C.6. Antiretroviral agents.

Question 1

What is the HAART regime?

Answer 1

Highly active antiviral therapy

which is a combination of drugs that are used to suppress the replication of HIV and restore the number of CD4 cells.

Question 2

What are the classes of antiviral therapy?

Answer 2

Each of the classes of the antiviral therapy target a different process of the virus:

1. Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIS).
2. Non nucleoside reverse transcriptase inhibitors (NNRTIS).
3. Protease inhibitors (PIS).
4. Entry inhibitors.
5. Integrase inhibitors.

Question 3

Indications to start HAART therapy

Answer 3

start the combo with 2NRTI and 1NNRTI or PI or intergrase inhibitor or maraviroc.

1. Incase of HIV symptoms (related to opportunistic infecitons).
2. If the CD4 cell count is lower than 200/ul (also recommeneded before 350).
3. Viral count is above 5000.
4. Pregnancy.

Question 4

NRTI
Mechanism:
name 2 of each group

Answer 4

Mechanism: Termination of DNA chain.
thymidine analogs: zidovudine (AZT), stavudine (4dt).
Cytidine analogs: Lamivudine (3tc), emtricitabine (ftc), zalcitabin (ddc),
purin analogs: didanosin (ddi), abacavir (ABC), tenofovir (tdf).

No cross resistance among the drugs!

Kinetics:
Primarily renally excreted.
Penetrate the CNS (besides tenofovir).
admin: Oral

Adverse effect: 
Lactate acidosis.
Pancreatitis, 
Liver toxicity.
peripheral neuropathia
bone abnormalities.
GI disorders
Anemia and leukopenia.

Question 5

AZT?

Answer 5

thymidine analogs: zidovudine (AZT),

Anemia leukopenia

Question 6

4dt?

Answer 6

thymidine analogs: stavudine (4dt).

pancreatitis and peripheral neruopathia

Question 7

3tc?

Answer 7

Cytidine analogs: Lamivudine (3tc),

pancreatitis and peripheral neruopathia

Question 8

ftc?

Answer 8

Cytidine analogs: emtricitabine (ftc),

Question 9

ddc?

Answer 9

Cytidine analogs: zalcitabin (ddc),

Question 10

ddi?

Answer 10

purin analogs: didanosin (ddi)

pancreatitis and peripheral neruopathia

Question 11

ABC

Answer 11

purine analogue: , tenofovir (tdf).

Question 12

tdf?

Answer 12

purine analogue: tenofovir

nephrooxic and bone abnormalities

Question 13

NNRTIS

Answer 13

1st generation: nevirapin, efavirenz.
2nd generation: etraviris or rilpivirn.

Mechanism: Inhibition of RNA dependant DNA polymerization (binds to P66 subunit).

Kinetics:
Nevirapin can penetrate CNS (only known one).
Admin: Oral

ADverse:
Liver and GI disorders
Steven johnson syndrome
CNS problems with nevirapine (since it penetrates CNS) and TERATOGENICITY (nevirapine).

Question 14

Protease inhibitors:

Answer 14

Ritonavir, indinavir, lopinavir, fosamprenavir, nelfinavir, atazanavir, saquinavir and more…
“-avirs”

Kinetics: Blocks the Gag and POL protease inhibitors.

Kinetics:
No CNS entry.
Orally taken

Adverse: 
Insulin resistance 
Hyperlipidemia and central obesity
Liver enzymes are elevated
GI and neurological disorders
allergic

No cross resistance between the drugs!

Question 15

Integrase inhibitors:

Answer 15

Raltegravir, elvitegravir, dolutegravir.

Mechanism: Binding to the integrase inhibits the intergration of the proviral dna to the host chromosome.

Admin Oral

Adverse: GI
headache,
Rhabdomyolysis
myopathy.

Question 16

entry inhibitor

Answer 16

enfuvirtid,
other -viritds are in trial
Binds to GP41 HIV and inhibits the binding to the cells (a fusion inhibitor- hiv will not be able to fuse its membrane with that of the host).

admin: subcutaneous administration

Adverse:
Well tolerated drug.

Question 17

CCR5 Coreceptor antagonist

Answer 17

Maraviroc
CCR5 coreceptor anatagonist on the macrophages but not effective on CXCR4.
Given orally
metabolized by liver

Adverse: Headache, dizziness, orthostatic hypotension
Pyrexia airway infection and CARCINOGENIC?