Cytomegalovirus antivirals

CMV Antivirals - The First Responders

• Ganciclovir & Valganciclovir (oral prodrug)

  • MOA: Guanosine analog. Must be phosphorylated by viral kinase UL97 to inhibit CMV DNA polymerase.
  • Toxicity: Myelosuppression (neutropenia, thrombocytopenia), fever, rash.

• Foscarnet

  • MOA: Pyrophosphate analog. Directly inhibits DNA polymerase. No viral kinase activation needed.
  • Toxicity: Nephrotoxicity, electrolyte imbalances (↓Ca²⁺, ↓Mg²⁺, ↓K⁺).
  • 📌 Mnemonic: Foscarnet chelates fosphate & other minerals.

• Cidofovir

  • MOA: Nucleotide analog. Bypasses need for viral kinase.
  • Toxicity: Severe dose-dependent nephrotoxicity. Administer with probenecid.

⭐ Resistance: Mutations in the UL97 gene prevent ganciclovir phosphorylation, conferring resistance. Foscarnet or cidofovir are used as alternatives.

Resistance & Rescue - The Backup Crew

• Primary Driver: Mutations in viral genes, most commonly selected for under drug pressure in immunocompromised hosts.

• Mechanisms of Resistance:

  • Ganciclovir/Valganciclovir: Most common resistance via UL97 gene mutation (a viral phosphotransferase). This prevents the crucial first monophosphorylation step needed for drug activation.
  • Foscarnet/Cidofovir: Resistance via mutations in the UL54 gene, which codes for the viral DNA polymerase itself. Can confer cross-resistance.

⭐ The most frequent cause of ganciclovir resistance is a mutation in the UL97 gene, which blocks the initial, necessary phosphorylation step for drug activation.

• Management of Resistance:

• 📌 Foscarnet Functions on the polymerase directly; Ganciclovir Gets stopped by UL97 mutations.

Prophylaxis Power - The Preventative Play

• Goal: Prevent CMV end-organ disease (retinitis, colitis, pneumonitis) in high-risk, immunocompromised hosts.
• High-Risk Scenarios:
  • Solid Organ Transplant (SOT): Highest risk in CMV D+/R- (Donor positive/Recipient negative).
  • Allogeneic Hematopoietic Stem Cell Transplant (HSCT).
• First-Line Prophylaxis: Valganciclovir (oral ganciclovir prodrug). Requires renal dose adjustments and monitoring for myelosuppression.
• HSCT-Specific Prophylaxis: Letermovir.
  • Novel mechanism: Inhibits the CMV terminase complex, crucial for viral DNA processing.
  • 📌 Letermovir lets the marrow live (no myelosuppression) & terminates CMV.

⭐ Letermovir is used for CMV-seropositive [R+] allogeneic HSCT recipients. Prophylaxis typically starts post-engraftment and continues through day +100 post-transplant.

High‑Yield Points - ⚡ Biggest Takeaways

• Ganciclovir and its prodrug valganciclovir are first-line for CMV, but cause significant myelosuppression.
• Ganciclovir requires viral kinase UL97 for activation; mutations in this gene confer resistance.
• Foscarnet and cidofovir treat ganciclovir-resistant CMV as they do not require viral kinase activation.
• Foscarnet is nephrotoxic and causes significant electrolyte imbalances (Ca²⁺, PO₄³⁻, Mg²⁺).
• Cidofovir's nephrotoxicity is managed with probenecid and saline hydration.
• Letermovir is for prophylaxis in HSCT patients, inhibiting the CMV terminase complex.