What is cidofovir?

What is Cidofovir?

Cidofovir is an intravenous antiviral nucleotide analogue FDA-approved for treating cytomegalovirus (CMV) retinitis in AIDS patients, but it has demonstrated activity against multiple DNA viruses including herpesviruses, adenoviruses, polyomaviruses, papillomaviruses, and poxviruses, though its use is severely limited by dose-limiting nephrotoxicity. 1

Mechanism and Spectrum of Activity

• Cidofovir is a nucleotide analogue of cytosine that undergoes intracellular activation to form diphosphates, which are potent inhibitors of viral DNA polymerases 2
• The drug has broad-spectrum antiviral activity against herpesviruses (including CMV, HSV, VZV, EBV), papillomaviruses, polyomaviruses, and poxviruses 3
• Cidofovir has a prolonged intracellular half-life, allowing for extended dosing intervals (typically every 2 weeks for maintenance therapy) 4
• The antiviral effect depends on intracellular concentrations of active phosphorylated metabolites, which persist much longer than serum drug levels would suggest 2

FDA-Approved Indication

• The only FDA-approved indication is for treatment of CMV retinitis in patients with AIDS 1
• Standard dosing for CMV retinitis: 5 mg/kg IV once weekly for 2 weeks (induction), then 5 mg/kg IV every 2 weeks (maintenance) 4

Off-Label Uses in Immunocompromised Patients

Adenovirus Infections

• Low-dose cidofovir (1 mg/kg three times weekly) has been effective in case reports of severe adenovirus infections in immunocompromised adults 5
• Cidofovir 5 mg/kg IV once weekly for 2 weeks, then every other week, has been used successfully in pediatric hematology patients with adenovirus outbreaks 5
• Treatment with cidofovir may be considered in severely ill immunocompromised patients with adenovirus-associated disease, though considerable nephrotoxicity must be weighed against potential benefits 5

CMV Gastrointestinal Disease

• Cidofovir is considered an alternative treatment for gastrointestinal CMV disease when ganciclovir or foscarnet fail or are contraindicated 5
• It should be considered second-line therapy after ganciclovir for CMV enteritis in hematologic malignancy and transplant patients 5

Vaccinia Complications

• Cidofovir is available under Investigational New Drug (IND) protocols from CDC for second-line treatment of smallpox vaccination complications 5
• It should only be used when patients fail to respond to vaccinia immune globulin (VIG), when patients are near death, or when VIG inventories are exhausted 5
• Proposed dose for vaccinia complications: 5 mg/kg IV once, with consideration of a second dose 1 week later if no response 5

BK Virus

• While cidofovir demonstrates effectiveness against BK virus (particularly in transplant recipients with hemorrhagic cystitis), renal toxicity is a significant complication 5
• There is currently insufficient data to support formal recommendations for BK virus treatment with cidofovir 5

Critical Safety Concerns

Nephrotoxicity (Dose-Limiting Toxicity)

• Renal impairment is the major toxicity of cidofovir, with cases of acute renal failure requiring dialysis and contributing to death occurring with as few as one or two doses 1
• Nephrotoxicity is potentially irreversible and can result in renal failure requiring dialysis 5, 4
• To reduce nephrotoxicity, cidofovir must be administered with IV saline prehydration and oral probenecid with each infusion 1, 5
• Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose 1
• Cidofovir is contraindicated in patients receiving other nephrotoxic agents 1

Other Serious Adverse Effects

• Carcinogenic in animal studies: Mammary adenocarcinomas developed in rats at 0.04 times human exposure 5, 1
• Teratogenic and causes hypospermia in animal studies 1
• Neutropenia has been observed and requires monitoring of neutrophil counts during therapy 1
• Other toxicities include proteinuria, decreased intraocular pressure/ocular hypotony, anterior uveitis/iritis, and metabolic acidosis 5

Administration Requirements

Mandatory Coadministration

• Oral probenecid must be given with each cidofovir infusion to block active tubular secretion and reduce nephrotoxicity 5, 2
• IV saline hydration before and after cidofovir is required 5
• Cidofovir is administered as a 60-minute IV infusion 5

Probenecid-Related Precautions

• Probenecid itself carries risks including headache, anorexia, nausea, vomiting, hypersensitivity reactions, anemia, hemolytic anemia, nephritic syndrome, hepatic necrosis, gout, uric acid stones, and renal colic 5
• Use probenecid with caution in children, pregnant women, and persons with sulfa drug allergy 5

Pharmacokinetics

• Cidofovir is dianionic at physiological pH with low oral bioavailability 2
• After IV administration, pharmacokinetics are dose-independent with systemic exposure proportional to dose 2

• 90% of an IV dose is recovered unchanged in urine over 24 hours 2

• The drug is cleared by the kidney with minimal metabolism 2
• Clearance in patients with renal impairment shows linear relationship to creatinine clearance, requiring dose adjustment 2

Key Clinical Limitations

• Cidofovir has never been used to treat vaccinia infections in humans, and its efficacy for this indication is based solely on animal models 5
• In animal models, cidofovir protects against orthopoxvirus growth only if administered within 24 hours after inoculation; no studies demonstrate effect on established orthopoxvirus infection 5
• No controlled clinical trials have tested cidofovir for efficacy against vaccinial infections 5
• The drug has poor penetration into CSF, limiting its utility for CNS infections like CMV encephalitis 5

Common Pitfalls to Avoid

• Never administer cidofovir without concurrent probenecid and IV hydration, as this dramatically increases nephrotoxicity risk 1, 5
• Never use cidofovir in patients on other nephrotoxic agents (absolute contraindication) 1
• Do not assume cidofovir will work for established viral infections based on prophylactic animal data 5
• Do not use cidofovir as first-line therapy when other options (ganciclovir, foscarnet, VIG) are available and appropriate 5
• Monitor renal function within 48 hours before each dose and adjust or discontinue if creatinine or proteinuria worsen 1