Antiretroviral therapy principles

ART Fundamentals - The Battle Plan

• Goal: Suppress HIV RNA to <50 copies/mL, restore/preserve immunologic function (↑ CD4 count), and reduce inflammation.
• Strategy: Use Combination Antiretroviral Therapy (cART) to prevent resistance. Adherence is critical.
• Standard Initial Regimen: 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) + 1 Integrase Strand Transfer Inhibitor (INSTI).
  • 📌 2 Turtles (NRTIs) + 1 Iguana (INSTI).

⭐ U=U: Undetectable equals Untransmittable. A person with a sustained undetectable viral load cannot sexually transmit HIV.

ART Drug Classes - The HIV Hit Squad

• Goal: Suppress HIV replication by targeting key viral enzymes & processes. Standard therapy combines drugs from different classes to prevent resistance.

• Major Classes & Mechanisms:
  • Nucleoside/tide Reverse Transcriptase Inhibitors (NRTIs): Faulty DNA building blocks; halt reverse transcription.
  • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): Directly bind & inhibit reverse transcriptase.
  • Protease Inhibitors (PIs): Block cleavage of viral proteins; prevent maturation of new virions.
  • Integrase Strand Transfer Inhibitors (INSTIs): Prevent HIV DNA from integrating into the host genome.
  • Entry Inhibitors:
    • CCR5 Antagonists: Block HIV from entering CD4 cells.
    • Fusion Inhibitors: Prevent the viral envelope from fusing with the cell membrane.

⭐ Exam Favorite: Modern ART regimens are typically built on an INSTI "anchor" drug combined with a 2-drug NRTI "backbone" (e.g., Tenofovir + Emtricitabine).

Initial Regimens - The A-Team Combo

Standard of care for most treatment-naïve adults involves a 3-drug regimen for rapid viral suppression and high genetic barrier to resistance.

• Backbone (2 Drugs): 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs).
  • Typically Tenofovir (TAF or TDF) + Emtricitabine (FTC) or Lamivudine (3TC).
• Core (1 Drug): 1 Integrase Strand Transfer Inhibitor (INSTI).
  • e.g., Bictegravir (BIC), Dolutegravir (DTG).

⭐ Exam Favorite: Always test for the HLA-B*5701 allele before initiating any regimen containing Abacavir (ABC) to prevent a potentially fatal hypersensitivity reaction (HSR).

ART Toxicities - Collateral Damage

• NRTIs (Nucleoside Reverse Transcriptase Inhibitors):

  • Class: Lactic acidosis, hepatic steatosis.
  • Zidovudine (ZDV): Anemia, myelosuppression.
  • Abacavir (ABC): Hypersensitivity reaction; screen for HLA-B*5701.
  • Tenofovir (TDF): Nephrotoxicity, bone density loss.

• NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors):

  • Class: Rash, including Stevens-Johnson Syndrome (SJS).
  • Efavirenz: CNS effects (vivid dreams, dizziness).
  • Nevirapine: Severe hepatotoxicity.

• Protease Inhibitors (PIs):

  • Class: Metabolic syndrome (hyperglycemia, dyslipidemia), GI intolerance.
  • Indinavir: Nephrolithiasis (crystal-induced).

• Integrase Inhibitors (INSTIs):

  • Generally well-tolerated; may cause weight gain.

⭐ Abacavir Hypersensitivity: A delayed-type (Type IV) hypersensitivity reaction strongly associated with the HLA-B*5701 allele. All patients must be screened before starting treatment.

Special Ops - Prophylaxis & Resistance

• PrEP (Pre-Exposure): Daily tenofovir + emtricitabine for high-risk individuals to prevent HIV acquisition.
• PEP (Post-Exposure): Start within 72 hours of exposure. 3-drug ART regimen for 28 days.
• Resistance: High viral mutation rate requires genotype testing before initiating or changing therapy to guide drug selection.

⭐ HIV's reverse transcriptase lacks proofreading, leading to high mutation rates and rapid drug resistance development.

High‑Yield Points - ⚡ Biggest Takeaways

• Combination antiretroviral therapy (cART) with at least 3 active drugs from ≥2 classes is the standard of care.
• The primary goal is an undetectable viral load (<50 copies/mL) to restore immune function and prevent transmission.
• Most initial regimens consist of a 2-NRTI backbone plus an Integrase Inhibitor (INSTI).
• Strict adherence is paramount to prevent viral rebound and the emergence of drug resistance.
• Genotypic resistance testing is crucial before initiating therapy to guide drug selection.