HIV/AIDS

Question 1

Key molecules of HIV replicative cycle

Answer 1

RT
cDNA
mRNA
tat
RnaseH
gp120

Question 2

tat

Answer 2

Protein that regulates viral Tx

Affects rate of replication

Question 3

gp120

Answer 3

Envelope glycoprotein

Question 4

1983

Answer 4

HIV isolated (took two years)

Question 5

1987

Answer 5

Zidovudine available to USA

Question 6

1993

Answer 6

AIDS leading cause of death of young adults in US

Question 7

1996

Answer 7

HAART

Development of resistance and SE

Question 8

2003

Answer 8

New class: fusion inhibitors

Question 9

Goals of HIV Tx

Answer 9

Maximally inhibit viral replication
Fully undetectable levels of virus
Lower the viral RNA --> lower rate of accumulation of drug resistance --> longer therapeutic effect
Avoid drug interactions
Encourage complicance
Drug combinations

Question 10

General Tx strategy:

Answer 10

COMBINATIONS
One of (NNRTI, PI, IntegraseI) + TWO NRTI

Question 11

NRTIs (nucleoSide)

Answer 11

Zidovudine (azidothymidine or AZT)
Lamivudine
Emtricitabine
Abacavir

“Emtrici, you and Aba go feed Zido some Lami on the back Side of the house.”

Question 12

NRTI (nucleoSide) mech

Answer 12

Competitiveliy inhibit RT
Incorporate into vDNA chain and cause termination
REQUIRES PHOSPHORYLATION by cellular enzymes to become active

Resistance to one –> resistance to another

Question 13

NRTI (nucleoSide) SE

Answer 13

FATAL: LACTIC ACIDOSIS WITH HEPATIC STEATOSIS probably due to mitochondrial toxicity
Fat redistribution
Hyperlipidemia
Drug drug interactions

Question 14

Zidovudine SE

Answer 14

Granulocytopenia and anemia (45% treated patients)
CNS disturbances:
severe HA
nausea
insomnia
malaise

Question 15

Lamivudine and Emtricitabine SE

Answer 15

Best tolerated of NRTIs

Question 16

Abacavir SE

Answer 16

Hypersensitivity

Question 17

NRTIs (nucleoTide)

Answer 17

Tenofovir

“Best ride on the Tide is a Ten*”

Question 18

NRTI (nucleoTide) mech

Answer 18

Competitively inhibit RT
Incorporate into vDNA chain and cause termination
DOES NOT REQUIRE PHOSPHORYLATION

Question 19

NRTI (nucleoTide) SE

Answer 19

Nausea
Vomiting
Diarrhea
Potential for renal failure
FATAL: LACTIC ACIDOSIS WITH HEPATIC STEATOSIS

Question 20

NNRTIs (non-nucleoSide)

Answer 20

Efavirenz
Etravirine

Efa plus Etra (mobsters) kill Vir with NNRTIs (weapons)

Question 21

NNRTIs mech

Answer 21

Bind directly to RT at side distinct from NRTI
RT can no longer produce vDNA
DOES NOT REQUIRE PHOSPHORYLATION

NO CROSS RESISTANCE WITH NRTIs or PIs

Question 22

NNRTIs SE

Answer 22

GI intolerance
Skin rash
Drug interactions: CYP450

Question 23

Efavirenz

Answer 23

QD
CNS effects (vivid dreams, nightmares, hallucinations)

Efa: once daily gets weird dreams

Question 24

Etravirine

Answer 24

Rash
Nausea
Peripheral neuropathy

Etra: Nausea, Neuropathy, Rash (NNRti)

Question 25

Protease Inhibitors (PI)

Answer 25

Atazanavir Ritonavir Darunavir "Darun Ate all the Rits crackers at the super bowl Party Intermission."

Question 26

PI mech

Answer 26

Prevents protease action required for MATURATION of fully assembled virus *WITHOUT THIS CLEAVAGE THE VIRUS IS NOT INFECTIOUS Prevents post-Ts cleavage of Gag-Pol polyproteins

Question 27

PI SE

Answer 27

``` GI disturbances Hepatotoxicity Hyperglycemia and insulin resistance Dyslipidemia Cardiac conduction abnormalities Peripheral lipoatrophy and central fat accumulation CYP3A4 hepatic ```

Question 28

Ritonavir boosting

Answer 28

high doses of PI ritonavir are POORLY TOLERATED Used at lower doses TO INCREASE SERUM CONC OF OTHER PIS and DECREASE DOSAGE FREQ OF OTHER PIs potent inhibitor of CYP3A4 (increases affectiveness of PIs)

Question 29

Fusion Inhibitors (FI)

Answer 29

EnfuvirTide (T-20) "Catching Enough (e nfu) Tides? No? Do this workout: FIT-20!"

Question 30

FI mech

Answer 30

Binds to gp41 and prevents the conformational change necessary for fusion of viral an host cell membranes to allow virus into cell

Question 31

Enfuvirtide

Answer 31

SubQ BID local reactions with pain, erythema, induration, nodules, cysts Active against other HIV-resistant antiretrovirals

Question 32

Integrase Inhibitors (INSTI)

Answer 32

Raltegravir "Walt's favorite: INSTant (insti) gravy" Ralt = Walt, gravi = gravy

Question 33

INSTI mech

Answer 33

Binds integrase Inhibits strand transfer, the final step of provirus integration INSTI: integrase Strand Transfer Inhibitors Fewer drug drug Intxns

Question 34

CCR5 Antagonist

Answer 34

Maraviroc

Question 35

CCR5/CXCR4 antagonist mech

Answer 35

Binds specifically and selectively to host CCR5 | CCR5: receptor HIV-1 uses to get into host cell

Question 36

CCR5 Ant SE

Answer 36

Pyrexia Rash Postural dizziness

Question 37

HAART

Answer 37

Highly active antiretroviral therapy RTIs in combo with PI HAART associate lipodystrophy

Question 38

HAART associated lipodystrophy

Answer 38

``` 25-50% patients affected Wasting of suQ fat Central adiposity Hyperlipidemia, insulin resistance, diabetes mellitus Most often seen with use of NRTIs and PI ```

Question 39

If reitonavir given in combo with darunavir, would you expect an increase, decrease, or no chance in serum conc. of daruavir computer to mono therapy with darunavir?

Answer 39

Would expect an increase in serum darunavir because ritonavir inhibits CYP450, which metabolizes PIs (darunavir).