antiretroviral pharm

Question 1

HIV life cycle

Answer 1

binding to CCR5 or CXCR4 receptors > fusion and uncoating > reverse transcription > integration > transcription > translation > virion assembly > budding and maturation

Question 2

Maximally suppressive antiretroviral therapy requires how many drugs

Answer 2

at least 3

Question 3

goals of anti-HIV therapy

Answer 3

Durable suppression of HIV viral load (< 50 copies/ml). Restoration of immune function (CD4 cell count). Prevent HIV transmission, prevent drug resistance, improve QOL

Question 4

Describe the general HIV treatment regimen

Answer 4

“Backbone” – typically 2 NRTIs. Tenofovir and emtricitabine preferred. “Base” – NNRTI (Efavirenz),OR protease inhibitor (Atazanavir or Darunavir), OR integrase strand transfer inhibitor (Raltegravir), OR CCR5 antagonist (Maraviroc)

Question 5

drugs used to prevent perinatal transmission of HIV

Answer 5

Ritonavir-Lopinavir-rLPV plus Zidovudine-ZDV and Lamivudine-3TC

Question 6

HLA screening for antiretrovirals

Answer 6

HLA 5701 can cause hypersensitivity to abacavir (NRTI)

Question 7

Which antiretroviral is contraindicated in pregnancy

Answer 7

efavirenz (NNRTI)

Question 8

List the NRTIs

Answer 8

Emtricitabine, Tenofovir disoproxil fumarate and abacavir, azidothymidine (AZT)

Question 9

NRTIs MOA and resistance

Answer 9

Nucleoside reverse transcriptase inhibitor. Prevents genome replication and establishment of provirus. prodrug- Activated by intracellular kinases to active triphosphate which competitively inhibits viral RT and causes chain termination. Resistance can arise via mutations on RT and cross resistance within class is common so certain NRTI combos are avoided

Question 10

NRTIs absorption, elimination, considerations

Answer 10

Oral. Intracellular half lives are longer than plasma half lives due to trapping inside cells. Abacavir undergoes hepatic metabolism. Emtricitabine and tenofovir undergo renal excretion (no DDIs) so once daily dosing

Question 11

NRTIs adverse rxns

Answer 11

Inhbition of mitochondrial DNA polymerase gamma can cause anemia, myopathy, neuropathy. Lactic acidosis and hepatic steatosis possible

Question 12

Best tolerated NRTIs

Answer 12

lamivudine and emtricitabine (least toxic): both are also active against HBV. and tenofovir

Question 13

disadvantages of dual NRTIs

Answer 13

Lactic acidosis and hepatic steatosis: lower risk with tenofovir and emtricitabine. Also lipodystrophy possible

Question 14

List the NNRTIs

Answer 14

Efavirenz (plus nevirapine, etravirine)

Question 15

NNRTIs MOA

Answer 15

Non-nucleoside RT inhibitors.•Prevents genome replication - establishment of provirus. Do NOT require activation by intracellular kinases. Bind to non-catalytic hydrophobic region > non-competitively inhibit HIV Reverse Transcriptase

Question 16

NNRTIs resistance

Answer 16

Single AA substitutions on RT. Cross resistance across multiple NNRTIs possible. Etravirine has high barrier to resistance

Question 17

NNRTIs absorption, DDIs

Answer 17

Oral. Nevirapine crosses placenta. Efavirenz induces CYP3A4 (decreases methadone levels)

Question 18

Efavirenz adverse rxns

Answer 18

Severe CNS effects possible. Pregnancy category D. Rash, dizziness, headahce, insomnia

Question 19

Nevirapine adverse rxns

Answer 19

Greater potential for toxicity than efavirenz including hepatic necrosis and serious cutaneous reactions

Question 20

Etravirine adverse rxns

Answer 20

•Generally well tolerated. Rash (less than nevirapine, but can be severe), nausea, hypertension, peripheral neuropathy

Question 21

Disadvantages of NNRTIs in initial therapy

Answer 21

Low genetic barrier to resistance - single mutation, Cross resistance among most NNRTIs, Rash, hepatotoxicity (esp. nevirapine), Potential CYP450 drug interactions, Transmitted resistance to NNRTIs more common than resistance to Pis.

Question 22

Advantages of NNRTIs in initial therapy

Answer 22

long half lives, less metabolic toxicity than Pis, Pis and INSTIs preserved for future use.

Question 23

List the protease inhibitors

Answer 23

Atazanavir, Darunavir

Question 24

Protease inhibitors MOA

Answer 24

•Noncleavable peptidomimetic agents that selectively target retroviral aspartyl proteases (not host proteases) HIV proteases cleaves and processes HIV gag and pol proteins necessary for survival and replication. Thus PIs prevents viral maturation.

Question 25

Protease inhibitors resistance

Answer 25

Requires multiple mutations. High barrier to resistance

Question 26

Protease inhibitors absorption, DDIs

Answer 26

oral. Metabolized by CYP3A4 so Ddis can occur if other drugs (like rotonavir) inhibit CYP3A4.

Question 27

Pis adverse rxns

Answer 27

GI upset, hyperglycemia, hyperlipidemia, risk of CAD, central fat accumulation. Darunavir can cause severe rash (Stevens Johnson syndrome)

Question 28

Pis advantages and disadvantages in intial therapy

Answer 28

advantages: high genetic barrier to resistance. Disadvantages: metabolic complications, GI intolerance, CYP450 drug interactions

Question 29

List the INSTIs

Answer 29

Raltegravir

Question 30

INSTIs MOA

Answer 30

Integrase Strand Transfer Inhibitors - Viral integrase catalyzes direct insertion of viral DNA into host cell DNA. INSTIs inhibit integrase activity preventing HIV-1 replication. No effect on human DNA polymerases

Question 31

INSTIs advantages and disadvantages in initial therapy

Answer 31

advantages: few adverse events, does NOT have DDIs via CYP3A4 interactions. Disadvantages: twice daily dosing, higher risk of resistance than Pis, myopathy, rhabdomyolysis and skin reactions possible

Question 32

HIV mechanisms of entry and when they occur

Answer 32

•HIV-1 virions using CCR5 called “R5 tropic”, present during initial and chronic phases. HIV-1 virions using CXCR4 called “X4 tropic”, associated with later stages and disease progression

Question 33

List the steps of HIV-1 entry

Answer 33

CD4 binding > gp120 conformational change and co-receptor binding > gp41 conformation change/fusion

Question 34

List the HIV entry inhibitors

Answer 34

Maraviroc

Question 35

Maraviroc MOA

Answer 35

antagonist of CCR5 receptor that inhibits its interaction with viral gp120. Indicated for treatment experienced adults with R5-tropic virus

Question 36

Maraviroc resistant

Answer 36

Most common when X4 strains are also present. Mutations in viral gp 120

Question 37

Maraviroc disadvantages

Answer 37

requires tropism testing before use (CCR5 vs CXCR4).

Question 38

Enfuvirtide MOA

Answer 38

Inhibits fusion of HIV-1 with host cell. Enfuvirtide is a synthetic peptidomimetic of the viral gp41 HR2 sequences . prevention of viral entry into cell and infection.

Question 39

Enfuvirtide absorption

Answer 39

•As peptide, must be administered subcutaneously

Question 40

Enfuvirtide adverse rxns

Answer 40

injection site reaction, eosinophilia, bacterial pneumonia, hypersensitivity rxns