L11 - Treatment of HIV Infection

Question 1

What sort of genetic material does the HIV virion have?

Answer 1

ssRNA (+)

Question 2

Describe the two types of glycoprotein expressed by the HIV virion

Answer 2

gp41 (transmembrane glycoprotein)

gp120 (surface glycoprotein)

Question 3

Describe the two antigens expressed by the HIV virion

Answer 3

p17 (matrix antigen)

p24 (capsid antigen)

Question 4

What sort of membrane does the HIV virion have?

Answer 4

Lipid bilayer envelope

Question 5

What three enzymes are responsible for inserting the HIV ssRNA (+) into the human genome?

Answer 5

Reverse Transcriptase
Integrase
Protease

Question 6

What is the function of reverse transcriptase?

Answer 6

To convert the ssRNA viral genome into cDNA

Question 7

What is the function of integrase?

Answer 7

To integrate the dsDNA produced by RT into the human genome

Question 8

What is the function of protease?

Answer 8

To cleave larger combination proteins into their functional forms

Question 9

What is Azidothymidine?

Answer 9

A nucleoside analogue reverse transcriptase inhibitor (NRTI) - 2’3’ dideoxy nucleoside analogue that is phosphorylated by host cells

Question 10

What is the MoA of Azidothymidine?

Answer 10

It acts as a DNA chain terminator and RT inhibitor

Question 11

What is the therapeutic life of Azidothymidine?

Answer 11

6 months

Question 12

What are ddC and ddI?

Answer 12

Both NRTIs (2’3’ dideoxy NAs) with the same MoA as Azidothymidine

Question 13

Define NRTIs

Answer 13

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

Question 14

Describe the general structure of NRTIs

Answer 14

All analogues of nucleotides, lack a 3’OH group on the ribose ring
Require phosphorylation by cellular kinases

Question 15

Give four examples of NRTIs and their corresponding nucleosides

Answer 15

Zidovudine/AZT (Thymidine)
Lamivudine (Cytosine)
Abacavir (Guanosine)
Didanosine (Adenosine)

Question 16

What is Tenofovir DF?

Answer 16

A nucleotide analogue RT inhibitor

Question 17

What is the MoA of Tenofovir DF?

Answer 17

Tenofovir DF is converted to Tenofovir (serum esterases)

Tenofovir is a nucleotide analogue of adenosine monophosphate

Question 18

What are the currently used NRTIs?

Answer 18

Zidovudine (AZT)
Stavudine (D4T)
Lamivudine (3TC)
Emtricitabine (FTC)
Abacavir (ABC)
Didanosine (DDI)
Tenofovir DF (TDF)

Question 19

What are the adverse effects of NRTIs?

Answer 19

Lactic acidosis
Hepatic steatosis
Peripheral neuropathy
Myopathy
Lipoatrophy

Question 20

What causes the adverse effects of NRTIs?

Answer 20

They may inhibit the activity of normal cellular DNA polymerases (mitochondrial DNA pol-Y)
May also interfere with CYP450 enzymes (D/D interactions)

Question 21

What are the first choice NRTIs?

Answer 21

Abacavir (ABC)
Tenofovir DF (TDF)

Question 22

Why are ABC & TDF the first choice NRTIs?

Answer 22

Minimal DNA pol-Y inhibitory effects

No interaction with CYP450 enzymes

Question 23

What is the main side effect of ABC?

Answer 23

Associated with a potentially fatal hypersensitivity syndrome

Question 24

What is the main side effect of TDF?

Answer 24

Nephrotoxicity

Question 25

Define NNRTIs

Answer 25

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors

Question 26

What is the MoA of NNRTIs?

Answer 26

They are non-competitive RT inhibitors that induce conformational changes within RT

Question 27

Give three examples of NNRTIs

Answer 27

Nevirapine Efavirenz Etavirine

Question 28

Describe combination therapy

Answer 28

Giving NRTIs AND NNRTIs together to increase and sustain the decrease in viral load

Question 29

What are the side effects of NNRTIs?

Answer 29

CNS s/e (vivid dreams, insomnia, hallucinations, depression) Teratogenicity Substrates of CYP enzymes (D/D interactions)

Question 30

What are Protease Inhibitors?

Answer 30

A class of antiretroviral HIV drugs

Question 31

What is the MoA of PIs?

Answer 31

PIs inhibit HIV protease-mediateed cleavage of HIV polyprotein precursors Renders virus particles non-infectious

Question 32

What are the problems associated with PIs?

Answer 32

They are heavily metabolised by CYP enzymes (+Ritonavir) | Resistance can develop

Question 33

What is the mechanism by which resistance to PIs arises?

Answer 33

Mutations modify the number/nature of points of contact between PI and protease

Question 34

What are the side effects of PIs?

Answer 34

Dyslipidaemia (leading to atherosclerosis) Insulin resistance Lower GI symptoms

Question 35

Give four examples of commonly used PIs

Answer 35

Lopinavir + Ritonavir (Kaletra) Atazanavir Darunavir

Question 36

What is the MoA of Entry Inhibitors

Answer 36

They block co-receptor binding/fusion to prevent the HIV virion binding to and entering human cells

Question 37

Give two examples of EIs

Answer 37

Maraviroc (block binding) | Enfurvitide (block fusion)

Question 38

Define INSTIs

Answer 38

Integrase Strand Transfer Inhibitors

Question 39

What is the MoA of INSTIs?

Answer 39

They block the strand transfer effect of HIV integrase | Inhibit both HIV-1 AND HIV-2

Question 40

What is the 1st approved INSTI?

Answer 40

Raltegravir

Question 41

Define HAART

Answer 41

Highly Active Antiretroviral Therapy

Question 42

Define cART

Answer 42

combination Antiretroviral Therapy | blocks selection of mutants

Question 43

How does cART block the selection of mutants?

Answer 43

Due to combination therapy multiple mutations are required simultaneously for resistance to occur to all drugs in the regimen

Question 44

When should ART begin?

Answer 44

``` History of AIDS-defining illness Symptomatic HIV disease CD4 count <350/ul HIV-infected pregnant women HIV-associated nephropathy When treating HBV infection Upon first diagnosis ```

Question 45

What is the ideal HAART regimen?

Answer 45

Two NRTIs + NNRTI/PI/INSTI | Tenofovir + Abacavir + Rilpiravirine/Darunavir/Raltegravir