HIV Pharm (HAART ARV's) Flashcards
All antivirals share a common property of being…
Virustatic. Active only against replicating viruses, not the viruses that already exist.
What virus is HIV-2 similar to? What anti-Retrovirals work for HIV-2?
Similar to “Simian Immunodifficient Virus” (SIV). Most Dx that work for HIV-1 also works for HIV-2, with the exception of NNRTI’s.
The gene “Pol” encodes what? (3 important enzymes)
- Reverse Transcriptase w/ RNAase activity.
- Protease.
- Viral Integrase
What does “Gag” encode?
It encodes a polyprotein that’s cleaved (probably by protease) in order to release the major structural proteins of the virus (which would be inactive if not released).
What does “Env” encode?
It encodes gp 160, which contains the gp’s necessary for HIV penetration into host cells.
What makes up the gp160?
It is made up of the external gp120, and the transmembrane gp 41.
How do we go from virion RNA → dsDNA?
RNA → (reverse transcriptase) → cDNA-RNA → (Reverse Transcriptase + RNAase) → dsDNA
Which tropism is responsible for all of the acquired (naturally) infections of HIV? What does a shift to the other tropism indicate?
CCR5 Tropism, a shift to CXCR4 indicates an advanced disease (granted this advance isn’t necessary to turn to AIDS)
If there is a shift to the CXCR4 tropism, this indicates that…
There is a massive CD4+ depletion.
When should anti-Retroviral treatment begin?
Classically when CD4+ count drops below 350 cells/mm3, but recently this has been changed to “anyone who has HIV”.
What does the HAART regimen consist of?
It has a 2 NRTI backbone + an NRTI, or a boosted PI, or an Integrase Inhibitor
How does HIV gain resistance to the drugs (assuming the cause isn’t a mutation?)
Via selective pressure: all the susceptible virus will be killed by the Tx, but those that survive will replicate and thus become resistant to the Tx.
What is HIV Lipodystrophy Syndrome?
Occurs in 10-40% of patients, it basically causes metabolic syndrome:
Insulin resistance induced → causes fat redistribution and hyperlipidemia.
What is the clinical presentation of HIV Lipodystrophy Syndrome?
Lipoatrophy (Peripheral Fat wasting), Central fat accumilation (fat in breast and buffalo hump), insulin resistance, incrased blood sugar and serum cholesterol and triglycerides → Basically the symptoms we would expect to see in Cushing’s Syndrome.
What is Immune Reconstitution Inflammatory Syndrome (IRIS)?
Accelerated immune response to overt or subclinical opportunistic infections, thought to be induced because Tx of the patient finally brought up the immune system to a level where it can mount a response → body freaks out and reacts to all the pathogens that it couldn’t react to before.
What agents seems to cause the trigger for IRIS?
TB, other mycobacteria, cryptococcus, Hepatitis virus, and pneumocystis pneumonia seem to trigger this.
What dangers do non-preg women expereince with anti-Retrovirals in general?
PI’s and NRTI’s can decrease blood levels of ethinyl estradiol, norethindrone or norgestinate which leads to decreased contraceptive efficacy or increase hormone levels that increase estrogen and progesterone related toxicity.
→ Basically OC’s action will be messed up, and if taking other drugs for estrogen and progesterone those will be pushed past the Tx window, potential risk of tox.
What is the expected outcome of ARV treatment?
HIV RNA conc to be 0 within 24 weeks, or below 50 cells/mL unless the patient is non complaint. If this is not the case, then a new drug regimen is needed.
What is the protocol for HIV infected peds to take ARVs?
Under 12 months must use the drugs, disease progression is slow from ages 1-5, but fast again when older than 5 (so presumably use if under 12 months or older than 5).
What are NRTI’s, chemically speaking?
Nucleotide or nucleotide reverse transcriptase inhibitors, meaning they are synthetic analogs.
Which are the Thymadine analogs of NRTIs?
Zidovudine and Stavudine
Which are the Cytosine analogs of NRTIs?
Lamivudine, Emtricibatine (This is the F added version of Lamivudine)
Zalcitabine (not marketed anymore)
Guanicine analog of NRTI?
Abacavir
Adenosine analog of NRTI?
Didanosine, Tenofovir.
Why should the “Viral Resistance Testing” be done?
Obtain when patient is taking the failing drug regimen to figure out the proper Tx.
Most NRTI’s are nucleo______, (side/tide) with the exception of… and this drug is formulated as…
Most are nucleotides, with the exception of Tenofovir which is a nucleoside. Its formulated as a prodrug (Tenofovir dipivoxel fumerate → (plasma esterase) → Tenofovir.
Which NRTI has the highest oral bioavilibility? The lowest?
Lamivudine, Emtricitabine, Stavudine, Abacavir have very high oral bioavailibility
Didanosine and Tenofovir have very poor bioavailibility (in that order)
Which NRTI’s are affected (bioavailibility) with food intake?
Zidovudine (decreases with high fat intake) whereas Tenofovir does the opposite.
Didenosine decreases in increased acidity.
What’s interesting about the half lives of NRTIs?
They range from 3-40 hours and thus it allowes for x1-2 daily dosing.
The drug Maraviroc is a substrate for which CYP?
CYP 3A4.
The drug Zidovudine is metobalized by?
60-80% hepatic by CYP 2A, 2C and 3A, also gets glucoronidated.
Which drug is metabolized by purine metabolism?
Didanosine.
How is Abacavir metabolised?
More than 80% by alcohol dehydrogenation and glucoronidation.
Which NRTI has the most renal excretion? The least?
Emtricitabine and Lamivudine; Tenofovir most renally excreted
Zidovudine and Didanosine least.
Which form of the NRTI blocks the replication of viral genome?
The tri-phosphorylated version of the NRTIs.
What is the MOA of NRTI’s? (It has a dual mechanism)
- Completely inhibits the incorporation of “real” nucleotides into nascent viral RNA-DNA duplex by inserting the “fake base” in its place.
- Real nucleotides have a 3’ OH group needed to elongate the proviral DNA, but this is lacking in the fake NRTI bases → Thus elongation of the DNA is terminated.
When is HIV susceptible to NRTIs?
NRTI’s can only prevent uninfected cells from becoming infected, it can do nothing about the ones already infected.
Which variations of HIV does NRTI’s treat?
Both HIV 1 and 2
Which is the common mutation that occur in HIV-1 that’s problematic? What does this mutation do?
184V, also called the M184V/I. This is a point mutation of methionine → Valine or Isoleucine substitution @ codon 184 of the HIV 1 virus. This confers high resistance to Lamivudine, Emtricitabine, Zalcitabine (all of these are cytosine analogs), Didanosine, and Abacavir. (The latter 3 have some resistance, not as bad as Lamivudine and Emtricitabine).
Despite the M184V/I mutation in HIV-1 making certain drugs less effective, which drug
HIV viruses that were resistant to Zidovudine ends up regaining susceptibility to it.
Name two “First Line” NRTI Dx that is genarally used, and who are the patients that should take this Dx regimen?
Tenofovir and Emtricitabine, but only if NON PREGNANT, treatment naive patients.
What is one major toxicity concern with the NRTIs?
Even though this class has a relatively high affinity for HIV RT enzyme, there is some affinity to host DNA polymerase alpha, beta, and gamma.
What is special about DNA polymerase gamma? Which drugs interact with this?
It is a mitochondrial enzyme; Stavudine, Zidovudine, Didanosine and Zalcitabine all have increased affinity for this enzyme → Increased risk of mitochondrial toxicity.
Which drugs do not cause this mitochondrial toxicity due to the affinity to the DNA polymerase gamma?
While there is no drug that will definitely not cause mitochondrial toxicity,Tenofovir, Abacavir, Lamivudine, Emtricitabine have a low incidence of causing it.
Describe the signs/symptoms of mitochondria tox
Myopathy, peripheral neuropathy, lipodystrophy (specifically lipoatrophy - loss of SubQ fat on face, arms, or legs). Pancreatitis, anemia, neutropenia, thrombocytopenia.
Mitochondrial toxicity manifistation with respect to the liver is…
Lactic acidosis and hepatic steatosis, rare but fatal.
Who are more at risk for the mitochondrial tox?
Female, obese, and those who have prolonged exposure to the drug
What are some signs that might lead you to discontinue NRTI tx?
Increased aminotransferase, progressive hepatomegaly or metabolic acidosis of unknown cause
Which CYP interacts with NRTIs?
There isnt too much CYP interactions with NRTIs as they are not major CYP subtrates
What are some DDI to watch out for with NRTIs
Drugs that block OATP drug transporter, they would compete for active tubular secretion and thus decrease renal clearance of the drug.
What are some known OATP inhibitors that can mess with NRTI’s?
Acyclovir, valcyclovir, gancyclovir, citofovir, adefovir, dipivocil, provenecid.
Would you use Zidovudine and Stavudine together?
No, they are both thimadine analogs, however thimadine kinase has increased affinity for Zidovudine so it would not phosphoralate Stavudine as much –> Stavudine becomes less effective.
Would you use Lamivudine and Zalcivudine?
No, they would inhibit intracellular phosphorylation of one another.
Tenofovir + abacavir/didanosine?
They would compete with each other at the same site of action and thus decrease efficacy and increase virulogic failure.
