Id 6.19

Front 1

HAART

Back 1

Highly Active Anti-Retroviral Therapy
Significantly improved mortality/morbidity of HIV infections

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What are the 4 class of anti-retroviral drugs?

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(1) Reverse Transcriptate Inhibitors: A) Nucleoside Analogs and B) Non-nucleoside Analogs
(2) Protease Inhibitors
(3) Fusion Inhibitors

Front 3

Reverse Transcriptase Inhibitors

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Nucleoside and Non-nucleoside analogs
Theory: prevent formation of dsDNA so virus cannot be incorporated into genome

Front 4

NucleoSide RT Inhibitors

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COMPETITIVE inhibition of RT enzyme
NOTE: Need active cellular activity (Nucleoside Kinase) to add phosphates
Only one nucleoTide RT inhibitor exists

Front 5

Nucleoside

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Sugar + Base
NucleoSides Stop at Sugar

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Nucleotide

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Sugar + Base + Phosphate
NucleoTides Take a PhosphaTE

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Nucleoside Diphosphate/Triphosphate

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Sugar + Base + 2/3 Phosphates

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Nucleoside RT Inhibitors
(mechanism of removal)

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Excretion through kidneys, therefore dose should be adjusted based on renal function

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Nucleoside RT Inhibitors: TOXICITY

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MITOCHONDRIAL TOXICITY
These analogs target RT AND inhibit mitochondrial DNA synthesis

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Non-nucleoside RT Inhibitors

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Mechanism: NON-COMPETITIVE inhibition of RT enzyme

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Non-nucleoside RT Inhibitors
(mechanism of removal)

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Metabolized via liver P450 system

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Non-nucleoside RT Inhibitors
(drug side effects)

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(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

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Protease Inhibitors
(Mechanism of Action)

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Protease: viral enzyme required to cleave viral polyproteins for proper virion assembly. PIs create tons of defective viral particles

Front 14

Protease Inhibitors
(mechanism of removal)

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Metabolized via P450
INHIBITORS of P450, therefore strong drug interactions ensue

Front 15

Boosted PI Concept

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Ritonavir strongly inhibits P450 and prolongs other PIs in circulation (that are metabolized by same system)

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Ritonavir

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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

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PI Side Effects

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Initial GI problems
Hepatitis (generally in patients w/underlying illness)
Hyperglycemia/lipidemia

Front 18

What labs should be ordered prior to beginning PI therapy?

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Blood sugar & lipids b/c PIs capable of elevating both

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Fusion Inhibitors

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Block viral entry into cells

Front 20

Fusion Inhibitors
(administration and removal)

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SubQ (usually gives rise to a mild, injection rxn) and metabolized through liver (hydrolysis, NOT P450)

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Viral Replication and Suppression

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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)

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Reason for lack of long-lasting viral suppression?

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RESISTANCE

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Viral Drug Resistance

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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

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Resolving Viral Drug Resistance

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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!

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Immune Reconstitution

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Restoring naive/memory CD4 levels to normal values
Significantly decreases chance for opportunistic infections

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Complications of HAART

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Multifactorial
Some are drug-specific (i.e. insulin resistance w/PIs and mitochonodrial toxicity w/NRTIs)

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Lipodystrophy Syndrome

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Fat wasting in extremities (lipoatrophy) and visceral fat accumulation (hyperadiposity)

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HAART side effects

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Increased CVD, bone and liver problems

Front 29

HAART
(When to start therapy?)

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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

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HAART
(Initial Therapy Guidelines)

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ALWAYS A 3 DRUG REGIMEN
2 NRTIs + PI/NNRTI

Front 31

Which HAART class causes neuropathy?

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NRTI b/c inhibit mitochondrial DNA synthesis

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Which HAART class causes high blood sugar/lipids?

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Protease Inhibitors

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Which HAART class is NOT metabolized by the liver?

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NRTIs

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Which HAART classes must be considered for drug interactions?

Back 34

NNRTIs and PIs (b/c they both work through the P450 system)

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Virologic Failure

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Viral detection after 6 months of HAART or viral detection following period of undetectable levels

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Virologic Failure
(why does this happen?)

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Failure to adhere to therapy and/or resistance