Term
| What is the pathophysiology of the AIDS virus? |
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Definition
- Infects CD4 T lymptocytes, macrophages, and dendritic cells
- 1-3 weeks post infection --> fever and an immune response followed by clinical latency. Slow decrease in CD4 cells until immune system cannot clear opportunistic infections
**Death from secondary infection |
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Term
| What are important proteins on the HIV virus? |
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Definition
- Gp120 + gp41 = initiate infection
- P24 - capsid
- Protease - makes viral proteins
- Integrase - integration into human DNA
- Reverse transcriptase - translates RNA to DNA |
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Term
| What are the 2 types of HIV? |
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Definition
HIV-1 - most prevalent and virulent
HIV-2 - west africa strain |
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Term
| What is acute HIV syndrome? |
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Definition
Initial rise in HIV leads to an immune response, goes back down to clinical latency. During this time, CD4 cells steadily decline as the virus hides in lymph nodes
**Antigens to p24 and g41 |
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Term
| What receptors are required for HIV to enter the cell? |
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Definition
| Virus binds to CD4 - required either CCR5 or CXCR4 co-receptors (or a mix) to drive entry into the cell. |
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Term
| What are the stages of HIV replication? |
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Definition
- RNA dependent DNA polymerase makes viral DNA from RNA
- Viral DNA merges with host DNA - makes proteins and other machinery |
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Term
| What steps are drug targets for HIV therapy? |
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Definition
- Attachment/Fusion - Fusion inhibitor and GPCR antagonists
- Reverse transcription - RT inhibitors (NRTIs and nNRTIs)
- Integrase inhibitors
- Protease inhibitors |
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Term
| What are key points to HIV therapy? |
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Definition
- Never monotherapy, always more than 1 drug, sometimes more that one drug in the same class
- Lack of adherence leads to death
- Hit early, hit hard
- Resistance common due to reverse transcriptase errors |
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Term
| What is the MoA of Zidovudine/Retrovir (AZT)? |
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Definition
Mimics thymidine - must be triphosphorylated to work. Insertion into viral DNA leads to obligate chain termination
**Resistance is high, suppresses bone marrow |
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Term
| What thymidine mimic has better affinity than AZT? |
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Definition
| - Stavudine/Zerit (D4T) - higher affinity for reverse transcriptase |
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Term
| What NNRTs are the 'Liotta' drugs? |
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Definition
- Lamivudine/Epivir (3TC) - cytosine mimic, works with other NNRTs except Emtriva
- Emtricitabine/Emtriva (FTC) - cross resistance
**These drugs select for -M184V resistant strains which are LESS virulent - a beneficial mutation |
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Term
| What NNRTs mimic adenosine? |
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Definition
- Didanosine/Videx (DDI)- incompatible with AZT. Activated to ddATP, then must be tri-phosphorylated
- Tenofovir/Viread (TDF) - cleaved to monophosphate. Liver dmg
- Abacavir/Ziagen (ABC) - analog of purines adenosine and guanine
**ABC hypersensitivity can be severe |
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Term
| What causes ABC hypersensitivity? |
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Definition
Allergy to Abacavir/Ziagen is linked to a specific allele - HLA-B*5701. Longer latency but HSR is possible.
**HLA-B*35 leads to faster onset of AIDS |
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Term
| What NNRT combo drugs exist? |
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Definition
- Combivir = AZT and Lamivudine
- Trizivir = AZT, Lamivudine, Abacavir
- Kivexa = Abacavir and Lamivudine
- Truvada = Emtricitabine and Tenofovir
- Atripla = Emtricitabine, Tenofovir, and Efacirenz (nNTRI) |
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Term
| What is the difference between NRTIs and nNRTIs? |
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Definition
- nNRTIs are synthetic, only active against HIV1, NOT phosphorylated, CYP metabolites
- NRTIs - triphosphorylated to work, work on HIV1 and HIV2 |
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Term
| What is the MoA of nNRTIs? |
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Definition
| Changes the conformation of the active site of reverse transcriptase |
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Term
| What drugs are 1st generation nNRTIs? |
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Definition
- Nevirapine/Viramune - 3A4 and 2B6 - other PIs. Good w/ AZT
- Delaviradine/Rescriptor - Tx may restore AZT susceptibility in AZT resistance
- Efavirenz/Sustiva - teratogen, 3A4 interactions
**Mutations in codon 103/108, drugs can't bind |
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Term
| What drugs are 2nd generation nNRTIs? |
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Definition
- Etravirine/Intelence - 3A4, 2C9 and 19 interactions
- Rilpivirine/Edurant - longer half life
**More potent, effective in resistence |
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Term
| What is the MoA of protease inhibitors? |
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Definition
Mimic transition states of recognition sites, preventing protease from cleaving polypeptide at (PHE-PRO)
**Resistance due to protease mutations, low doses, or monotherapy
**All are pGp efflux substrates |
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Term
| What are considerations for protease inhibitors? |
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Definition
- Monotherapy leads to resistance
- Only works on HIV1
- All inhibit or are substrates of CYP
- ALL will cause dyslipidemia!!! |
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Term
| What is the pharmacokinetic enhancer effect? |
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Definition
| Seen in Ritonavir/Norvir, it's 3A4 interaction is used to increase the activity of other protease inhibitors with poor bioavailability! |
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Term
| What drugs are protease inhibitors? |
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Definition
- Ritonavir/Norvir - increases other drug concentrations
- Saquinavir/Invirase - combo w/ Norvir = arrhythmia
- Indinavir/Crixivan
- Amprenavir - HIV1 and 2
- Fosamprenavir/Lexiva - prodrug, HIV1 and 2. Can give sulfa allergy
- Lopinavir/Kaletra
- Tipranavir/Aptivus - major AE
- Atazanavir/Reyataz - longer t1/2 |
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Term
| What drug is a 2nd generation protease inhibitor? |
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Definition
| Darunavir/Prezista - better against resistance |
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Term
| What drugs are fusion inhibitors? |
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Definition
- Enfuvirtide/Fuzeon - In HIV1, binds to gp41 to inhibit fusion
**For MDR-HIV |
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Term
| What drug is a CCR5 Antagonist? |
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Definition
Maraviroc - only used in CCR5 tropic HIV1
**Motivate trial - CXCR5 = resistance
**A 3A4 substrate. Must decrease dose w/ inhibitors, decrease dose with inducers. Contraindicated w/ St. John's wort |
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Term
| What drug is an Integrase inhibitor? |
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Definition
| Raltegravir/Isentress - used for MDR-HIV1 |
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