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ID 6.19


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Highly Active Anti-Retroviral Therapy
Significantly improved mortality/morbidity of HIV infections
What are the 4 class of anti-retroviral drugs?
(1) Reverse Transcriptate Inhibitors: A) Nucleoside Analogs and B) Non-nucleoside Analogs
(2) Protease Inhibitors
(3) Fusion Inhibitors
Reverse Transcriptase Inhibitors
Nucleoside and Non-nucleoside analogs
Theory: prevent formation of dsDNA so virus cannot be incorporated into genome
NucleoSide RT Inhibitors
COMPETITIVE inhibition of RT enzyme
NOTE: Need active cellular activity (Nucleoside Kinase) to add phosphates
Only one nucleoTide RT inhibitor exists
Sugar + Base
NucleoSides Stop at Sugar
Sugar + Base + Phosphate
NucleoTides Take a PhosphaTE
Nucleoside Diphosphate/Triphosphate
Sugar + Base + 2/3 Phosphates
Nucleoside RT Inhibitors
(mechanism of removal)
Excretion through kidneys, therefore dose should be adjusted based on renal function
Nucleoside RT Inhibitors: TOXICITY
These analogs target RT AND inhibit mitochondrial DNA synthesis
Non-nucleoside RT Inhibitors
Mechanism: NON-COMPETITIVE inhibition of RT enzyme
Non-nucleoside RT Inhibitors
(mechanism of removal)
Metabolized via liver P450 system
Non-nucleoside RT Inhibitors
(drug side effects)
(1)May induce P450 system and cause decreased levels of other medications
(2) RASH (do NOT institute other NNRTIs if previous Hx of drug rxn)
(3) Some are teratogenic
(3) Hepatitis
Protease Inhibitors
(Mechanism of Action)
Protease: viral enzyme required to cleave viral polyproteins for proper virion assembly. PIs create tons of defective viral particles
Protease Inhibitors
(mechanism of removal)
Metabolized via P450
INHIBITORS of P450, therefore strong drug interactions ensue
Boosted PI Concept
Ritonavir strongly inhibits P450 and prolongs other PIs in circulation (that are metabolized by same system)
Strongly inhibits metabolism of other PIs (b/c it inhibits P450 system)
Used in conjunction w/other PIs for boosted effect
NOTE: itself is RARELY used as anti-retroviral therapy (b/c it has such strong side effects, esp. GI problems); therefore it is administered below therapeutic dose to boost the effect of other drugs
PI Side Effects
Initial GI problems
Hepatitis (generally in patients w/underlying illness)
What labs should be ordered prior to beginning PI therapy?
Blood sugar & lipids b/c PIs capable of elevating both
Fusion Inhibitors
Block viral entry into cells
Fusion Inhibitors
(administration and removal)
SubQ (usually gives rise to a mild, injection rxn) and metabolized through liver (hydrolysis, NOT P450)
Viral Replication and Suppression
With HAART, can see viral load drop to below detectable levels how the virus CANNOT BE ERADICATED (it persits in resting lymphocytes and other long-lived cells)
Reason for lack of long-lasting viral suppression?
Viral Drug Resistance
RT in inherently error-prone
Result? Tons of "quasispecies" floating around in body
Therefore, in the absence of maximal viral suppression the chance for acquiring resistance is VERY HIGH
Resolving Viral Drug Resistance
Maintain high dose levels (Ritonavir-boosted PIs) and use combination of different drugs (lowers chance of virus acquiring all necessary mutations to beat drugs) but above all else . . . ADHERENCE TO TREATMENT!
Immune Reconstitution
Restoring naive/memory CD4 levels to normal values
Significantly decreases chance for opportunistic infections
Complications of HAART
Some are drug-specific (i.e. insulin resistance w/PIs and mitochonodrial toxicity w/NRTIs)
Lipodystrophy Syndrome
Fat wasting in extremities (lipoatrophy) and visceral fat accumulation (hyperadiposity)
HAART side effects
Increased CVD, bone and liver problems
(When to start therapy?)
Depends on risk for progression of disease (higher viral counts and lower CD4 counts); you'll always start HAART if CD4 <200
Also must consider relative risks/benefits of therapy and patient's willingness to comply
(Initial Therapy Guidelines)
Which HAART class causes neuropathy?
NRTI b/c inhibit mitochondrial DNA synthesis
Which HAART class causes high blood sugar/lipids?
Protease Inhibitors
Which HAART class is NOT metabolized by the liver?
Which HAART classes must be considered for drug interactions?
NNRTIs and PIs (b/c they both work through the P450 system)
Virologic Failure
Viral detection after 6 months of HAART or viral detection following period of undetectable levels
Virologic Failure
(why does this happen?)
Failure to adhere to therapy and/or resistance

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