Topic 6-Antiretroviral agents Flashcards
Indications of starting the antiretroviral therapy (cART : Combined Antiretroviral Therapy)
- ) in case of clinical HIV related symptoms (opportunistic infections) or HBV coninfection
- )CD4+ is lower than 200/ul
- )If viral load (HIV RNA count) is above 5000-10000/mL
- )During pregnancy (except efavirenz)
- )Post exposition prophylaxis for medical staff
- )For children, more aggressive treatment
- ) For HIV discordant sexual partners
What is the cART?
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)
Antiretroviral agent mechanisms
- )Entry/Fusion/Attachment inhibitors
- )Nucleoside/Nucleotide and Non-Nucleoside Reverse Transcriptase inhibitor
- )Integrase inhibitor
- )Maturation inhibitor
- )Protease inhibitor
Nucleoside/nucleotide RT inhibitors (NRTI)
Thymidine analogue:?
Thymidine analogue: Zidovudine
Nucleoside/nucleotide RT inhibitors (NRTI)
Cytidine analogues:?
Cytidine analogues: Lamivudine, Emtricitabine
Nucleoside/nucleotide RT inhibitors (NRTI)
Purine analogues:?
Purine analogues: Abacavir, tenofovir
Mechanism of action of the NRTI (nuceoside/nucleotide RT inhibitors)
RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replication of HIV and other retroviruses.
What is the resistance like for NRTIs?
Lots of mutations are needed and no cross resistance between drugs
Which NRTI penetrates the CNS
tenofovir
Which NRTIs excreted through kidneys
zidovudin, abacavir, and didanosin
Which NRTIs are active agaisnt HBV
Lamivudin, emtricitabin, and tenofovir
Main adverse effects of NRTIs
GI issues, headache, fatigue, lactic acidosis, hepatomegalia, lypodystrophy, hepatitis, transaminase elevation
Main adverse effect of zidovudin?
anemia, leukopenia
Stavudin and Didanosin side effects?
Pancreatitis and peripheral neuropathy (these drugs aren’t used anymore)
Main adverse effect of abacavir?
Hypersensitivity reaction for HLA-B*5701
Main adverse effect of tenofovir?
Nephrotoxicity and bone abnormality (given with disoproxil and alafenamide to lower toxicity)
Initial treatment with NRTIs?
one cytidine and one purine are combined and identical analogues should not be combined
1st generation non-nucleoside RT inhibitors (NNRTI)
1st generation Nevirapin, Efavirenz
2nd generation non-nucleoside RT inhibitors
2nd generation Etravirin, Rilpivirin
NNRTIs are effective against
HIV-1
A single point-mutation can cause resistance in which generation of NNRTIs
1st generation
NNRTIs are metabolized where?
liver
Which NNRTI penetrates well into the CNS
Efavirenz
Which NNRTIs have low penetration
etravirin and rilpivirin, but enough to control HIV
General adverse effects of NNRTIs
liver and GI issues, rash (Steven Johnson syndrome)
Efavirenz can cause CNS issues and is teratogenic
What are the protease inhibitors
Ritonavir Lopinavir Atazanavir Darunavir Tipranavir
Mechanism of protease inhibitors
Cleaves Gag and Gag-Pol polyproteins of HIV, that have key role in maturation of HIV (no cross reaction with human proteases)
Adverse effects of protease inhibitors? Resistance?
insulin resistance, hyperlipidemia, abdominal fat uptake, transaminase elevation, GI, and neurological issue, and allergic reactions
No cross resistance between PIs
Kinetics of PI
Oral availability
Don’t enter CNS
Metabolized by CYP3A4 in liver
Half life is variable
Which PI is metabolized by CYP2C19?
nelfinavir
Which PI blocks CYP3A4?
Ritonavir
What are the three integrase inhibitors
Raltegravir
Elvitegravir
Dolutegravir
Mechanism of action of Raltegravir?
Kinetics?
Inhibits the integration of NA transcripted HIV into the human DNA chain oral administration (twice a day), conjugated by glururonic acid
Adverse effects of Raltegravir
GI issues, headache, dizziness, skin rash CK elevation, myopathy
Details of Elvitegravir
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
Details of Dolutegravir
- Low cross-resistance, higher genetic barrier
- Side effects: Sever hypersensitive reactions, insomnia, headache
Entry inhibitor for HIV
Enfuvirtid
Details of Enfuviritd
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
CCR5 coreceptor antagonist
Maraviroc
Maraviroc is effective in which case
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
Adverse effects of Maraviroc
Headache, dizziness, orthostatic hypotension, airway infections, allergic liver disorder, increased prevalence of malignancies
Kinetics of Maraviroc? Initial treatment?
Orally administered, metabolzed in liver (CYP3A4 interactions)
Not recommended as initial treatment
