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Block 4: Antiviral: Intro to the Principles of HIV Therapuetics


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Antiretroviral therapy, pregnancy, co-infxn with Hep B or C
HIV infxn--early disease considerations
Prophylaxis against reactivation of latent infxn, long term toxicity of antiretroviral tx
HIV infxn--middle stage disease considerations
Tx of opportunistic infxns/malignancy, supportive therapy
HIV infxn--late/advanced stage disease consideration
Viral replication begins when in infxn?
Right from the start
CD4 turnover is slow or rapid in infected cells?
Rapid (t 1 1/2 = 3 days)
Resistance develops faster or slower in early disease?
Immune fxn is better or worse early in disease?
Five goals of antiretroviral therapy (ART)
1)suppress viral replication
2)preserve immune response
3)delay immune dysfxn
4)improve quality of life
5)improve overall survival
Four things to consider before starting tx
1)pt willingness to commit to complicated drug regimen
2)likelihood of adherence
3)degree of immune deficiency, CD4 count, viral load
4)likelihood of disease progression
What percentage adherence must a pt acheive for tx to be effective?
No tx, recommend tx, consider tx, optional tx: pt with CD4>350 and viral load <100,000
No tx
No tx, recommend tx, consider tx, optional tx: pt with CD4<350 and VL>100,000
Recommend tx
No tx, recommend tx, consider tx, optional tx: pt with CD4<200
Recommend tx
No tx, recommend tx, consider tx, optional tx: pt with opportunistic infxn, whatever the CD4 count
Recommend tx
No tx, recommend tx, consider tx, optional tx: pt with symptomatic HIV infxn
Recommend tx
No tx, recommend tx, consider tx, optional tx: pregnant women
Recommend tx
No tx, recommend tx, consider tx, optional tx: asymptomatic pt with CD4 between 201 and 350
Consider tx
Most docs would treat asymptomatic pt with CD4 between 201 and 350 if what?
If pt is committed
Lower CD4 counts predict what?
More rapid progression to AIDS
No tx, recommend tx, consider tx, optional tx: asymptomatic pt with CD4>350 and VL>100,000
Consider tx
Minimum recommendation for asymptomatic pt with CD4>350 and VL>100,000?
Close monitoring for 3 mos
Why might some docs treat asymptomatic pt with CD4>350 and VL>100,000?
At risk for immune deterioration
No tx, recommend tx, consider tx, optional tx: pt actively seroconverting
Optional tx
No tx, recommend tx, consider tx, optional tx: pt within 6 mos of seroconverting
Optional tx
All the Nucleoside Reverse Transcriptase Inhibitors (NRTIs) live on DAZZLES CT.
1)Didanosine (ddI)
2)Abacavir (ABC)
3)Zidovudine (AZT)
4)Zalcitabine (ddC)
5)Lamivudine (3TC)
6)Emtricitabine (FTC)
7)Stavudine (d4T)
Combavir is a combo of what two NRTIs?
(zidovudine + lamivudine)
Trizavir is a combo of what three NRTIs?
(abacavir + zidovudine + lamivudine)
What three side effect are associated with the NRTIs?
Pancreatitis, neuropathy, lactic acidosis (rare but life-threatening)
If a drug has "T" in its abbreviation, it's a *what* analog?
Thymidine analog
If a drug has "C" in its abbreviation, it's a *what* analog?
Cytosine analog
If a drug has "I" in its abbreviation, it's a *what* analog?
What is the only drug with "I" in its abbreviation?
Didanosine (ddI)
Which two drugs may cause hyperpigmentation of the palms/soles?
Zidovudine (AZT) and Emtricitabine (FTC)
Which drug is considered to be the safest NRTI?
Lamivudine (3TC)
Rash and anaphylaxis may be seen with what NRTI?
Abacavir (ABC)
Should you rechallenge with Abacavir (ABC)?
Name the three Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Nevirapine (NVP), Delavirdine (rarely used) and Efavirenz (EFV)
Nevirapine increases or decreases the AUC of protease inhibitors (PIs)?
Delavirdine increases or decreases the AUC of PIs?
Serious hepatotoxicity is associated with early tx with which NNRTI?
Nevirapine (NVP)
Paradoxically, NVP's hepatotoxicity is associated with what?
Good immune fxn (possibly something to do with BMI or cyp450 activity)
EFV's long half life (40-55h) confers what benefit?
One-a-day dosing
Should you take EFV with or without food?
Doesn't matter
EFV can get into what important compartment?
The brain-- it can cross the BBB
EFV has what characteristic but not totally unpleasant side effect?
Nightmares/vivid dreams for first few weeks
EFV is good salvage for pts who fail on which two drugs?
Delavirdine and NVP
What is the only NucleoTide Reverse Transcriptase Inhibitor for HIV tx?
Tenofovir (TNF)

(cidofovir- resistant CMV retinitis
adefovir- HBV)
What are three good qualities of TNF?
1)once-a-day dosing
2)it's well-tolerated
3)considered very safe
What quality of TNF gives it faster onset?
It's monophosphorylated
In general, protease inhibitors do what?
They block proteolytic cleavage of the viral precursor gag-pol
PIs are highly protein-bound, leading to what undesirable side effect?
Poor bioavailability
PIs interact with CYP450s, leading to what undesirable side effect?
Many drug interactions
PIs make a FAIR SNAK(L)
1)Fosamprenavir (FOS)
2)Atazanavir (TAZ)
3)Indinavir (IND)
4)Ritonavir (RIT)
5)Saquinavir (SAQ)
6)Nelfinavir (NEL)
7)Amprenavir (AMP)
8)Kaletra (KAL)
9) Lopinavir
Kaletra is a combo of what two drugs?
Lopinavir + ritonavir
Kaletra may be used to salvage failures of what two PIs?
saquinavir and nelfinavir
This form of saquinavir (SAQ) has improved absorption
Fortovase soft gel tab
This saquinavir (SAQ) formulation is absorbed poorly
When should saquinavir be taken in relation to meals?
Within two hours of meals
When should ritonavir (RIT) be taken in relation to meals?
With meals
This PI is used at low doses to block clearance of a 2nd PI.
Ritonavir (it's called "ritonavir boosting")
When should indinavir (IND)be taken in relation to meals?
Should be taken on an empty stomach
Two side effects of indinavir (vaguely kidney-related)
Nephrolithiasis and insulin resistance
When should nelfinavir (NEL)be taken in relation to meals?
Take it with food.
This side effect of nelfinavir (NEL) is predictable and easily controlled with fiber.
What is the dietary concern with taking amprenavir (AMP)?
Take it with or without food, just don't take it with fatty food.
Amprenavir (AMP) may cause this derm side effect
Is it okay to rechallenge with amprenavir (AMP) once the rash is gone?
What NRTI also causes a rash and SHOULDN'T be rechallenged?
Abacavir (ABC)
When do you take kaletra (KAL) in relation to meals?
With meals
Kaletra is a less-effective salvage for pts treated how?
With multiple PIs
What beneficial side effect is associated with atazanavir (TAZ)?
Increased HDL level
Atazanavir (TAZ) may not helpful in pts resistant to what?
Other PIs
Atazanavir may cause what inapparent side effect (hint: he doesn't look yellow to me!)
Asymptomatic hyperbilirubinemia
TRUE or FALSE: you should take fosamprenavir (FOS) on an empty stomach.
False. You can take it with or without food.
Fosamprenavir (FOS) is a prodrug of what other PI?
Fosamprenavir (FOS) increases what more than what?
Triglycerides more than cholesterol
TRUE or FALSE: fusion inhibitors are good early tx for HIV infxn
FALSE. Fusion inhibitors are last ditch therapy (hard to inject 2x/day for the rest of your life)
FIs block HIV fusion by binding to what region of what?
The HR1 region of Gp41
FIs block what interaction needed for fusion?
What are four common side effects of FIs?
1)injxn site irritation
2)bacterial pneumonia
3)increased AST and ALT
What is the starting NNRTI regimen for drug-naive pts?
Efavirenz + (AZT or Tenofovir) + (3TC or Emtricitabine)
Why might you replace efavirenz with nevirapine in the initial NNRTI regimen?
You suspect pregnancy
Why wouldn't you use delavirdine in place of efavirenz?
Not potent enough
What is the starting PI regimen for drug-naive pts?
Kaletra + AZT + (3TC or emtricitabine)
What four PIs **shouldn't** be used in the PI regimen?
2)ritonavir alone
3)unboosted indinavir
4)unboosted saquinavir
This type of regimen should be used only when an NNRTI- or PI-based regimen cannot be used.
Triple NRTI regimen
What drugs make up the triple NRTI regimen?
TRUE or FALSE: tx is recommended in ALL preggos, regardless of CD4 count or viral load.
In women with a VL<1000, this drug can be used alone.
This drug has a long half life and is good for women in labor w/o any prior retroviral tx.
3 other agents recommended for HIV (+) preggos (1 is a combo)
Nelfinavir, saquinavir and AZT + 3TC
You should NEVER use these 3 drugs in preggos (high teratogenicity)
Efavirenz, ddC and delvirdine
C section is recommended for what 2 types of women?
Women on no Rx or only on AZT w/unknown VL
But recent data suggests what about C-section?
elective C-section may benefit all women.
When should you start giving drugs to an HIV (+) pregnant woman?
Week 14
What if she's already taking Rx?
Stop the meds, then restart at week 14
When should you start treating the newborn?
Within 6-12 hours of birth
How long does it take HIV (+) people w/Hep C to develop cirrhosis?
20% have it in 20 yrs (3x rate seen in HIV (-) )
You treat for Hep C co-infxn when what 2 criteria are met?
detectable plasma HCV RNA and liver biopsy showing bridging or portal fibrosis
Tx works best in pts with what type of CD4 count?
What drug combo can you use to treat Hep C co-infxn?
pegylated interferon + ribavin
What should the viral load look like by 8 weeks of tx?
should be a 1 log decline by 8 weeks
By how much should T cell counts increase each year?
100-150 cells (more in first three months)
What accounts for initial rapid rise in CD4 cells?
Redistribution of memory cells
Repeated VL>400 copies after 24 wks of tx is defined as...
incomplete response
VL detectable after sustained period of suppression is called...
What 2 criteria make up "immunologic failure"?
1)failure to increase CD4 count by 20-25 cells over baseline in first year of therapy
2)decrease in CD4 count below baseline
"Clinical progression" is defined as...
occurrence or recurrence of an HIV-related event after 3 mos tx
What are four causes of tx failure>
Genotypic testing
1)most commonly used
2)reverse transcriptase/protease genes are sequenced
3)mutations are polymorphisms vs. drug resistance mutations
phenotypic testing
helps define inter-relationship between mutations (some are synergystic, some cancel each other out)
Resistance testing is recommended when...
pt fails successful regimen/has incomplete response
Resistance testing is suggested for...
pts seroconverting that you want to give drugs
Resistance testing should be considered in...
chronically infected pts initiating therapy
Secondary prophylaxis protects against what?
Recurring non-life-threatening infxns (thrush, HSV)
Primary prophylaxis is used for what?
Potentially lethal conditions (PCP, TB)
Name 4 complications of long term antiviral tx?
1)lactic acidosis
2)diabetes mellitus
3)fat redistribution
How do NRTIs cause lactic acidosis?
They have an affinity for DNA polymerase gamma that leads to mitochondrial dysfxn
How do antivirals cause DM?
beta cell destruction
How do antivirals cause fat redistribution?
Again, mito dysfxn
This drug, used to battle CMV retinitis, comes as ocular implant and an oral form
ganciclovir (oral form called valganciclovir)
Name 3 drugs given IV for sight-threatening CMV retinitis
ganciclovir, foscarnet, cidofovir
Name 2 ways to treat non-sight-threatening CMV retinitis
1)antiviral therapy only
2)oral valganciclovir
Generally, how do you treat active MAC infxn?
a macrolide AB (clarithromycin) + ethambutol +/- rifabutin (may block PI absorption)
What is the goal of therapy in end stage disease?
control symptoms

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