C.6

Question 1

Antiretroviral agents

Answer 1

1. NRTIs: Abacavir, Zidovudine, Lamivudine, Emtricitabine, Tenofovir
2. NNRTI: Etravirine
3. Protease inhibitors: Darunavir, Ritonavir
4. Integrase inhibitor: Dolutegravir
5. Entry inhibitor: Maraviroc

Question 2

Zidovudine, Lamivudine, Emtricitabine, Tenofovir, Abacavir

Answer 2

MOA: NRTIs→ Terminate the growing DNA chain→ inhibit binding of nucleotides to reverse transcriptase (RNA-dependent DNA polymerase);
IND: HIV1,2 infections, lamivudine, emtricitabine and tenofovir are also for HBV;
SEs: GI symptoms, headache, hepatotoxicity, lactic acidosis;
Kinetics: p.o administration, All penetrate CNS except tenofovir, renal excretion, no cross resistance

Question 3

Zidovudine (AZT)

Answer 3

MOA: Thymidine analog, NRTI;
SEs: BM suppression (anemia, leukocytopenia)

Question 4

Lamivudine (3TC), Emtricitabine (FTC)

Answer 4

MOA: Cytidine analogs, NRTIs;
SEs: lamiduvine- peripheral neuropathy

Question 5

Tenofovir (TDF), Abacavir (ABC)

Answer 5

MOA: TDF- is a nucleotide analog (doesn’t need to be phosphorylated), ABC- Purine analog, NRTIs;
SEs: ABC- hypersensitivity reactions.
TDF- nephrotoxicity, bone damage

Question 6

Etravirine

Answer 6

MOA: 2nd generation NNRTI, binds to RT and denatures it → enzyme cannot produce viral DNA;
IND: HIV1 only;
Kinetics: administered p.o, hepatic metabolism, higher potency than gen1 NNRTIs, longer T1/2, less SEs;
SEs: hepatotoxicity and GI disorders, skin reactions, even SJS

Question 7

Darunavir, Ritonavir

Answer 7

MOA: PI→ inhibition of HIV protease→ they usually cleave precursor polypeptides (Gag + Gag-Pol) that form the final structural proteins of the virus;
IND: HIV infections, Ritonavir-ONLY as booster;
SEs: insulin resistance, hyperlipidemia, peripheral lipodystrophy, transaminase elevation, GI and neurological disorders, allergic reactions;
Kinetics: various p.o BA, no CNS penetration, T1/2: variable, Hepatic metabolism by CYP3A4, no general cross-resistance between PIs;
Boosters: ↑p.o BA and elevate plasma levels of other PIs,
Ritonavir: blocks CYP3A4, induces CYP1A2 and P-glycoprotein

Question 8

Dolutegravir

Answer 8

MOA: binds integrase and inhibits the integration of pro-viral DNA to host chromosome;
IND: HIV1;
Kinetics: low cross resistance, higher genetic barrier; SEs: severe hypersensitivity reactions, insomnia; Contra-IND: pregnancy

Question 9

Maraviroc

Answer 9

MOA: CCR5 coreceptor antagonist→ prevent interaction between viral gp120 and CD4 on target cell→ no entry;
IND: HIV, given only after tropism testing of HIV;
SEs: allergic liver disorders, increased prevalence of malignancies;
Kinetics: administered p.o, Hepatic metabolism (CYP3A4)

Question 10

HIV

Answer 10

HIV has 2 strains but since HIV2 is quite rare, when we say HIV it almost always refers to HIV1 since it’s much more common worldwide. HIV targets CD4+ cells (macrophages, dendritic cells and T cells), HIV attaches to CD4 via gp120 and then it also binds to a co-receptor CXCR4 (mainly on T cells) or CCR5 (Tcells, monocytes, macrophages and dendtritic cells).
Once HIV binds CXCR4/CCR5 it etnters the cell and can use its RT enzyme to produce a pro-viral DNA and can be integrated in the human DNA. when the immune system gets activated it will also transcribe and translate more viral proteins and more viruses. HIV can mutate during replication, it’s still HIV but the mutated strains can behave a bit differently, and can target different cells in the host, this host cell preference is called TROPISM.

Question 11

Tropism testing

Answer 11

help your doctor find out which co-receptors the HIV in your body uses. If you have HIV that uses CCR5 co-receptors, then it can be treated with maraviroc. If your HIV uses CXCR4 co-receptors, then maraviroc or other drugs that block CCR5 will not work.