HSV That Won't Heal on Acyclovir: Foscarnet's Proof or Cidofovir's Simpler Schedule
A single patient, five weeks post-transplant, with a perianal ulcer that has only grown despite appropriately-dosed acyclovir. The disagreement is between the drug with the stronger track record and the one that spares him thrice-daily infusions he's already struggling to tolerate.
K.S., a 45-year-old warehouse supervisor, is five weeks out from an allogeneic stem-cell transplant for acute lymphoblastic leukemia, now dealing with mild skin graft-versus-host disease on top of everything else his body is managing. A perianal ulcer appeared three weeks ago, swabbed and confirmed as HSV-2 by PCR, and started on standard-dose IV acyclovir. It hasn't healed. If anything it's grown, now nearly four centimeters across, painful enough that he's stopped sitting in the recliner his wife brought from home and instead spends most of the day lying on his side. Genotypic testing sent when the lack of response became clear has confirmed a thymidine kinase mutation — the mechanism Piret and Boivin's review of herpesvirus antiviral resistance identifies behind the large majority of clinical acyclovir resistance, meaning the ulcer's persistence reflects a genuinely resistant virus rather than inadequate dosing or absorption.
Both remaining options work independently of the mutated thymidine kinase, since neither requires viral kinase activation the way acyclovir does — foscarnet inhibits the viral DNA polymerase directly at the pyrophosphate-binding site, and cidofovir, already a phosphorylated nucleotide analog when it enters the cell, bypasses the same activation step. Foscarnet has the deeper record specifically for acyclovir-resistant HSV — Safrin and colleagues' randomized comparison against vidarabine in acyclovir-resistant mucocutaneous HSV is the study that made it first-line, and nothing comparable has been run for cidofovir in this indication — but it demands thrice-daily infusions with close electrolyte monitoring — it characteristically wastes calcium, magnesium, and phosphate, on top of its own nephrotoxicity — in a patient who's already fatigued, on a GVHD regimen with its own metabolic effects, and has been vocal with his transplant team about how much the current infusion schedule is wearing on him. Cidofovir's once-weekly dosing is a real logistical relief by comparison, but it comes with its own distinct nephrotoxicity profile requiring aggressive hydration and probenecid, and its evidence base for this specific indication, while real, is thinner than foscarnet's. It is worth noticing that "the drug he can tolerate" and "the drug that works" are being handled here as two separate axes, and for a four-centimeter ulcer in a man five weeks post-transplant with GVHD skin that will not stay dressed, they may not be separable at all.
Transplant ID consult, week three
I'd start foscarnet, thrice daily, with structured electrolyte monitoring. It has the deeper, more established track record specifically for acyclovir-resistant HSV and is generally regarded as first-line for exactly this situation. His renal function is normal right now — that gives us real room to manage foscarnet's known toxicity properly rather than reaching for a less-proven option out of scheduling convenience.
His renal function is the room I have to work with, and rooms like that close. I'd rather use it now than discover in a fortnight that it has.
I'd lean toward cidofovir instead, once weekly. He's told his care team directly how hard he's finding the current infusion schedule — that's not a minor preference, it's a real clinical factor in an already exhausting transplant course. A regimen he can actually sustain may end up producing a more reliable treatment course than one that's more effective on paper but harder for him to get through.
I'm not disputing foscarnet's stronger evidence base — I'm saying his tolerance and adherence aren't separate from efficacy, they're part of what determines whether either drug actually works for him in practice.
I'd still choose foscarnet, and I want to separate two things that are getting combined here: his fatigue and infusion burden are real and deserve a direct response — schedule optimization, symptom support, whatever his transplant team can offer — but I don't think the fix for that problem should be picking the less-proven antiviral. That solves a tolerability problem by accepting a real evidence gap for a treatment-resistant infection.
Both problems are legitimate. I'd rather solve his fatigue directly than let it steer the antiviral choice away from the option with the stronger track record for exactly what he has.
Agreed: foscarnet started with a structured electrolyte-monitoring protocol, and a separate consult with the transplant team's supportive care service to address his infusion burden and fatigue directly.
Not fully settled: the transplant physician's point — that tolerance and adherence are part of what determines real-world efficacy, not separate from it — was accepted as a genuine consideration for future decisions, and the team agreed that if his fatigue worsens meaningfully or his renal function changes, cidofovir returns to the table rather than being treated as permanently ruled out.