Antivirals 2 Flashcards

1
Q

HIV - Reverse transcriptase inhibitors

Reverse transcriptase (RT) has three activities
1) RNA dependent DNA polymerase
2) ___ H
3) DNA dependent DNA polymerase

RT does the following
- Copies plus-strand RNA to produce minus-strand ___
- Degrades RNA template from RNA-DNA hybrid
- Synthesizes ___ -strand ___ from minus-strand DNA template

A
  • Ribonuclease
  • DNA
  • plus, DNA
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2
Q

Nucleoside RT inhibitors (NRTIs) mechanism

NRTIs are nucleoside analogs that lack the ___
- Sometimes called false nucleotides

Two effects
- ___ inhibitor of reverse transcriptase
- DNA chain ___ - inhibit elongation

A
  • 3’ OH
  • competitive
  • terminator
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3
Q

Nucleoside RT inhibitors (NRTIs)

backbone of initial therapy

Used in combination
- 2 NRTIs plus NNRTI or PI or integrase inhibitor

Some combinations of NRTIs work better than others
- Tenofovir and ___
- ___ and lamivudine

all must be activated by celluar kinases to ___ form

A
  • emtricitabine
  • Abacavir
  • triphosphate
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4
Q

analogs

abacavir: __
tenofovir: __
lamivudine: __
emtricitabine: __

A

G
A
C
C

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5
Q

NRTIs must be phosphorylated

  • Each NRTI is phosphorylated to triphosphate.
  • Use ___ enzymes.
  • ___ with normal nucleosides and NRTIs that are analogs of the same nucleoside
A

cellular
Compete

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6
Q

Tenofovir alafenamide (TAF)

Activated by different pathway than previous tenofovir
- Lower plasma concentrations of tenofovir (good so no kidney damage)
- Increased accumulation in ___
- However, TAF is associated with higher ___ levels compared to tenofovir disoproxil fumarate

May be even better at targeting HIV
TAF is converted to ___

Different activation pathway of TAF allows for 10-fold ___ dose compared to TDF

A
  • lymphocytes
  • lipid
  • TFV
  • lower
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7
Q

Activation of NRTIs - summary

Activated NRTIs ___ with dATP, dCTP, dGTP, and dTTP to be incorporated into the growing DNA chain by RT (ratio important)
- NRTIs have a higher affinity for HIV ___ than for cellular DNA ___
- TAF must be processed to TFV by ___ enzymes before phosphorylation
- requires 2 phosphorylation steps

A

compete
- RT, polymerases
- cellular

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8
Q

Resistance to anti-HIV drugs

Why do resistant mutations arise so quickly?
- HIV polymerase is error prone
- RT inhibitors are unable to suppress viral replication > 90%
- Large amounts of virus present

Rate at which mutations appear is ___ related to the serum drug concentration
- Need to maintain drug levels above MIC

Resistance
- ___ mutations - bouncer
- ___ mutations - plucked out

A
  • inversely
  • Discriminatory
  • Excision
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9
Q

Resistance to NRTIs - Key points

  • Mutations are mainly near the RT ___ site, but can occur at more distant locations

Mutations can either
- help the RT to distinguish between normal dNTPs and NRTIs - bouncer
- promote removal of NRTIs after they’ve been incorporated into the growing chain - plucked out

Individual NRTIs have a ___ genetic barrier of resistance

A
  • active
  • low
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10
Q

Some mutations confer resistance to a subset of NRTIs, but make RT more ___ to inhibition by others.
- NRTIs in preferred ___ for initial therapy to take advantage of this phenomenon.

A
  • susceptible
  • combination
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11
Q

Adverse effects of NRTIs

___ toxicity
- Leads to anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis
- Lactic acidosis and hepatic steatosis

___ – loss of body fat

___ Hypersenstivity Reaction: Black Box Warning.
- Highly associated with the ___ allele

A
  • Mitochondrial
  • lipoatrophy
  • Abacavir, HLA-B*5701
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12
Q

Nonnucleoside RT inhibitors (NNRTIs)

Bind directly to site on RT
- Hydrophobic pocket ___ catalytic site
- Near, but distinct from that of NRTIs
- Binding affects ___ of enzyme
- NNRTIs do NOT compete with nucleotides for binding - ___ inhibitors
- NNRTIs do not have to be ___
- Block RNA- and DNA-dependent DNA ___ activities

A
  • near
  • flexibility
  • non-competetive
  • phosphorylated
  • polymerase
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13
Q

NNRTI mechanism of action

  • In the presence of NNRTI, nucleoside
    triphosphate and template bind tightly to RT, but nonproductively.
  • Blocks ___
  • ___ mutation in binding site can promote resistance
A
  • polymerization
  • single
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14
Q

First generation NNRTIs
1) ___
2) efavirenz
3) delavirdine

2nd gen - Designed to be inherently ___
- can bind in multiple orientation
- binds to mutant that are resistant to othe NNRTIs
1) Etravirine
2) ___

A
  • Nevirapine
  • flexible
  • Rilpivirine
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15
Q

Adverse Effects: NNRTIs

All NNRTIs:
- rash
- drug-drug interaction

___ – hepatotoxicity (may be severe and life- threatening), rash including Stevens-Johnson syndrome

___ - neuropsychiatric, teratogenic in nonhuman primates (FDA Pregnancy Category D)

A
  • nevirapine
  • Efavirenz
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16
Q

Metabolism of NNRTIs

All are metabolized by ___

Potential for interactions with other drugs that are metabolized by CYP3A
- inducers ( ___ ) can reduce levels
- inhibitors can increase levels

A

CYP3A
rifampin

17
Q

Summary of NNRTIs

  • NNRTIs do NOT require activation, do NOT ___ with dNTPs, and are NOT incorporated into DNA
  • NNRTIs do NOT bind to cellular DNA polymerases
  • Resistance to NNRTIs can be acquired through a ___ mutation
A
  • compete
  • single
18
Q

T or F: Mutations that confer resistance to NNRTIs cause resistance to NRTIs.

19
Q

Integrase inhibitors (INI)

Inhibits ___ of HIV DNA into the human genome
- ___ available
- Compatible with other antiretroviral drugs
- Some do not interact with ___

A

insertion
- orally
- CYPs

20
Q

Integrase function

Inserts HIV DNA into host cell DNA

steps:
1) 3’-processing
2) strand transfer

Integrase inhibitors block the ___ step

integrase uses divalent ___ ions to catalyze insertion
- Chelates both metal ions and stabilizes
enzyme-DNA complex

Drugs mimic: ___ acid
4 drugs (-gravir)

A

strand transfer
metal
Diketo
Raltegravir, Elvitegravir, Dolutegravir, Bictegravir

21
Q

Integrase inhibitor resistance

Caused by primary mutations that reduce ___ susceptibility

Secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness

22
Q

Integrase inhibitor resistance

Elvitegravir
- Metabolized by CYP3A4
- Currently available only in coformulation with ___ (COBI) - Role is to boost elvitegravir concentrations by inhibiting metabolism by CYP3A4

Dolutegravir
- ___ plasma half life (14h) - once daily dosing
- No boosting required
- No interactions with CYP3A4
- Higher barrier for resistance

Bictegravir
- Low risk of resistance
- Few drug interactions
- Can be started without___ testing
- Cannot be used with rifampin
- Raises ___ levels (~0.1 mg/dL) through inhibition of tubular secretion of creatinine

A
  • Cobicistat
  • long
  • HLA-B*5701
  • SCr
23
Q

Cobicistat

Designed to inhibit ___
- peptidomimetic

24
Q

HIV protease inhibitors

HIV protease is an aspartic protease - aspartic acid in active site

___ - active site formed at interface

Inhibitors are ___ state mimetics
- Peptidomimetic
- Nonpeptide compounds

A
  • dimer
  • transition
25
# HIV protease mechanism Peptide bond cleavage is a ___ reaction Protease catalyzes addition of water to the amide, forms intermediate Breaks down to the two products, a carboxylic acid and an amine
hydrolysis
26
# HIV protease inhibitors (PIs) Amide bond is replaced by non-cleavable linkages All PIs except ___ are considered peptidomimetics Inhibitor binding causes a conformation change in protease - “flaps” ___ Metabolism All are substrates and some are inhibitors of ___ - High potential for drug interactions - Low doses of ___ inhibit CYP3A4 (increase PI serum [ ]) - reduces resistance and improves compliance Disadvantages - Drug-drug interactions with ritonavir - Increased risk of ___
tipranavir close CYP3A4 ritonavir hyperlipidemia
27
# PI - Atazanavir (ATV) Once-daily dosing and minimal lipid and glycemic effect - Most potent protease inhibitor in vitro prior to darunavir - Different resistant mutation profile - Efavirenz and tenofovir ___ ATV concentrations
reduce
28
# PI - Darunavir (DRV) Novel peptidomimetic PI - Preferred PI for initial antiretroviral combinations - DRV can inhibit both wildtype and mutants that are resistant to other PIs Two unique features 1) Makes extensive ___ bonds with protease backbone 2) Inhibits HIV protease ___ DRV retains activity against most PI-resistant mutant proteases
- H - dimerization
29
# Tipranavir (TPV) - PI - Novel ___ PI - Retains activity against proteases in highly treated patients, including those resistant to DRV - Selects for different set of resistance mutations - ___ substrate and inducer
- nonpeptidic - CYP3A4
30
# Resistance to protease inhibitors - ___ genetic barrier of antiretrovirals - Mutations can be in active site or far away - Protease inhibitors bind tightly to protease - Natural substrates have variable, less tight binding - Resistance mutations have ___ effect on PI than natural substrate - Multiple mutations are usually needed to confer high level resistance
- Highest - greater
31
# PI - AEs - ___ - insulin resistance and ___ - lipodystrophy - elevated liver function tests - Possible increased bleeding risk - Drug-drug interactions
- hyperlipidemia - diabetes
32
# Treatment: Preferred Regimens Biktarvy - bictegravir ( ___ ) - emtricitabine ( ___ ) - tenofovir alafenamide ( ___ )
- INI - NRTI - NRTI
33
# Treatment: Preferred Regimens Triumeq - dolutegravir ( ___ ) - abacavir ( ___ ) - lamivudine ( ___ )
- INI - NRTI - NRTI
34
# Treatment: Preferred Regimens Dovato - dolutegravir ( ___ ) - lamivudine ( ___ )
- INI - NRTI
35
# Treatment: Preferred Regimens Genvoya - elvitegravir/ ___ ( ___ and booster) - emtricitabine ( ___ ) - tenofovir alafenamide ( ___ )
- cobicistat, INI - NRTI - NRTI
36
# Long-acting injectable therapies Cabotegravir ( ___ ) and ___ (NNRTI) is administered as monthly or bimonthly injections Lenacapavir is a capsid inhibitor developed by Gilead with biannual injection for HIV treatment and prevention. - Binds on the HIV capsid p24 protein - Interferes with virus replication by preventing virus assembly of the capsids into a stable structure. - First in class medication
- INI - rilpivirine