HSV-1, HSV-2, VZV. Rapid replication. Latency in sensory ganglia. All encode viral TK → acyclovir activated. Coverage: acyclovir, valacyclovir, famciclovir. Resistance: primarily TK gene mutations. Ganciclovir and foscarnet also active.
CMV, HHV-6, HHV-7. Slow replication. Latency in hematopoietic cells. CMV lacks viral TK → intrinsically resistant to acyclovir. CMV uses UL97 phosphotransferase to activate ganciclovir. Coverage: ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir.
EBV (HHV-4), KSHV (HHV-8). Lymphotropic. Associated with malignant transformation (PTLD, Kaposi sarcoma). EBV: low TK activity — acyclovir minimal clinical benefit. No licensed agent reliably treats EBV or KSHV disease. Management is immunological, not antiviral.
Step 1: Viral TK phosphorylates acyclovir to monophosphate — 40–100× more efficient in infected cells. Step 2: Cellular kinases convert to triphosphate. Step 3: Competitively inhibits viral DNA polymerase AND causes obligate chain termination (no 3′-OH on acyclic sugar). Selectivity: 10–30× preference for viral vs. cellular polymerase. Valacyclovir = L-valyl ester prodrug → 3–5× higher plasma levels than oral acyclovir.
Step 1: CMV UL97 phosphotransferase phosphorylates ganciclovir to monophosphate (CMV has no TK). Step 2: Cellular kinases convert to triphosphate. Step 3: Competitively inhibits CMV UL54 DNA polymerase; incorporated into viral DNA → slows/terminates replication. Lower selectivity than acyclovir (~10×) → more myelosuppression. Valganciclovir = oral prodrug equivalent to IV ganciclovir exposure.
Does NOT require viral TK or UL97 for activation → active against TK-deficient acyclovir-resistant HSV and UL97-mutant ganciclovir-resistant CMV. Binds pyrophosphate-binding site of viral DNA polymerase → blocks pyrophosphate release → halts chain elongation. Broad spectrum: HSV-1, HSV-2, VZV, CMV, HHV-6. Major toxicity: nephrotoxicity (up to 30%) + electrolyte disturbances (hypocalcemia, hypomagnesemia, hypokalemia). No myelosuppression → preferred when ganciclovir neutropenia is severe.
Does NOT require viral TK or UL97 → cellular enzymes activate directly to cidofovir diphosphate. Broad spectrum: CMV, HSV, VZV, adenovirus, BKPyV, orthopoxviruses (smallpox, mpox). Dose-limiting nephrotoxicity via OAT1 transporter accumulation in proximal tubules. Mandatory protocol: probenecid (OAT1 inhibitor) + saline pre-load before every infusion. Brincidofovir = lipid conjugate; avoids OAT1 → reduced nephrotoxicity; FDA-approved for smallpox.
Almost exclusively in immunocompromised patients on prolonged acyclovir. Primary mechanism: TK gene mutations (TK-null or TK-partial) → acyclovir not phosphorylated. Cross-resistance: ALL TK-dependent agents (acyclovir, valacyclovir, penciclovir, famciclovir) lose activity simultaneously. Treatment pivot: foscarnet (does not need TK) or cidofovir. Less common: DNA polymerase mutations → may have partial foscarnet cross-resistance → cidofovir only option.
Suspect when CMV viral load fails to decline ≥1 log10 after 2 weeks adequate ganciclovir. Test: UL97 + UL54 genotyping. UL97 mutations (codons 460, 594, 595): ganciclovir resistance only → foscarnet and cidofovir remain active. UL54 mutations: may cross-resist ganciclovir, foscarnet, cidofovir. Combined UL97+UL54: high-level multidrug resistance → maribavir (UL97 kinase inhibitor, distinct binding site) or combination foscarnet + ganciclovir. Letermovir: no cross-resistance with any of the above.
IV acyclovir 20 mg/kg q8h immediately. Duration by syndrome: SEM disease = 14 days; encephalitis or disseminated = 21 days. Follow with oral acyclovir suppression 300 mg/m² TID for 6 months (CNS/disseminated disease) → reduces recurrence and improves neurodevelopment.
Lower threshold for IV acyclovir in immunocompromised patients: disseminated HSV/VZV, HSV encephalitis, visceral VZV → IV acyclovir 10–12 mg/kg q8h. Acyclovir-resistant HSV/VZV (progressive lesions after 5–7 days adequate IV acyclovir) → switch to foscarnet.
SOT D+/R- (highest risk): universal prophylaxis with valganciclovir 3–6 months. HSCT CMV-seropositive: letermovir prophylaxis day 0–100 (no myelosuppression). Pre-emptive strategy: monitor CMV PCR; treat when viral load exceeds threshold before symptoms. Late-onset CMV: occurs after prophylaxis discontinuation — more common with D+/R- SOT.
Every cidofovir infusion: probenecid 2 g PO 3 h before + 1 g at 2 h and 8 h after; 1 L normal saline IV pre-infusion; check creatinine and urine protein within 48 h of each dose. Hold if creatinine rises ≥0.3 mg/dL above baseline or proteinuria ≥2+. Contraindicated if CrCl <55 mL/min.