Treatment of HIV

Question 1

RTIs

Answer 1

Reverse Transcriptase Inhibitors

Question 2

Zidovudine

Answer 2

The prototype NRTI

• nucleoside antimetabolite (G or C)
• converted to active form via phosphorylation reactions

Question 3

NRTIs

Answer 3

Nucleoside Reverse Transcriptase Inhibitors

General characteristics:

1. All are prodrugs & chain terminators (non-specific)
2. Are components of most drug regimens used in HIV
3. COMPETITIVE INHIBITION
4. Lactic Acidosis = General Side Effect

Question 4

Which class of drugs are typically given with NRTIs in the treatment of HIV?

Answer 4

PIs (protease inhibitors)

Question 5

NNRTIs

Answer 5

Non-Nucleoside Reverse Transcriptase Inhibitors

1. Inhibit reverse transcriptase at a site different from the one NRTIs bind to
2. Are not myelosuppressant
3. NON-COMPETITIVE INHIBITION
4. General Side Effect = RASH

Question 6

Nevirapine, Efavirenz, Delavirdine, Etravirine, Ripivirine

Answer 6

NNRTIs

Question 7

What is Nevirapine good for?

Answer 7

A single does decreases vertical transmission of HIV by 50%

Remember: it also induces P450

Question 8

Side effects of Nevirapine

Answer 8

Rash and increased LFTs

Question 9

What is the classic side effect of Efavirenz?

Answer 9

1. NIGHTMARES

Also:

2. False positive marijuana test
3. Teratogenic

Question 10

What are the other names of Zidovudine?

Answer 10

Azidothymidine, ZDV, and AZT (remember all 4 for Step 1)

Question 11

MOA for Zidovudine

Answer 11

1. Phosphorylated nonspecifically to a triphosphate that can inhibit reverse transcriptase by competing with natural nucleotides
2. Incorporated into viral DNA to cause chain termination

**Resistance occurs by mutations in the gene that codes for RT

Question 12

Pol Gene

Answer 12

Gene that codes for Reverse Transcriptase

(also encodes Integrase and Protease)

Question 13

Emtricitabine (FTC), Abacavir (ABC), Didanosine (DDI), Lamivudine (3TC), Zalcitabine (DDC), and Stavudine (D4T)

Answer 13

Other NRTIs

• MOA identical to that of zidovudine
• Not complete cross-resistence between NRTIs
• Drugs differ in their toxicity profiles and are less bone marrow suppressing

Question 14

Major side effect of AZT?

Answer 14

Hematotoxicity (dose-limiting)

Megoblastic anemia from Bone Marrow Suppression

Question 15

Major side effect of Didanosine (DDI)?

Answer 15

Pancreatitis (dose-limiting)

Other drug that causes pancreatitis is Ritonavir (a PI)

Question 16

Unique characteristics of Lamivudine (3TC)?

Answer 16

Least toxic of the NRTIs & Active in Hepatitis B

Question 17

Major side effect of Zalcitabine (DDC)?

Answer 17

Peripheral Neuropathy (dose-limiting)

Question 18

Major side effect of Stavudine (D4T)?

Answer 18

Peripheral Neuropathy (dose-limiting)

Question 19

Which NRTI combinations do you have to avoid?

Answer 19

DDI (didanosine) w/ DDC (zalcitabine)

and

AZT (zidovudine) w/ D4T (stavudine)

NOTE: DDC and D4T are older drugs that are not used much anymore

Question 20

PIs

Answer 20

Protease Inhibitors

Major side effect = GI Intolerance

Question 21

MOA for PIs

Answer 21

NOTE: HIV protease (inhibited by PIs) is similar to the protease that clips off c-peptide to form active insulin from a prodrug

1. Aspartate protease (pol gene encoded) is a viral enzyme that cleaves precursor polypeptides in HIV buds to form the proteins of the mature virus core
2. Enzyme contains a dipeptide structure not seen in mammalian proteins (PIs bind this dipeptide and inhibit the enzyme)

Question 22

Resistance to PIs

Answer 22

Occurs via specific point mutation in the pol gene

Question 23

Ritonavir

Answer 23

Prototype PI

Major drug interactions with:

Inhibits P450 (useful to increase duration of other drugs)

Question 24

Lopinavir, atazanavir, and darunavir

Answer 24

PIs commonly coformulated with ritonavir

Question 25

Side effects of Indinavir

Answer 25

Crystalluria (maintain hydration) AKA KIDNEY STONES

Question 26

General side effects of PIs

Answer 26

Syndrome of disordered lipid and CHO metabolism with central adiposity and insulin resistance (aka Type II DM)

Question 27

Raltegravir

Answer 27

Integrase Inhibitor Prevents integration of viral genome in host cell DNA

Question 28

IRIS

Answer 28

Immune Reconstitution Inflammatory Syndrome BLUF: hypersensitivity rxn after restoring immune system in an HIV infected patient Increase in functional CD4 cells = brisk immune response againt CMV, HIV and TB

Question 29

What steps do you take if IRIS occurs following ART treatment?

Answer 29

Paradoxical response (i.e., CONTINUE treatment)

Question 30

Major side effect of Abacavir (ABC)

Answer 30

NRTI that causes life-threatening hypersensitivity Heptomegaly in HLA-B\*5701 patients

Question 31

Patient is being treated for HIV and develops kidney stones (which 2 drugs might they be taking)?

Answer 31

Indinvair and Atazanavir

Question 32

Patient being treated for HIV develops jaundice (which drug might they be taking)?

Answer 32

Atazanavir (causes increased bilirubin)

Question 33

Which drug can be given to an HIV patient with dual tropism (i.e., CCR5 and CXCR4) to inhibit gp120?

Answer 33

NONE. Maraviroc binds to CCR5 and prevents gp120 from binding and undergoing a conformational change. If a patient has a single CD4 cell infected with HIV (CXCR4 tropism), then this treatment is not indicated