HIV entry inhibitors

HIV Entry - Blocking the Gates

• CCR5 Antagonist: Maraviroc
  • Allosterically binds to the host cell CCR5 coreceptor, preventing interaction with viral gp120.
  • 📌 Maraviroc stops HIV from marrying the T-cell at the CCR5 door.
• Fusion Inhibitor: Enfuvirtide
  • Binds to the first heptad repeat (HR1) of the viral gp41 subunit, preventing the conformational change required for membrane fusion.
  • Administered via subcutaneous injection; risk of local injection site reactions.

⭐ Tropism Assay Required: Before initiating Maraviroc, an assay must confirm the virus is exclusively CCR5-tropic. It is not active against CXCR4-tropic or dual/mixed-tropic HIV-1.

Entry Inhibitors - The Agents

• CCR5 Antagonist: Maraviroc

  • Mechanism: Binds to the human CCR5 co-receptor, preventing viral gp120 from interacting with it. This blocks entry of CCR5-tropic HIV strains.
  • Metabolism: Substrate of CYP3A4; dose adjustments needed with inhibitors/inducers.
  • Adverse Effects: Hepatotoxicity (may be preceded by a systemic allergic reaction), postural hypotension.
  • 📌 Mnemonic: Maraviroc blocks the CCR5 rock (receptor).

• Fusion Inhibitor: Enfuvirtide (T-20)

  • Mechanism: A synthetic peptide that binds to the viral gp41 subunit, preventing the conformational change required for membrane fusion.
  • Use: Reserved for treatment-experienced patients with multidrug-resistant HIV.
  • Administration: Subcutaneous injection twice daily.
  • Adverse Effects: Almost universal injection-site reactions (pain, erythema, nodules); increased risk of bacterial pneumonia.

• Attachment Inhibitor: Fostemsavir

  • Mechanism: A prodrug converted to temsavir, which binds directly to viral gp120, inhibiting attachment to host CD4 cells.

⭐ Exam Favorite: Before starting Maraviroc, a tropism assay (e.g., Trofile) is mandatory to confirm the patient has a CCR5-tropic virus. It is ineffective against CXCR4-tropic or dual/mixed-tropic HIV variants.

Clinical Use & Resistance - Salvage Strategy

• Primary Role: Salvage therapy for treatment-experienced patients with multi-drug resistant (MDR) HIV-1. Not for initial therapy.
• Maraviroc (CCR5 Antagonist):
  • Only for CCR5-tropic virus (requires tropism test).
  • Resistance: Shift to CXCR4-tropism or gp120 mutations.
• Enfuvirtide (Fusion Inhibitor):
  • For MDR-HIV with limited options due to injection site reactions and cost.
  • Resistance: Mutations in gp41.
• Ibalizumab & Fostemsavir:
  • Newer options for heavily treatment-experienced adults with MDR-HIV.

⭐ Before starting Maraviroc, a tropism assay is mandatory. It is only effective against CCR5-tropic HIV, not CXCR4-tropic or dual-tropic strains.

Adverse Effects - The Trade-Offs

• Maraviroc (CCR5 Antagonist):

  • ⚠️ Black Box Warning: Hepatotoxicity, often preceded by a systemic allergic reaction (e.g., rash, eosinophilia).
  • Cardiovascular events (e.g., orthostatic hypotension).
  • Increased risk of upper respiratory infections.

• Enfuvirtide (Fusion Inhibitor):

  • Local injection site reactions are nearly universal (>90%), causing pain, erythema, and nodules.
  • Increased risk of bacterial pneumonia.
  • Systemic hypersensitivity reactions.

⭐ Before starting Maraviroc, a tropism test is mandatory to confirm CCR5-tropic HIV-1 strain.

High‑Yield Points - ⚡ Biggest Takeaways

• Maraviroc binds the host CCR5 coreceptor, blocking interaction with viral gp120. A tropism assay is required.
• Enfuvirtide binds viral gp41, inhibiting the conformational change for membrane fusion.
• Ibalizumab is a monoclonal antibody against CD4, acting as a post-attachment inhibitor.
• These agents are typically reserved for salvage therapy in multidrug-resistant HIV.
• Key toxicities: hepatotoxicity for Maraviroc and severe injection-site reactions for Enfuvirtide.