Flashcards in Fitz, HIV Anti-Virals Deck (52):
Three main viral processes that are targeted by the drug combos used in INITIAL therapy.
1. HIV reverse transcriptase
2. HIV integrase
3. HIV protease
What are the two reservoirs that HIV can reside?
Which 2 NRTIs and 1NNRTIs can get into the brain?
- Reservoir - GALT and spinal cord/brain.
NRTI - AZT, d4T
NNRTI - nevirapine
Name the three NRTIs that are Purines.
Name the four NRTIs that are Pyrimidines
What must host cells do to the ingested NRTI?
Host enzymes must metabolize the prodrug into a NucleoTide Triphosphate >> Emtricitabine(FTC)-analog in the cell!
What does the NRTI-Triphosphate do inside CD4 cells harboring replicating HIV?
Emtricitabine(FTC)-TPs are incorporated into the viral DNA by viral DNA polymerase and then ---> terminate viral DNA synthesis.
How do NRTI-TPs terminate viral DNA synthesis?
Because they lack a 3' hydroxyl group.
How many NRTIs are given to all HIV patients?
N/V/abdominal pain, weight loss, myalgia, geatures of HEPATIC DYSFUNCTION, HM, peripheral edema, ascites, encephalopathy.
These show what?
Black box warning of all NRTIs. Potentially fatal.
Why do all NRTIs have the potential for lactic acidosis?
Because they DNA reverse transcriptase AND they inhibit mt-DNA-polymerase-gamma
How does inhibition of mt-DNA-polymerase-gamma result in lactic acidosis?
Inhibition of mt-DNA-polymerase-gamma ---> deficient proteins needed for OxPhos, so inhibits aerobic metabolism and increases ANAEROBIC metabolism ---> LACTIC ACIDOSIS.
The three NRTIs that inhibit mt-DNA formation MOST.
Didanosine > Stavudine ≥ Zidovudine
The three NRTIs that inhibit mt-DNA formation LEAST.
All the first line NRTIs:
Tenofovir = Lamivudine = Emtracitabine = Abacavir
All NRTIs have what adverse effect?
Disrupt triglyceride metabolism throught the body - morphological/fat deposits.
In what three settings should NRTI be suspended?
1. Rapidly rising aminotransferase levels
2. Progressive HM
3. Metabolic acidosis of unknown cause
Pts with ___ should avoid Tenofovir? Why?
Renal insufficiency - Tenofovir is already phosphorylated upon ingestion (nucleoTide) ---> RENAL elimination
Substitute what for tenofovir?
A pt is on a NRTI and develops fever, rash, GI, respiratory symptoms, lethargy or malaise. What drug is this person on?
Abacavir - this is systemic abacavir hypersensitivity
Abacavir can be used safely in what individuals?
They are Negative for HLA-B*5701 genotype.
Positive = abacavir hypersensitivity
**Preferred NRTI combination.
NRTI combination for an individual HLA-B(-) and at risk for renal or bone toxicity?.
Caution using what NRTI combination for an individual HLA-B(+) and at risk for renal or bone toxicity?
Caution use of abacavir in the abacavir-lamivudine combo.
NRTI combination for a pregnant individual.
What three NRTIs are active against HepB?
MOA of Non-Nucleoside Reverse Transcriptase Inhibitors
Bind to reverse transcriptase at site different form NRTIs.
How is the activation of Non-Nucleoside Reverse Transcriptase Inhibitors different than NRTIs?
Do not require phosphorylation to be active or compete with nucleosides.
**What NNRTI is avoided in pregnancy?**
What NNRTI is used during pregnancy or if a woman is trying to conceive?
Nevirapine (1st line alternative).
**What NNRTI is used if resistance to other NNRTIs is developed?
Etravirine (1st line alternative).
If a woman is on efavirenz and becomes pregnant, what should be done?
If viral suppression has been achieved, continue efavirenz-containing regimen.
Rash/hypersensitivity - think what class of drugs?
A HIV+ pt is taking a NNRTI and develops a skin burn-type reaction. What is this reaction and which drug are they most likely taking?
Why do you start a TB+ and HIV+ pt on TB tx-regiment first?
- Because the NNRTIs have a -life-threatening hepatotoxicity (nevirapine).
- Because NNRTIs induce CYP450 (efavirenz)
K103N mutation - associate with what?
What is the one drug exception that can be used?
Point mutation in virus that confers drug resistance to NNTRIs.
**Preferred combo of NTRIs and NNTRI (not pregnant)**
Other than HIV, what else does it treat?
NTRI - Tenofovir+Emtracitabine
NNTRI - Efavirenz
Also treats HepB
**Preferred combo of NTRIs and NNTRI (pregnant)**
NTRI - Zedovidine-Lamivudine (Lamivudine=HepB)
NNTRI - Nevirapine
MOA of Protease inhibitors
PIs prevent maturation of new viruses because it inhibits the HIV-1 protease (pol gene), which normally cleaves products of HIV mRNA into functional parts.
**Significance of ritonavir
"Boosting" - CYP3A inhibitor
Used with other oral protease inhibitors (atazanavir or lopinavir) to inhibit their hepatic metabolism
**MOA of ritonavir's boosting effects.
Decreases the extensive first pass hepatic metabolism of the other Protease Inhibitors - **Atazanavir, Lopinavir**
A HIV+ person (about to start tx regimen) has PCP pneumonia and tx with TMP-SMX. They develop a life threatening allergic reaction. What PI is contraindicated?
Darunavir and fosamprenavir, and tipranavir are sulfonamides, so should not be given to a person with a sulfonamide allergy (allergy to SMX)
Short term adverse effect of Protease Inhibitors.
Hepatotoxicity (*atanazavir and PPIs, CYP450 interactions, esp with ritonavir**)
Adding PI to the regimen of NRTIs increases what adverse effect?
Triples the prevalence of lipodystrophy (compounds already present in NRTIs).
Preferred treatment combos (4) for NRTIs + PIs
NRTIs - Tenofovir + Emtracitabine
A person (nonpregnant) gets a needle puncture wound and/or is exposed to blood or semen of a HIV infected individual. What is the appropriate Post-exposure Prophylaxis?
Tenofovir + emtricitabine + Lopinavir + Ritonavir
(Four weeks, 1x/day)
A person (pregnant) gets a needle puncture wound and/or is exposed to blood or semen of a HIV infected individual. What is the appropriate Post-exposure Prophylaxis?
Zidovudine + Lamivudine + Lopinavir + Ritonavir (Four weeks, 2x/day)
Post-exposure Prophylaxis - add what class to NRTIs?
Overall Preferred REgimen in HIV+ Women:
2 NRTIs + PIs
Zidovudine + Lamivudine + Lopinavir + Ritonavir (2x/day)
MOA of Integrase strand transfer Inhibitors (IIs) and name of drug.
Inhibits HIV genome integration into host cell chromosome by irreversibly inhibiting HIV integrase
Advantage of using Raltegravir over a protease inhibitor?
Does not cause lipid-causing morphologic changes.
MOA of fusion inhibitor enfuvirtide.
Binds gp41, inhibiting viral entry.
MOA of fusion inhibitor maraviroc.
Binds CCR-5 on surface of T cells/monocytes, inhibiting interaction with gp120.