Anti-HIV Drugs I

Question 1

CD4+ count / HIV-1 RNA levels have been used for decades to measure

Answer 1

HIV progression

Question 2

Measure the state of the patients immune system and susceptibility to opportunistic infections

Answer 2

CD4+

Question 3

Particularly effective at monitoring therapeutic intervention

Answer 3

HIV-1 RNA levels

Question 4

RNA levels drop 10-100 fold within week of treatment with

Answer 4

Protease or RT inhibitor

Question 5

99% of plasma HIV arises from recently infected

Answer 5

CD4 lymphocytes

Question 6

For viral entry, CD4 receptor or CCR5 coreceptoron CD4+ cells strip

Answer 6

gp120 from viral surface

Question 7

Then, naked gp41 transmembrane protein uncoils and sticks end into nearby

Answer 7

CD4 cells

Question 8

The uncoiled protein reassociatesN and C terminal regions, thus reeling in

Answer 8

CD4

Question 9

Peptide binds specifically in the groove of a coiled coil in the gp41 protein

-Binds the N36 helix

Answer 9

Enfuvirtide

Question 10

Synthetic 36 amino acid that works on HIV-1 but not HIV-2

-Provides significant benefit when added to cocktail of other drugs

Answer 10

Enfuvirtide

Question 11

High first pass metabolism. Requires subcutaneous injection twice a day

Answer 11

Enfuvirtide

Question 12

What are the side effects of Enfuvirtide?

Answer 12

Skin reaction at site of infection and greater incidence of penumonia

Question 13

Resistance to enfuvirtide correlates with the appearance of mutations in the N-terminal portion of

Answer 13

gp41

Question 14

Blocks HIV entry by binding the human CCR5 coreceptor

Answer 14

Maraviroc

Question 15

Discovered because individuals with certain CCR5 mutations were highly HIV resistant

Answer 15

Maraviroc

Question 16

Maraviroc only works for HIV isolates that utilize

Answer 16

CCR5

Question 17

Maraviroc does not work for those that use

Answer 17

CXCR4

Question 18

Drug is metabolized by P450s so inducers and inhibitors of system may influence levels

Answer 18

Maraviroc

Question 19

1% of patients using maraviroc can experience

Answer 19

MI’s

Question 20

Resistance to miraviroc is due to the emergence of mutant strains that use

Answer 20

CXCR4 to gain entry

Question 21

FDA approved (2018), monoclonal antibody therapy for multi-drug resistant HIV who fail other treatment protocols

Answer 21

Ibalizumab

Question 22

Binds CD4 receptor and blocks viral entry. Works for CCR5 and CXCR4 tropic HIV isolates

Answer 22

Ibalizumab

Question 23

Ibalizumab does not interfere with normal

Answer 23

CD4 activity

Question 24

Taken by IV infusion every 14 days

-Adverse effects include, diarrhea, dizziness and rash

Answer 24

Ibalizumab

Question 25

RT and all other polymerases that create DNA strands must work off a free

Answer 25

3' Hydroxyl end

Question 26

In this case, serves as a 3' hydroxyl primer

Answer 26

tRNA

Question 27

In reverse transcription, RNA is degraded as the first DNA strand is

Answer 27

Synthesized

Question 28

The final bit of RNA is left to serve as a primer for the

Answer 28

Second DNA strand synthesis

Question 29

During reverse transcription, double stranded HIV DNA genome is integrated into host

Answer 29

Genome

Question 30

RT polypeptide contains both the

Answer 30

RT and RNAse activities

Question 31

The RT crystal structure resembles a

Answer 31

Hand

Question 32

Located at the fingers area

Answer 32

RT

Question 33

The RNAseH active site is located at the junction of the

Answer 33

"Wrist"

Question 34

The nucleoside reverse transcriptase inhibitors are essentially just

Answer 34

Nucleoside analogues without a free 3' OH

Question 35

In DNA synthesis, 3'-OH of growing DNA chain is catalyzed to attack the alpha phosphate of a

Answer 35

dNTP

Question 36

When a chain terminator is incorporated, there is no

Answer 36

3' OH to continue rection

Question 37

Act as suicide substrates by poisoning RT chain elongation -Drugs bind the active site of the HIV RT

Answer 37

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Question 38

Selectivity because drugs do not bind well to nuclear DNA polymerases

Answer 38

NRTIs

Question 39

Prodrugs that must be triphosphorylated by cytoplasmic enzymes -Taken orally and generally well absorbed from GI

Answer 39

NRTIs

Question 40

The half-life of NRTIs is usually extended by transport into the cell and subsequent

Answer 40

Phosphorylation

Question 41

NRTIs can poison host DNA polymerases, particularly mitochondrial polymerases, which leads to potentially fatal

Answer 41

Lactic Acidosis

Question 42

Resistance to NRTIs is due to mutations in the

Answer 42

RT active site

Question 43

Develops more rapidly than other NRTIs

Answer 43

Lamivudine resistance

Question 44

NRTIs are prodrugs because they lack some or all phosphates necessary for

Answer 44

DNA synthesis

Question 45

This is necessary though because if drugs were triphosphates, their excessive charge would prevent transport into the

Answer 45

Body

Question 46

Instead, prodrugs enter cell, and are then converted to triphosphates by

Answer 46

Host enzymes

Question 47

Traps the NRTIs inside the cell, thereby adding to efficacy

Answer 47

Phosphorylation

Question 48

Fluorinated analog of lamivudine with long t1/2

Answer 48

Emtricitabine

Question 49

Clinically significant drug-drug (p450) interactions have not been identified with

Answer 49

Emtricitabine

Question 50

Synthetic adenosine analog with a phosphate. Technically a nucleotideRT inhibitor

Answer 50

Tenofovir

Question 51

Presence of first phosphate overcomes rate limiting phosphorylation step

Answer 51

Tenofovir

Question 52

Drug acts by competing with dATP for binding HIV RT and then chain terminates

Answer 52

Tenofovir

Question 53

Long term use of tenofovir can cause nephrotoxicity and a decrease in

Answer 53

Bone mineral density

Question 54

The newest version of tenofovir which shows less bone and kidney toxicity than the previous tenofovir disoproxil, but higher lipid levels

Answer 54

Tenofovir alafenamide

Question 55

Emtricitabine and tenofovir alafenamide are coformulated as

Answer 55

Descovy

Question 56

Bind adjacent to the RT active site, inducing a conformational change that blocks RT activity

Answer 56

Non-NRTIs

Question 57

Non-NRTIs do not require

Answer 57

Cellular activation

Question 58

Non-NRTIs act on

Answer 58

HIV-1 but not HIV-2

Question 59

Resistance to non-NRTIs develops

Answer 59

Rapidly

Question 60

NNRTIs interact with P450 CYP3A4 and either inhibit or induce

Answer 60

P450 activity

Question 61

Some non-NRTI patients can undergo methadone withdrawal on nevirapinedue to

Answer 61

CYP3A induction

Question 62

Increases levels of co-administered PIs

Answer 62

Delavirdine

Question 63

Can lead to a false positive cannabinoid test, and central nervous system and psychiatric problems

Answer 63

Efavirenz

Question 64

Selected on the basis of activity toward HIV-resistant to more common NNRTIs -Next generation NNRTI

Answer 64

Etravirine

Question 65

Persistent activity of etravirine despite mutations in active site is based on concept of

Answer 65

Strategic flexibility

Question 66

The drug will likely be reserved for patients who have failed traditional treatment protocols and developed resistance to NNRTIs

Answer 66

Etravirine

Question 67

Stalled integrating DNA is degraded or converted to non-replicating

Answer 67

DNA circles

Question 68

By cleaving termini of virus, the integrase creates active 3'-hydroxyl ends that are poised to integrate into DNA of the

Answer 68

Human genome

Question 69

Only bind the Integrase/Viral DNA complex

Answer 69

Integration inhibitors

Question 70

Binds Mg2+ and displaces the terminal nucleotide from the active site

Answer 70

HIV integrase inhibitor (MK2048

Question 71

The first HIV integrase strand transfer inhibitor (INSTI)

Answer 71

Raltegravir

Question 72

Inhibits strand-transfer actions mediated by HIV viral integrase

Answer 72

Raltegravir

Question 73

Binds Mg2+in the active site of Integrase-DNA complex

Answer 73

Raltegravir

Question 74

Raltegravir does not interact with the

Answer 74

P450 system

Question 75

Raltegravir is metabolized by

Answer 75

Glucuronidation

Question 76

A first-line therapy -Extremely potent

Answer 76

Raltegravir

Question 77

FDA approved in 2012 for use in once-a-day combo pill (Stribild) -Similar mechanism and resistance profile as raltegravir

Answer 77

Elvitegravir

Question 78

Boosts elvitegravir half-life by inhibiting CYP3A4 metabolism -Has no anti-viral activity of its own

Answer 78

Cobicistat

Question 79

Remains active in patients who have become resistant to earlier integrase inhibitors -Does not require boosting by cobicistat

Answer 79

Dolutegravir

Question 80

Co-formulated as Triumeq with abacavir and lamivudine. Once daily dosing

Answer 80

Dolutegravir

Question 81

Avoid in HLA-B*5701 positive patients because of potential abacavir sensitivity

Answer 81

Dolutegravir

Question 82

FDA approved in March 2018 for use in once-a-day combo pill (Biktarvy), which also contains tenofovir alafenamide and emtricitabine

Answer 82

Bictegravir

Question 83

Bictegravir does not require boosting by

Answer 83

Cobicistat

Question 84

Recommended for treatment-naive patients, as well as an alternative for patients who are effectively treated by other regimes (>50 HIV RNA c/mL)

Answer 84

Bictegravir

Question 85

Bictegravir is a substrate for

Answer 85

CYP3A4

Question 86

Before using bictegravir, we want to test patients for co-infection with

Answer 86

Hep B

Question 87

Cleaves the chimeric gag-pol protein into a set of active enzymes (reverse transcriptase, protease, integrase) and into a set of structural proteins (p17, p24, p9, and p7)

Answer 87

HIV proteases

Question 88

Recognition by proteases is based on

Answer 88

Shape (not volume)

Question 89

Each subunit of the protease dimer contributes an aspartic acid to form the

Answer 89

Catalytic site

Question 90

Human aspartic acid proteases function as monomers and thus evade

Answer 90

Viral protease inhibitors

Question 91

Each is an analog of the transition state. A tertiary alcohol often with a recognizable phenylalanine

Answer 91

Protease inhibitor

Question 92

All viral protease inhibitors bind the active site

Answer 92

Reversibly

Question 93

These residues activate a water molecule that attacks HIV peptide between Phe(or Tyr) and Pro

Answer 93

Protease active site aspartate residues

Question 94

Lower plasma RNA levels 100-1000 fold within 4-12 weeks of therapy

Answer 94

Protease inhibitors

Question 95

When combined with two nucleoside analogs, 60-95% of first-time patients achieve viral levels below detection limit

Answer 95

Protease inhibitors

Question 96

Generally occurs in a stepwise manner

Answer 96

Resistance to protease inhibitors

Question 97

Changes in body fat distribution, i.e. lipodystrophy syndrome or pseudo-Cushing's syndrome are examples of the adverse effects of

Answer 97

Protease inhibitors

Question 98

Protease inhibitors can also cause

Answer 98

Hyperlipidemia