Protease Inhibitor

Aka: Protease Inhibitor

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II. Definitions

  1. Protease
    1. Enzyme that breaks peptide bonds

III. Mechanism

  1. Protease Inhibitors (PI) block viral proteases
    1. Protease Inhibitors are not limited to HIV Infection management
    2. In Covid19, Nirmatrelvir/r (Paxlovid) is a Protease Inhibitor
  2. In the case of HIV, Protease Inhibitors bind the catalytic site of HIV protease
    1. HIV protease is prevented from cleaving viral Protein precursors (e.g. gag-pol) into mature functional Proteins
    2. Prevents HIV virus maturation, viral replication and release from infected CD4+ Cells

IV. Medications: Boosters

  1. Most Protease Inhibitors are "boosted" with either Ritonavir or Cobicistat
  2. As with Protease Inhibitors in general, these boosting agents have numerous Drug Interactions
  3. Ritonavir (Norvir)
    1. Protease Inhibitor used at low dose in combination with other PI (limited by adverse gastrointestinal effects)
    2. Suffix '/r' added when a protease inhibutor is combined with Ritonavir
  4. Cobicistat (Tybost)
    1. Strong CYP2A4 Inhibitor (also inhibits multiple other metabolic pathways)
    2. Combined with either Atazanavir and Darunavir

V. Medications: Protease Inhibitors

  1. Amprenavir (Agenerase)
  2. Atazanavir (Reyataz, ATV, ATV/r, or combined with Cobicistat)
    1. Unboosted (without Ritonavir) has least adverse effect on lipids
  3. Darunavir (DRV, DRV/r or combined with Cobicistat)
    1. Less adverse effects on lipid profile
  4. Fosamprenavir (Lexiva, FPV or FPV/r)
  5. Indinavir (Crixivan)
  6. Lopinavir with Ritonavir (Kaletra, LPV/r)
  7. Nelfinavir (Viracept)
  8. Ritonavir (Norvir, /r)
  9. Saquinavir (Fortovase)
  10. Saquinavir Mesylate (Invirase)
    1. Precaution: Saquinavir and SaquinavirMesylate are not equivalent
  11. Tipranavir (Aptivus)

VI. Adverse Effects

  1. See each individual agent for specific adverse effects
    1. Nephrolithiasis (Indinavir)
    2. Severe Diarrhea (Nelfinavir)
  2. Gastrointestinal upset
  3. Lipodystrophy
  4. Osteopenia
  5. Spontaneous bleeding in Hemophilia
  6. Insulin Resistance and Hyperglycemia
    1. Manage with lifestyle changes (diet, Exercise)
    2. Consider medications
      1. Thiazolidinediones (eg Rosiglitazone, Pioglitazone)
      2. Glucophage
  7. Severe lipid abnormalities
    1. Effects
      1. Hypertriglyceridemia
      2. Low HDL
    2. Management
      1. Consider Atazanavir (unboosted or boosted) or boosted Darunavir (DRV)
      2. Can be treated with Pravastatin (see below)
      3. Resolves with discontinuation of Protease Inhibitor
  8. Hepatotoxicity
    1. Increased risk with concurrent use of other HIV agents
    2. Increased risk with comorbid Hepatitis C
    3. Monitor LFTs every 2 weeks for first month, then every 3 months

VII. Drug Interactions

  1. Drug Interactions are common
    1. Protease Inhibitors cause the most Drug Interactions of all Antiretrovirals
    2. Use formal Drug Interaction applications when prescribing
    3. Protease Inhibitors and Cobicistat inhibit CYP3A4 resulting in numerous interactions
  2. Statin drugs (used for PI-induced lipid abnormalities)
    1. Pravastatin is first choice Statin for use with PI
    2. Rosuvastatin (Crestor) or Atorvastatin (Lipitor) may also be used with caution
    3. Do not use Simvastatin or Lovastatin with PI
  3. Apixiban or Rivaroxaban
    1. Metabolized by CYP3A4 and P-Glycoprotein
    2. Protease Inhibitors strongly inhibit CYP3A4 or P-Glycoprotein, with associated bleeding risk

VIII. Monitoring

  1. Fasting lipid panel with Glucose every 3-6 months

IX. References

  1. (1998) Med Lett Drugs Ther 40(1041):115 [PubMed]
  2. (2009) Treat Guidel Med Lett 7(78): 11-22 [PubMed]
  3. Reust (2011) Am Fam Physician 83(12): 1443-51 [PubMed]

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