16 Pharmacogenomics in Viral Infections

Question 1

What part of the genome contains most of the genetic mutations?

Answer 1

Promoter region and Introns

Question 2

What is usually done in Phase 1 Metabolism?

Answer 2

Done through CYP enzymes

Question 3

What is usually done in Phase 2 Metabolism?

Answer 3

Done through UGTs, Sulfation, etc

Question 4

What are the biggest inhibitors of OATP1B1?

Answer 4

Cyclosporin, Rifamycin, Rifampin

Question 5

What class of drugs commonly inhibits OATP1B1?

Answer 5

Statins (Atorva > Lova > Simva > Rosuva

Question 6

What do CYP 2B6 SNPs predict?

Answer 6

Efavirenz and Nevirapine plasma levels

Question 7

What do CYP 2C19 SNPs predict?

Answer 7

Predicts Nelfinavir plasma levels

Question 8

What does HLA predict?

Answer 8

Nevirapine rash and/or liver toxicity

Question 9

What do UGT1A1 variants predict?

Answer 9

Atazanavir and Indinavir bilirubin levels

Question 10

What does APOC predict?

Answer 10

Plasma lipids on protease inhibitors

Question 11

What does SLCO1B1 predict?

Answer 11

Lopinavir plasma levels

Question 12

What is UDP Glucuronyl Transferase 1A1 responsible for?

Answer 12

Responsible for Gilbert’s Bilirubinemia. Absent in ~15% of Caucasians (> 50% in AA and Hispanics). Decreased activity in hypoglycemic and malnourished conditions, so Gilbert’s hyperbilirubinemia is “revealed” by these conditions

Question 13

Which CYP enzyme is most active in fetus?

Answer 13

CYP 3A7, gets replaced by CYP 3A4 after birth

Question 14

What are the major Pgp substrates?

Answer 14

Digoxin. Verapamil. Fexofenadine (Allegra). HIV Protease Inhibitors. Erythromycin

Question 15

What are the major Pgp inhibitors?

Answer 15

Macrolides (except Azithromycin). Cyclosporin. Itraconazole, Ketoconazole

Question 16

What are the major Pgp inducers?

Answer 16

Rifampin and St. Johns Wort

Question 17

Which genotype for MDR-1 has the best CD4 count response with Nelfinavir?

Answer 17

TT > CT > CC

Question 18

What MDR-1 genotype do AA have?

Answer 18

68% have CC. This causes them to have very high plasma concentrations –> CNS ADRs. Low intracellular levels, poor outcomes. CC genotype also causes Hepatotoxicity with Nevirapine treatment

Question 19

How does ethnicity effect Efavirenz?

Answer 19

Decreased EFV clearance associated with AA race. EFV concentrations not associated with CNS virologic suppression or CNS toxicity. Trend toward increased EFV concentration and increased discontinuation

Question 20

When it comes to CYP 2B6 genotype and Efavirenz, what do AAs have?

Answer 20

AAs have TT > GT > GG, which causes very high Efavirenz plasma levels

Question 21

Which transports do RTV block?

Answer 21

MRPs and Pgp

Question 22

How can adding RTV and TFV cause cellular death?

Answer 22

TFV is brought into the cell through OAT-1, it would then usually be pumped into the lumen (urine flow) through MRPs and Pgp. RTV blocks these pumps, causing TFV –> TFV-MP –> TFV-DP, which gets into the mitochondria and causes damage

Question 23

Which genotype of IL28 has the best response to therapy?

Answer 23

CC