Fitz, HIV Anti-Virals

Question 1

Three main viral processes that are targeted by the drug combos used in INITIAL therapy.

Answer 1

1. HIV reverse transcriptase
2. HIV integrase
3. HIV protease

Question 2

What are the two reservoirs that HIV can reside?

Which 2 NRTIs and 1NNRTIs can get into the brain?

Answer 2

• Reservoir - GALT and spinal cord/brain.
  NRTI - AZT, d4T
  NNRTI - nevirapine

Question 3

Name the three NRTIs that are Purines.

Answer 3

Abacavir
Didanosine
Tenofovir

Question 4

Name the four NRTIs that are Pyrimidines

Answer 4

Lamivudine
Emtricitabine
Zudovudine
Stavudine

Question 5

What must host cells do to the ingested NRTI?

Answer 5

Host enzymes must metabolize the prodrug into a NucleoTide Triphosphate&raquo_space; Emtricitabine(FTC)-analog in the cell!

Question 6

What does the NRTI-Triphosphate do inside CD4 cells harboring replicating HIV?

Answer 6

Emtricitabine(FTC)-TPs are incorporated into the viral DNA by viral DNA polymerase and then —> terminate viral DNA synthesis.

Question 7

How do NRTI-TPs terminate viral DNA synthesis?

Answer 7

Because they lack a 3’ hydroxyl group.

Question 8

How many NRTIs are given to all HIV patients?

Answer 8

Two

Question 9

N/V/abdominal pain, weight loss, myalgia, geatures of HEPATIC DYSFUNCTION, HM, peripheral edema, ascites, encephalopathy.

These show what?

Answer 9

LACTIC ACIDOSIS

Black box warning of all NRTIs. Potentially fatal.

Question 10

Why do all NRTIs have the potential for lactic acidosis?

Answer 10

Because they DNA reverse transcriptase AND they inhibit mt-DNA-polymerase-gamma

Question 11

How does inhibition of mt-DNA-polymerase-gamma result in lactic acidosis?

Answer 11

Inhibition of mt-DNA-polymerase-gamma —> deficient proteins needed for OxPhos, so inhibits aerobic metabolism and increases ANAEROBIC metabolism —> LACTIC ACIDOSIS.

Question 12

The three NRTIs that inhibit mt-DNA formation MOST.

Answer 12

Didanosine > Stavudine ≥ Zidovudine

Question 13

The three NRTIs that inhibit mt-DNA formation LEAST.

Answer 13

All the first line NRTIs:

Tenofovir = Lamivudine = Emtracitabine = Abacavir

Question 14

All NRTIs have what adverse effect?

Answer 14

Disrupt triglyceride metabolism throught the body - morphological/fat deposits.

Question 15

In what three settings should NRTI be suspended?

Answer 15

1. Rapidly rising aminotransferase levels
2. Progressive HM
3. Metabolic acidosis of unknown cause

Question 16

Pts with ___ should avoid Tenofovir? Why?

Answer 16

Renal insufficiency - Tenofovir is already phosphorylated upon ingestion (nucleoTide) —> RENAL elimination

Question 17

Substitute what for tenofovir?

Answer 17

Abacavir

Question 18

A pt is on a NRTI and develops fever, rash, GI, respiratory symptoms, lethargy or malaise. What drug is this person on?

Answer 18

Abacavir - this is systemic abacavir hypersensitivity

Question 19

Abacavir can be used safely in what individuals?

Answer 19

They are Negative for HLA-B*5701 genotype.

Positive = abacavir hypersensitivity

Question 20

**Preferred NRTI combination.

Answer 20

Tenofovir-Emtracitabine

Question 21

NRTI combination for an individual HLA-B(-) and at risk for renal or bone toxicity?.

Answer 21

Abacavir-Lamivudine

Question 22

Caution using what NRTI combination for an individual HLA-B(+) and at risk for renal or bone toxicity?

Answer 22

Caution use of abacavir in the abacavir-lamivudine combo.

Question 23

NRTI combination for a pregnant individual.

Answer 23

Zidovidine-Lamivudine

Question 24

What three NRTIs are active against HepB?

Answer 24

Tenofovir
Emtracitabine
Lamivudine

Question 25

MOA of Non-Nucleoside Reverse Transcriptase Inhibitors

Answer 25

Bind to reverse transcriptase at site different form NRTIs.

Question 26

How is the activation of Non-Nucleoside Reverse Transcriptase Inhibitors different than NRTIs?

Answer 26

Do not require phosphorylation to be active or compete with nucleosides.

Question 27

**What NNRTI is avoided in pregnancy?**

Answer 27

Efavirenz (DOC)

Question 28

What NNRTI is used during pregnancy or if a woman is trying to conceive?

Answer 28

Nevirapine (1st line alternative).

Question 29

**What NNRTI is used if resistance to other NNRTIs is developed?

Answer 29

Etravirine (1st line alternative).

Question 30

If a woman is on efavirenz and becomes pregnant, what should be done?

Answer 30

If viral suppression has been achieved, continue efavirenz-containing regimen.

Question 31

Rash/hypersensitivity - think what class of drugs?

Answer 31

All NNRTIs

Question 32

A HIV+ pt is taking a NNRTI and develops a skin burn-type reaction. What is this reaction and which drug are they most likely taking?

Answer 32

Stevens-Johnson | think Nevirapine.

Question 33

Why do you start a TB+ and HIV+ pt on TB tx-regiment first?

Answer 33

- Because the NNRTIs have a -life-threatening hepatotoxicity (nevirapine). - Because NNRTIs induce CYP450 (efavirenz)

Question 34

K103N mutation - associate with what? | What is the one drug exception that can be used?

Answer 34

Point mutation in virus that confers drug resistance to NNTRIs. -Etravirine

Question 35

**Preferred combo of NTRIs and NNTRI (not pregnant)** | Other than HIV, what else does it treat?

Answer 35

NTRI - Tenofovir+Emtracitabine NNTRI - Efavirenz Also treats HepB

Question 36

**Preferred combo of NTRIs and NNTRI (pregnant)**

Answer 36

NTRI - Zedovidine-Lamivudine (Lamivudine=HepB) | NNTRI - Nevirapine

Question 37

MOA of Protease inhibitors

Answer 37

PIs prevent maturation of new viruses because it inhibits the HIV-1 protease (pol gene), which normally cleaves products of HIV mRNA into functional parts.

Question 38

**Significance of ritonavir

Answer 38

"Boosting" - CYP3A inhibitor | Used with other oral protease inhibitors (atazanavir or lopinavir) to inhibit their hepatic metabolism

Question 39

**MOA of ritonavir's boosting effects.

Answer 39

Decreases the extensive first pass hepatic metabolism of the other Protease Inhibitors - **Atazanavir, Lopinavir**

Question 40

A HIV+ person (about to start tx regimen) has PCP pneumonia and tx with TMP-SMX. They develop a life threatening allergic reaction. What PI is contraindicated?

Answer 40

Darunavir and fosamprenavir, and tipranavir are sulfonamides, so should not be given to a person with a sulfonamide allergy (allergy to SMX)

Question 41

Short term adverse effect of Protease Inhibitors.

Answer 41

Hepatotoxicity (*atanazavir and PPIs, CYP450 interactions, esp with ritonavir**)

Question 42

Adding PI to the regimen of NRTIs increases what adverse effect?

Answer 42

Triples the prevalence of lipodystrophy (compounds already present in NRTIs).

Question 43

Preferred treatment combos (4) for NRTIs + PIs

Answer 43

``` NRTIs - Tenofovir + Emtracitabine PIs (Preferred): 1. **Atazanavir+Ritonavir 2. Darunavir+Ritonavir PIs (Alternates): 3. **Lopinavir+Ritonavir** 4. Fosamprenavir+Ritonavir ```

Question 44

A person (nonpregnant) gets a needle puncture wound and/or is exposed to blood or semen of a HIV infected individual. What is the appropriate Post-exposure Prophylaxis?

Answer 44

Tenofovir + emtricitabine + Lopinavir + Ritonavir | Four weeks, 1x/day

Question 45

A person (pregnant) gets a needle puncture wound and/or is exposed to blood or semen of a HIV infected individual. What is the appropriate Post-exposure Prophylaxis?

Answer 45

Zidovudine + Lamivudine + Lopinavir + Ritonavir (Four weeks, 2x/day)

Question 46

Post-exposure Prophylaxis - add what class to NRTIs?

Answer 46

Protease Inhibitor

Question 47

Overall Preferred REgimen in HIV+ Women:

Answer 47

2 NRTIs + PIs Zidovudine + Lamivudine + Lopinavir + Ritonavir (2x/day)

Question 48

MOA of Integrase strand transfer Inhibitors (IIs) and name of drug.

Answer 48

Raltegravir | Inhibits HIV genome integration into host cell chromosome by irreversibly inhibiting HIV integrase

Question 49

Advantage of using Raltegravir over a protease inhibitor?

Answer 49

Does not cause lipid-causing morphologic changes.

Question 50

MOA of fusion inhibitor enfuvirtide.

Answer 50

Binds gp41, inhibiting viral entry.

Question 51

MOA of fusion inhibitor maraviroc.

Answer 51

Binds CCR-5 on surface of T cells/monocytes, inhibiting interaction with gp120.

Question 52

Which Protease Inhibitor ahs a black box label?

Answer 52

Tripranavir - fatal hepatitis and IC hemorrhage.