HIV Chemotherapy

Question 1

Describe how influenza gets into cell.

Answer 1

Influenza: Uncoating. Gets into cell through vesicle and then spreads virions.

Question 2

Describe how HIV gets into cell.

Answer 2

HIV: Lipid membrane of viral capsule fuses with PM of cell it is trying to enter. Virions then enter cytoplasm of cell.

Question 3

Retrovirus

Answer 3

Retrovirus
• RNA genome
• Must make DNA copy of RNA
• DNA copy of RNA genome can be inserted into chromosome of infected cell (integrase)
• Reverse transcriptase: RNA directed DNA polymerase to make DNA copy

Question 4

Inhibits infection of NEW cell

Answer 4

Inhibits infection of new cell
• Binding and Fusion
• Reverse transcriptase
• Integrase

Question 5

Protease

Answer 5

Protease inhibits proliferation of virus and spread from infected cells to uninfected cells

Question 6

Cell surface recognition site for HIV binding

Answer 6

CCR5

Once bound starts process of internalization of virus

Question 7

Nucleoside analog =

Answer 7

Antimetabolite

Question 8

Protease Inhibitors

Answer 8

Protease Inhibitors
• Lopinavir, Ritonavir, Indinavir
• Inhibit HIV Protease
-Product of Pol gene
-Job is to cleave long polypeptides into smaller, functional units
-Inhibition blocks reverse transcriptase, protease, integrase, structural proteins
-Viral particles are not able to mature: they will bud off from cells but will be noninfectious b/c functional elements inhibited

Question 9

Both gag and pol (HIV genes) form

Answer 9

Both gag and pol (HIV genes) form long polypeptides that get cleaved by protease into functional units.

Question 10

Blocking protease in gag causes

Answer 10

Loss of p24 (capsid)

Question 11

Blocking protease in pol causes

Answer 11

No reverse transcriptase, integrase or protease

Question 12

Protease Inhibitor S/E

Answer 12

Many S/E: N/V
Hyperlipidemia and hyperglycemia from insulin resistance, contributing to higher rate of cardiovascular disease among pts with chronic HIV infection
Characteristic fat distribution: Loss of fat in extremities but increased fat in abdomen and base of neck (buffalo hump). Barrier to compliance.

Question 13

Indinavir

Answer 13

Protease inhibitor

S/E: Kidney stones so pts must stay well hydrated

Question 14

Ritonavir

Answer 14

Ritonavir
• Inhibits cytochrome p450 system
• Low dose (less S/E) used to “boost” other protease inhibitors
• Primary use is drug boosting
Ritonavir/Lopinavir combo allows lower dosage of both drugs and less S/E

Question 15

NRTIs: Nucleoside Reverse Transcriptase Inhibitors

Answer 15

NRTIs: Nucleoside Reverse Transcriptase Inhibitors
• Reverse transcriptase synthesizes DNA using RNA as template
• Reverse transcriptase picks up triphosphorylated nucleotides inside of cells and use them to synthesize a strand of DNA from RNA
• NRTIs work by mimicking structure of nucleotide
Reverse transcriptase will pick up NRTI analog and incorporate it into growing strand of DNA, terminating chain

Question 16

Zidovudine, Lamivudine, Tenofovir, Didanosine

Answer 16

Zidovudine, Lamivudine, Tenofovir, Didanosine
• Nucleotide analog (ACGT)
• Lack -OH group through which nucleotides attach to one another. Results in DNA chain termination.
Reverse transcriptase is inhibited

Question 17

Zidovudine (AZT)

Answer 17

Zidovudine (AZT)
• One of first HIV drugs on market
• Analog to thymidine (same base and ribose sugar)
• Zidovudine is different from thymidine b/c it does not have 3’ hydroxyl group that gets linked to next nucleic acid
Once Zidovudine is incorporated into growing DNA chain, elongation terminates

Question 18

What needs to happen to Zidovudine for it to be picked up by reverse transcriptase and incorporated in to DNA strand?

Answer 18

Triphosphorylation by kinase

Question 19

Nucleotide

Answer 19

Nitrogenous base
Sugar
Phosphate group

Question 20

Nucleoside

Answer 20

Base and sugar

No phosphate group (-OH instead)

Question 21

Tenofovir

Answer 21

Tenofovir
• Different from other NRTIs b/c nucleotide (not nucleoside) so contains one phosphate group
• Di-phosphorylation required
• Inhibits reverse transcriptase as mimic of adenosine

Question 22

Zidovudine, Lamivudine and other NRTIs are

Answer 22

Zidovudine, Lamivudine and other NRTIs are nucleosides

• Tri-phosphorylation required

Question 23

NRTIs S/E

Answer 23

NRTIs S/E
• Mitochondrial toxicity (mitochondria have their own DNA)
-Mitochondrial enzyme DNA polymerase gamma helps synthesize mitochondrial DNA
-DNA polymerase gamma can become inhibited by the NRTIs in the same manner as reverse transcriptase
-Loss of mitochondria
-Sx: Peripheral neuropaty (pain/paresthesias), myopathy, pancreatitis, lactic acidosis
-Inhibition of oxidative phosphorylation results in anaerobic metabolism. Sever, life-threatening lactic acidosis can occur
-Presentation of lactic acidosis complication: HIV pt on chronic therapy develops hyperventilation, very low bicarbonate level, and signs/sx of lactic acidosis

Question 24

Zidovudine S/E

Answer 24

S/E: Bone marrow suppression
• Zidovudine can be incorporated into DNA strands growing in bone marrow by reverse transcriptase
• Inhibition of new cell synthesis in bone marrow can be improved with bone-stimulating meds (G-CSF or EPO)

Question 25

Zidovudine can prevent

Answer 25

Can be given to prevent maternal-fetal infection
• Prenatal to mothers
• Given to infant
New WHO guidelines recommend multi-drug combinations to prevent transmission

Question 26

Abacavir

Answer 26

Abacavir
Guanosine analog
5% of pts get fever/rash hypersensitivity reaction
Respiratory distress
GI upset
Can be mistaken for opportunistic infection

Question 27

Lamivudine (3TC)

Answer 27

Lamivudine (3TC)
• Cytosine nucleotide
• Least toxic NRTI
Can also be used for Hep B (also uses reverse transcriptase)

Question 28

Tenofovir S/E

Answer 28

Severe GI upset
Fanconi syndrome
-Loss of proximal tubule function
-Proteinuria, urinary phosphate wasting, glycosuria
-Metabolic acidosis, hypophosphatemia, hypokalemia
-Classic presentation: polyuria and muscle weakness

Question 29

NNRTIs

Answer 29

NNRTIs
• Non-nucleoside reverse transcriptase inhibitors
• Inhibit reverse transcriptase but do not mimic nucleosides
• Nevirapine, Efavirenz, Delaviridine
• Inhibit reverse transcriptase by binding to different site than NRTIs
• NNRTIs bind to reverse transcriptase and modify protein so that it can no longer function
• Do not require phosphorylation
• Do not suppress bone marrow (only affect reverse transcriptase)
• Not effective for HIV-2 (West Africa)
• S/E:
-GI upset
-Skin rash (rarely Stevens-Johnson Syndrome)

• Metabolized by cytochrome p450 system in liver  -Levels can go up and down with coadministration of other drugs

Question 30

Nevirapine

Answer 30

Nevirapine induces metabolism by P450 system in liver

Question 31

Delavirdine

Answer 31

Delavirdine: Inhibits metabolism by P450 system in liver

Question 32

Efavirenz

Answer 32

Efavirenz: Has a mixed effect on metabolism of P450 system in liver.

Question 33

Raltegravir

Answer 33

Raltegravir
• Integrase inhibitor
• Integrase inserts viral DNA into cellular genome
Loss of activity disrupts viral life cycle

Question 34

Enfuvirtide

Answer 34

Enfuvirtide
• Binds to surface molecule gp41
Inhibits fusion/entry HIV into cells

Question 35

Maraviroc:

Answer 35

Maraviroc:
• Blocks CCR5 receptor on macrophages
• Entropic versions of HIV must bind to CCR5 to enter cells

Question 36

HLA-B*5701 negative means

Answer 36

pt can take Abacavir

Question 37

Protease inhibitors that are not contraindicated in pregnancy

Answer 37

Atazanavir
Darunavir
Lopinavir (second choice)

Question 38

CYP3A4 significance

Answer 38

Controls pharmacokinetics in 50-60% of drugs

Question 39

Rare S/E of integrase inhibitors

Answer 39

Rhabdomyolysis

Question 40

Protease inhibitors are never

Answer 40

used by themselves

Question 41

Which drug has most profound inhibitory effect on P450?

Answer 41

Ritonivir