Micro - Antimicrobials (HIV therapy)

Question 1

What does HAART stand for? What are the criteria for it to be initiated?

Answer 1

Highly active antiretroviral therapy (HAART): initiated when patients present with AIDS-defining illness, low CD4 cell counts (<500 cells/mm^3), or high viral load.

Question 2

What makes up the HAART regimen?

Answer 2

Regimen consists of 3 drugs to prevent resistance: [2 nucleoside reverse transcriptase inhibitors (NRTIs)] + [1 non-nucleoside reverse transcriptase inhibitors (NNRTI) OR 1 protease inhibitor OR 1 integrase inhibitor]

Question 3

What are 7 examples of protease inhibitors? What is common to all of them?

Answer 3

(1) Atazanavir (2) Darunavir (3) Fosamprenavir (4) Indinavir (5) Lopinavir (6) Ritonavir (7) Saquinavir; All protease inhibitors end in -navir; “NAVIR (never) TEASE a PROTEASE”

Question 4

Explain how protease inhibitors work against HIV.

Answer 4

Assembly of virions depends on HIV-1 protease (pol gene), which cleaves the polypeptide products of HIV mRNA into their functional parts. Thus, protease inhibitors prevent maturation of new viruses.

Question 5

What effect can Ritonavir have on other drug concentrations, and how?

Answer 5

Ritonavir can “boost” other drug concentrations by inhibiting cytochrome P-450.

Question 6

What are 3 toxicities associated with protease inhibitors in general?

Answer 6

(1) Hyperglycemia (2) GI intolerance (nausea, diarrhea) (3) Lipodystrophy

Question 7

What are 2 toxicities associated with Indinavir?

Answer 7

(1) Nephropathy (2) Hematuria (Indinavir)

Question 8

What are 7 examples of NRTIs?

Answer 8

(1) Abacavir (ABC) (2) Didanosine (ddI) (3) Emtricitabine (FTC) (4) Lamivudine (3TC) (5) Stavudine (d4T) (6) Tenofovir (TDF) (7) Zidovudine (ZDV, formerly AZT)

Question 9

What is the mechanism of NRTIs?

Answer 9

Competitively inhibits nucleotide binding to reverse transcriptase and terminate the DNA chain (lack a 3’ OH group).

Question 10

What kind of molecules are most NRTIs? What is required for their activation? What is the exception to this rule?

Answer 10

Tenofovir is a nucleoTide; the others are nucleosides and need to be phosphorylated to be active

Question 11

What is ZDV? In what 2 contexts is it used?

Answer 11

ZDV is used for general prophylaxis and during pregnancy to lower risk of fetal transmission; Think: “haVE YOU DINED (vudine) with my NUCLEAR (NUCLEOsides) family?”

Question 12

What are 6 toxicities associated with NRTIs? Where applicable, clarify which toxicities apply to which NRTIs.

Answer 12

(1) Bone marrow suppression (can be reversed with granulocyte colony-stimulating factor [G-CSF] and erythropoietin) (2) Peripheral neuropathy (3) Lactic acidosis (nucleosides) (4) Rash (non-nucleosides) (5) Anemia (ZDV) (6) Pancreatitis (didanosine)

Question 13

How can NRTI-induced bone marrow suppression be reversed?

Answer 13

Bone marrow suppression (can be reversed with granulocyte colony-stimulating factor [G-CSF] and erythropoietin)

Question 14

What are 3 examples of NNRTIs?

Answer 14

(1) Efavirenz (2) Nevirapine (3) Delavirdine

Question 15

What is the mechanism of NNRTIs? How do they differ from NRTIs?

Answer 15

Bind to reverse transcriptase at site different from NRTIs. Do not require phosphorylation to be active or compete with nucleotides.

Question 16

What is 2 toxicities are common to all NNRTIs?

Answer 16

Rash and hepatotoxicity are common to all NNRTIs

Question 17

What are 2 toxicities common to efavirenz?

Answer 17

Vivid dreams and CNS symptoms are common with Efavirenz.

Question 18

What 2 NNRTIs are contraindicated in pregnancy?

Answer 18

Delavirdine and Efavirenz are contraindicated in pregnancy

Question 19

What is the name of a specific Integrase inhibitor?

Answer 19

Raltegravir

Question 20

What is the mechanism of Raltegravir?

Answer 20

Inhibits HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase

Question 21

What toxicity is associated with Raltegravir?

Answer 21

Hypercholesterolemia

Question 22

What are 2 examples of Fusion inhibitors?

Answer 22

(1) Enfuvirtide (2) Maraviroc

Question 23

What is the mechanism of Enfuvirtide, and what effect does it have?

Answer 23

Binds gp41, inhibiting viral entry

Question 24

What is the mechanism of Maraviroc, and what effect does it have?

Answer 24

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

Question 25

What is the toxicity associated with fusion inhibitors?

Answer 25

Skin reaction at injection sites