CFM5: HIV Therapeutics

  1. Mechanism of nucleoside RT inhibitors
    • Converted intracellularly to triphosphate
    • Acts as alternate substrate for RT, causing DNA chain termination (no OH group to bind next nucleoside)
  2. Nucleoside RT inhibitor side effects
    • Lactic acidosis (mitochondrial damage) (limited use of NRTIs that have high rates of this)
    • Anemia
    • Hypersensitivity (abacavir - only in patients positive for a certain HLA)
    • Renal failure (tenofovir)
    • Resistance
  3. Non-nucleoside RT inhibitor mechanism
    Non-competitive binding to RT without intracellular conversion
  4. Non-nucleoside RT inhibitor side effects
    • First generation: liver failure, CNS toxicity from efavirenz
    • Second generation: Rash
    • Second generation drugs exist because of possible resistance to first generation; second generation NNRTIs are less likely to have resistance
  5. Protease Inhibitor Mechanism
    Prevent the cleavage of viral proprotein
  6. Protease Inhibitor side effects
    • Hyperlipidemia (high cholesterol, LDL, TG; concern for cardiovascular events)
    • Insulin resistance, hyperglycemia, diabetes
    • Lipodystrophy
    • Lipoatrophy, fat redistribution, buffalo hump
    • Hepatic (hyperbilirubinemia and elevated liver enzymes)
    • Osteonecrosis, osteoporosis, osteopenia
    • Aseptic necrosis of the hip; needs hip replacement
    • Resistance (initially drug specific but if therapy is continued long enough then it is class resistance)
  7. Maraviroc
    • CCR5 Inhibitor
    • HIV strain must be CCR5-tropic, so do tropism assay
  8. Fusion Inhibitor
    • Enfuvirtide
    • Binds gp41 subunit of HIV envelope glycoprotein, preventing fusion with CD4 plasma membrane
    • PATIENTS DO NOT LIKE IT!! 2x/day subcutaneous injection, causes local injection reactions
  9. Integrase Inhibitor Mechanism
    Prevent HIV DNA from integrating with host DNA
  10. Integrase Inhibitor side effects
  11. Boosting using ARV interactions
    Small dose of ritonavir used as a "booster" given with a protease inhibitor to pharmacologically enhance exposure to the latter protease inhibitor through the inhibition of cytochrome P450
Card Set
CFM5: HIV Therapeutics