CMV: ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir, maribavir.
Adenovirus: cidofovir (off-label); brincidofovir (emerging).
HHV-6: foscarnet (preferred), ganciclovir (alternative) — clinical trial data limited.
EBV/PTLD: no antiviral benefit (PTLD driven by latent EBV, not lytic replication). Manage with rituximab + reduced immunosuppression.
JC virus/PML: no proven antiviral. Restore immune surveillance (ART in HIV; natalizumab withdrawal + PLEX in MS).
BKPyV nephropathy: no proven antiviral. Reduce calcineurin inhibitor dose when plasma BKPyV >10,000 copies/mL. Monitor for rejection risk.
All opportunistic viral infections: reducing immunosuppression to restore T-cell surveillance is always the most important adjunct to any antiviral regimen.
Blood CMV PCR is frequently undetectable or low in isolated CMV colitis — virus replicates locally in colonic mucosa without producing detectable systemic viremia. Do NOT use negative blood CMV PCR to rule out CMV colitis in symptomatic immunocompromised patients. Diagnosis requires colonoscopy with biopsy (CMV cytopathic effect on immunohistochemistry). Treatment: IV ganciclovir induction 3–6 weeks, then oral valganciclovir consolidation. Monitor clinically and endoscopically — not by blood PCR.
HSCT recipients: mortality 30–50% despite antiviral therapy. Treatment: IV ganciclovir + IVIG (combination superior to ganciclovir alone in retrospective data). Intervene early: treat CMV detected in BAL samples before symptoms of pneumonitis develop. CMV CNS disease: combination ganciclovir + foscarnet for maximum antiviral potency; diagnose by CSF PCR (sensitivity >80%).
Acyclovir and ganciclovir do not treat PTLD — PTLD is driven by latent EBV in B cells, not by lytic replication that antivirals target. Monitor EBV viral load by PCR in high-risk HSCT recipients (T-cell-depleted grafts, ATG conditioning). Rising EBV viral load → pre-emptive rituximab (anti-CD20 mAb) depletes EBV-infected B cells. Reduce immunosuppression when clinically feasible. Established PTLD: rituximab then CHOP chemotherapy for non-responders.
No antiviral (cidofovir, cytarabine) has proven clinical benefit in controlled studies. HIV-associated PML: initiate or optimize ART to restore CD4 >200 cells/mm³ — only intervention consistently improving outcomes. PML-IRIS occurs in 10–30% of HIV patients initiating ART with active PML; manage with corticosteroids. Natalizumab-associated PML: stop natalizumab immediately; plasma exchange (PLEX) to accelerate drug clearance and restore lymphocyte CNS trafficking. Pembrolizumab: signals of benefit in small series (checkpoint inhibitor to enhance JCPyV-specific T cells).
Approximately 1% of the population carries HHV-6 integrated into the germline (ciHHV-6) → stable very high HHV-6 DNA in ALL nucleated cells (>5.5 log10 copies/mL whole blood). ciHHV-6 is NOT active viral replication — antivirals cannot suppress integrated DNA. Treat only true reactivation (fluctuating viral load, IgM anti-HHV-6, symptoms). HHV-6B encephalitis: bilateral hippocampal T2 signal on MRI + CSF PCR positive → treat with foscarnet (preferred) for 3–6 weeks.
Screen: plasma BKPyV PCR monthly for first 12 months post-kidney transplant. Plasma viral load >10,000 copies/mL → reduce calcineurin inhibitor dose. No proven antiviral therapy — cidofovir, leflunomide, and IVIG have been used without robust trial evidence. Balance: sufficient immunosuppression reduction to control BKPyV vs. rejection risk. Allograft biopsy: distinguishes BKPyV nephropathy from rejection (critical distinction — treatment is opposite).