Topic 6-Antiretroviral agents

Question 1

Indications of starting the antiretroviral therapy (cART : Combined Antiretroviral Therapy)

Answer 1

1. ) in case of clinical HIV related symptoms (opportunistic infections) or HBV coninfection
2. )CD4+ is lower than 200/ul
3. )If viral load (HIV RNA count) is above 5000-10000/mL
4. )During pregnancy (except efavirenz)
5. )Post exposition prophylaxis for medical staff
6. )For children, more aggressive treatment
7. ) For HIV discordant sexual partners

Question 2

What is the cART?

Answer 2

2NRTI and Integrase inhibitors or 1 NNRTI or PI or maraviroc
Life long treatment is need, hold application
Very few examples of total eradication (once after bone marrow transplant and once in a connate case)

Question 3

Antiretroviral agent mechanisms

Answer 3

1. )Entry/Fusion/Attachment inhibitors
2. )Nucleoside/Nucleotide and Non-Nucleoside Reverse Transcriptase inhibitor
3. )Integrase inhibitor
4. )Maturation inhibitor
5. )Protease inhibitor

Question 4

Nucleoside/nucleotide RT inhibitors (NRTI)

Thymidine analogue:?

Answer 4

Thymidine analogue: Zidovudine

Question 5

Nucleoside/nucleotide RT inhibitors (NRTI)

Cytidine analogues:?

Answer 5

Cytidine analogues: Lamivudine, Emtricitabine

Question 6

Nucleoside/nucleotide RT inhibitors (NRTI)

Purine analogues:?

Answer 6

Purine analogues: Abacavir, tenofovir

Question 7

Mechanism of action of the NRTI (nuceoside/nucleotide RT inhibitors)

Answer 7

RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.

Question 8

What is the resistance like for NRTIs?

Answer 8

Lots of mutations are needed and no cross resistance between drugs

Question 9

Which NRTI penetrates the CNS

Answer 9

tenofovir

Question 10

Which NRTIs excreted through kidneys

Answer 10

zidovudin, abacavir, and didanosin

Question 11

Which NRTIs are active agaisnt HBV

Answer 11

Lamivudin, emtricitabin, and tenofovir

Question 12

Main adverse effects of NRTIs

Answer 12

GI issues, headache, fatigue, lactic acidosis, hepatomegalia, lypodystrophy, hepatitis, transaminase elevation

Question 13

Main adverse effect of zidovudin?

Answer 13

anemia, leukopenia

Question 14

Stavudin and Didanosin side effects?

Answer 14

Pancreatitis and peripheral neuropathy (these drugs aren’t used anymore)

Question 15

Main adverse effect of abacavir?

Answer 15

Hypersensitivity reaction for HLA-B*5701

Question 16

Main adverse effect of tenofovir?

Answer 16

Nephrotoxicity and bone abnormality (given with disoproxil and alafenamide to lower toxicity)

Question 17

Initial treatment with NRTIs?

Answer 17

one cytidine and one purine are combined and identical analogues should not be combined

Question 18

1st generation non-nucleoside RT inhibitors (NNRTI)

Answer 18

1st generation Nevirapin, Efavirenz

Question 19

2nd generation non-nucleoside RT inhibitors

Answer 19

2nd generation Etravirin, Rilpivirin

Question 20

NNRTIs are effective against

Answer 20

HIV-1

Question 21

A single point-mutation can cause resistance in which generation of NNRTIs

Answer 21

1st generation

Question 22

NNRTIs are metabolized where?

Answer 22

liver

Question 23

Which NNRTI penetrates well into the CNS

Answer 23

Efavirenz

Question 24

Which NNRTIs have low penetration

Answer 24

etravirin and rilpivirin, but enough to control HIV

Question 25

General adverse effects of NNRTIs

Answer 25

liver and GI issues, rash (Steven Johnson syndrome) | Efavirenz can cause CNS issues and is teratogenic

Question 26

What are the protease inhibitors

Answer 26

``` Ritonavir Lopinavir Atazanavir Darunavir Tipranavir ```

Question 27

Mechanism of protease inhibitors

Answer 27

Cleaves Gag and Gag-Pol polyproteins of HIV, that have key role in maturation of HIV (no cross reaction with human proteases)

Question 28

Adverse effects of protease inhibitors? Resistance?

Answer 28

insulin resistance, hyperlipidemia, abdominal fat uptake, transaminase elevation, GI, and neurological issue, and allergic reactions No cross resistance between PIs

Question 29

Kinetics of PI

Answer 29

Oral availability Don't enter CNS Metabolized by CYP3A4 in liver Half life is variable

Question 30

Which PI is metabolized by CYP2C19?

Answer 30

nelfinavir

Question 31

Which PI blocks CYP3A4?

Answer 31

Ritonavir

Question 32

What are the three integrase inhibitors

Answer 32

Raltegravir Elvitegravir Dolutegravir

Question 33

Mechanism of action of Raltegravir? | Kinetics?

Answer 33

``` Inhibits the integration of NA transcripted HIV into the human DNA chain oral administration (twice a day), conjugated by glururonic acid ```

Question 34

Adverse effects of Raltegravir

Answer 34

GI issues, headache, dizziness, skin rash CK elevation, myopathy

Question 35

Details of Elvitegravir

Answer 35

Administered once with „booster” (CYP3A inhibitor: ritonavir or cobicistat) - Cross- resistance with raltegravir - Combined tablet: elvitegravir(+cobicistat)+emtricitabin+ tenofovir - Side effects: similar to raltegravir - Simple administration but many interactions

Question 36

Details of Dolutegravir

Answer 36

- Low cross-resistance, higher genetic barrier | - Side effects: Sever hypersensitive reactions, insomnia, headache

Question 37

Entry inhibitor for HIV

Answer 37

Enfuvirtid

Question 38

Details of Enfuviritd

Answer 38

``` Binds to Gp41 of HIV and inhibits the binding to the cells Polypeptide structure,subcutaneous administered Well tolerated (local rxn, headache, nausea, bacterial pneumonia) Used for multidrug resistant cases ```

Question 39

CCR5 coreceptor antagonist

Answer 39

Maraviroc

Question 40

Maraviroc is effective in which case

Answer 40

macrophage infecting viruses, not effective on CXCR4 and mixed trop viruses CCR5 viruses are mainly present in earlier stages of the diseases CXCR4 viruses, which prefer T-cells, mainly appear later

Question 41

Adverse effects of Maraviroc

Answer 41

Headache, dizziness, orthostatic hypotension, airway infections, allergic liver disorder, increased prevalence of malignancies

Question 42

Kinetics of Maraviroc? Initial treatment?

Answer 42

Orally administered, metabolzed in liver (CYP3A4 interactions) Not recommended as initial treatment