceptibility of other PIs
24
Q

Unique features of DRV

A

-two unique features: make extensive hydrogren bonds with protease backbone and inhibits protease dimerization. The peptide backbones of both wildtype and mutant HIV protease have very similar structures. DRV hydrogen-bonds with the peptide backbone so it is less affected by changes in amino acid side chains. DRV can inhibit both wildtype and mutants that are resistant to other PIs.

25
Q

Main toxic effects of protease inhibitors

A

-HLD, insulin resistance and DM, lipodystrophy (changes in fat accumulation), elevated LFTs, increased bleeding risk for hemophiliacs, drug-drug interactions

26
Q

NRTI and CYP3A4

A

NRTIs are not metabolized by the CYP450 system

27
Q

NNRTIs and CYP3A4

A

all NNRTIs are metabolized by CYP3A4.

  • Efavirenz, Nevirapine, and Etravirine are moderate inducers
  • Efavirenz and delavirdine are inhibitors of CYP3A4
  • interactions with CYP3A4 (rifampin) can reduce levels and CYP3A4 inhibitors can increase levels
28
Q

Integrase inhibitors and CYP3A4

A

-all but Elvitegavir do not get metabolized by CYP450 system.
Elvitegravir is metabolized by CYP3A4 and is currently only co-formulated with cobicistat, FTC, and TDF/TAF with cobicistat inhibiting CYP3A4 metabolism

29
Q

Protease inhibitors and CYP3A4

A
  • all are substrates and some are inhibitors of CYP3A4

- low doses of ritonavir inhibit CYP3A4

30
Q

PI-boosting

A
  • ritonavir is the most potent PI inhibitor of CYP450s. Subtherapeutic doses of ritonavir can be combined with other PIs (PI boosting).
  • increases trough levels reduces emergence of resistant viruses
  • improves compliance by reducing dosing, fewer pills, eliminates food restrictions
31
Q

Recommended initial ART regimen

A
  • INSTI base: DTG + ABC/3TC (only if HLA-B*507 neg)
  • DTG (QD) + tenofovir/FTC
  • EVG/COBI + tenofovir/FTC
  • RAL + tenofovir/FTC
32
Q

Fusion inhibitor drug(s)

A

Enfuvirtide (ENF/T-20)

33
Q

Entry Inhibitor (s)

A

Maraviroc (MVC)

34
Q

Nucleoside Reverse Transcriptase Inhibitors

A
  • Tenofovir (TDF/TAF/TFV)
  • Emtricitabine (FTC)
  • Zidovudine (ZDV/AZT)
  • Abacavir (ABC)
35
Q

Non-nucleoside reverse transcriptase inhibitors

A
  • Etravirine (ETR) - second gen

- Rilviripine (RPV) - second gen

36
Q

Integrase inhibitor drug(s)

A
  • Raltegravir (RAL)
  • Dolutegravir (DTG)
  • Elvitegrvair (EVG)
37
Q

Protease inhibitor drug(s)

A
  • Atazanavir (ATV)
  • Darunavir (DRV)
  • Tipranavir (TPV) - non-peptidomimetic
38
Q

PK boosters

A
  • Ritanovir (RTV)

- Cobicistat (COBI)