Antiviral Agents- 2

Question 1

List a nucleoside Reverse Transcriptase Inhibitor

Answer 1

Emtricitabine, FTC

Question 2

List a NONnucleoside reverse transcriptase inhibitor (NNRTI)

Answer 2

Efavirenz, EFV

Question 3

List a protease inhibitor

Answer 3

Atazanavir, ATV

Question 4

T/F: A general principal of antiretroviral therapy is drug resistance with monotherapy.

Answer 4

True- must give multiple drugs simutaneously

Question 5

HAART stands for:

Answer 5

Highly active antiretroviral therapy

Question 6

General MOA for NRTIs (Emtricitabine)

Answer 6

1) Incorporated into DNA and terminate chain elongation.

2) Also inhibit cellular DNA polymerases, particularly mitochondrial polymerases.

Question 7

What antiviral drug is this: Analogue of cytidine; can be taken orally or given IV.

Answer 7

Emtricitabine

Question 8

Adverse Symptoms of Emtricitabine

Answer 8

Adverse: Diarrhea, headache, nausea, rash.

• Toxic effects uncommon
• Severe: Hepatotoxicity, lactic acidosis, relatively rare but high fatality

Question 9

Resistance to NRTIs (Emtricitabine)

Answer 9

• Results mainly from mutations in the reverse transcriptase gene.
• Mutations accumulate gradually and after one year about 1/3 of patients are resistant.

Question 10

Metabolism of NRTIs (Emtricitabine)

Answer 10

Primarily by the KIDNEY, rather than CYP system.

Question 11

Mitochondrial toxicities related to NRTIs (7)

Answer 11

• Neuropathy
• Myopathy
• Myocarditis
• Pancreatitis
• Hepatic Steatosis
• Lipodystrophy
• Lactic acidosis

Question 12

Drug interactions of NRTIs (Emtricitabine) (3)

Answer 12

• Bone marrow toxic drugs
• Rifampin
• Fluconazole and TMP-SMX

Question 13

What drug has these effects:

• Vivid dreams, poor concentration
• Hepatitis, rash uncommon
• False positive cannabis test
• Non human primate teratogenicity so do not use in pregnancy

Answer 13

Efavirenz (NNRTI)

Question 14

What drug can lower Efavirenz (NNRTI) levels?

Answer 14

Rifampin

Question 15

MOA for Efavirenz (NNRTI) (3)

Answer 15

• Act in noncompetitive manner and do not compete with naturally occurring dNTPs.
• Bind directly to the RT at the site adjacent to the active site and cause conformational change and disrupt the enzyme’s catalytic site (allosteric inhibition).
• Do not require dephosphorylation to be active and no incorporated into viral DNA.

Question 16

Resistance to Efavirenz (NNRTI)

Answer 16

• Results form mutations in the RT.
• Develops rapidly if used alone or with one nucleoside
• Cross resistance to all NNRTIs
• HIV isolates resistant to NRTIs and PIs remain sensitive to NNRTIs

Question 17

1) How is Efavirenz (NNRTI) taken?
2) How is Efavirenz (NNRTI) metabolized?
3) Does Efavirenz (NNRTI) have a long or short half life?

Answer 17

1) Excellent oral absorption.
2) Metabolized by hepatic cytochrome P450 (primarily 3A4).
3) Long half lives

Question 18

Toxicity of Efavirenz (NNRTI)

Answer 18

• Skin rashes most common. Usually mild to moderate but can progress to Steven-Johnson syndrome.
• Liver enzyme elevation and hepatitis
• Fever, nausea, headache, somnolence

Question 19

Efavirenz (NNRTI) drug interactions

Answer 19

Can occur with PIs and many other drugs. They are metabolized by CYP enzymes and are both inhibitors and inducers of these enzymes.

Question 20

What antiretroviral drug is considered the most effective and act in the later stages of the replication cycle?

Answer 20

Protease Inhibitors -Atazanavir

Question 21

Protease inhibitors bind 1) (irreversible/reversibly) to the active site of the HIV protease to inhibit the HIV protease preventing post-2)_____________ processing of the viral polyproteins and thus blocking subsequent viral maturation.

Answer 21

1) Reversibly

2) Translational

Question 22

How does resistance to protease inhibitors occur?

Answer 22

By stepwise mutation in the protease gene. Cross resistance among PI inhibitors occurs.

Question 23

True False: PIs (Atazanavir) are:

1) Poor oral availability.
2) Metabolized through the kidney.
3) Substrates for p-glycoprotein.

Answer 23

1) True
2) False: All metabolized by hepatic cytochrome P450 enzymes (CYP 3A4). - Little drug is excreted by the kidney.
3) True

Question 24

Dual protease inhibitor combinations can increase potency, reduce dose, and reduce pill burdens. What drug is given as a “boost”?

Answer 24

Ritonavir (XXX/r)

Question 25

What is the most common toxicity seen with PIs (Atazanavir). What are other toxicities?

Answer 25

Most common: GI intolerance (Diarrhea, nausea, discomfort).
-Long term metabolic effects include peripheral fat wasting, abnormal fat redistribution, hyperlipidemia, hyperglycemia, new onset or worsening diabetes and insulin resistance.

Question 26

T/F: Protease Inhibitors (Atazanavir) has a lot of drug interactions.

Answer 26

True. EX: Amiodarone should not be used with Ritonavir. PIs increase AUC statins. Etc…

Question 27

Antiretroviral therapy (ART) is recommended for all HIV-infected individuals. What does ART do? (2)

Answer 27

• Reduce disease progression.
• Prevent transmission.
• Emphasize need to need to commit to treatment, adherence is key.

Question 28

Patients naive to antiretroviral therapy should be started on what combination?

Answer 28

2 NRTIs plus:

• NNRTI
• PI (preferably boosted with ritonavir)
• INSTI

Pregnancy: PI/r + 2NRTIs (Special recommendations)

Question 29

Metabolic disorders associated with PIs:

Answer 29

Insulin resistance/glucose intolerance/diabetes

Question 30

What mycobacterial drug should be avoided in HIV/TB therapy?

Answer 30

Rifampin- check CDC guidelines for HIV/TB therapy.