What is the recommended cidofovir induction regimen for a patient with a severe viral infection, such as cytomegalovirus (CMV), considering potential nephrotoxicity and neutropenia?

Cidofovir Induction Regimen

Primary Recommendation

For cidofovir induction therapy in severe viral infections such as CMV retinitis, administer 5 mg/kg IV once weekly for 2 consecutive weeks, infused over 60 minutes at a constant rate, with mandatory probenecid and aggressive saline hydration to mitigate nephrotoxicity. 1, 2, 3

Mandatory Nephroprotective Protocol

Every cidofovir dose must be accompanied by the following measures to prevent potentially irreversible renal failure:

Probenecid Administration

• 2 grams orally 3 hours before cidofovir infusion 1, 2, 3
• 1 gram orally 2 hours after infusion completion 1, 2, 3
• 1 gram orally 8 hours after infusion completion (total 4 grams per dose) 1, 2, 3
• Consider prophylactic antiemetic and food intake with probenecid to reduce nausea 1

Saline Hydration

• Minimum 1 liter 0.9% normal saline IV over 1-2 hours immediately before cidofovir 1, 2, 3
• Second liter (if tolerated) at start of or immediately after cidofovir infusion, over 1-3 hours 1, 2, 3

Pre-Treatment Eligibility Criteria

Cidofovir is contraindicated if any of the following are present 1:

• Serum creatinine >1.5 mg/dL 1
• Calculated creatinine clearance ≤55 mL/min 1
• Urine protein ≥100 mg/dL (≥2+ proteinuria) 1

Calculate creatinine clearance using the Cockcroft-Gault formula before initiating therapy, as serum creatinine alone may not accurately reflect renal function in patients with advanced AIDS 1

Monitoring Requirements

Before Each Dose (Within 48 Hours)

• Serum creatinine and calculated creatinine clearance 1, 2
• Urinalysis for proteinuria (measured in clinical laboratory, not dipstick alone) 1, 2
• Complete blood count to assess for neutropenia 1, 2

During Therapy

• Intraocular pressure monitoring for hypotony risk 1, 2
• Serum bicarbonate for metabolic acidosis 1, 2

Dose Modification Algorithm

For Renal Function Changes During Therapy

• Serum creatinine increase of 0.3-0.4 mg/dL above baseline: Reduce maintenance dose from 5 mg/kg to 3 mg/kg 1
• Serum creatinine increase ≥0.5 mg/dL above baseline OR ≥3+ proteinuria: Discontinue cidofovir immediately 1

Proteinuria may be an early indicator of nephrotoxicity; continued administration can lead to Fanconi syndrome with glycosuria, decreased serum phosphate/uric acid/bicarbonate, and acute renal failure requiring dialysis 1

Critical Safety Warnings

Nephrotoxicity

• Dose-dependent nephrotoxicity is the major dose-limiting toxicity 1, 4
• Acute renal failure requiring dialysis has occurred after as few as 1-2 doses 1
• Renal function may not return to baseline after drug discontinuation 1, 4
• Deaths have been reported from irreversible renal failure 1, 4

Other Serious Toxicities

• Neutropenia requiring monitoring of neutrophil counts 1, 4, 2
• Decreased intraocular pressure/ocular hypotony and anterior uveitis/iritis 1, 4, 2
• Metabolic acidosis associated with proximal tubular injury, sometimes with liver dysfunction and pancreatitis resulting in death 1, 4
• Carcinogenicity and teratogenicity demonstrated in animal studies 4, 1

Clinical Context and Indications

FDA-Approved Indication

• CMV retinitis in patients with AIDS 4

Off-Label/IND Protocol Uses

• Vaccinia-related complications as second-line therapy when VIG fails (CDC IND protocol) 4, 2
• Severe adenovirus infections in immunocompromised children, particularly post-hematopoietic stem cell transplantation 2

Special Populations

Pediatric Patients

• Insufficient data exists for appropriate dosing in children 3, 4
• The standard adult dosing of 5 mg/kg IV once weekly for 2 weeks induction is recommended by some societies, but dosages must be determined in consultation with CDC or DoD specialists 4, 2, 3
• Cidofovir has not been studied in pediatric CMV disease 3

Pregnant/Nursing Women

• Administer only if clearly needed; fetal harm and effects on reproductive capacity are unknown 4

Drug Interactions and Contraindications

• Avoid concurrent nephrotoxic agents: aminoglycosides (tobramycin, gentamicin, amikacin), amphotericin B, foscarnet, IV pentamidine, vancomycin, NSAIDs 1
• Probenecid interacts with metabolism or renal tubular excretion of many drugs 1
• Sulfa drug allergy: Exercise caution, as cross-reactivity with probenecid may occur 2

Common Pitfalls to Avoid

• Never exceed recommended dose, frequency, or infusion rate 1
• Never omit probenecid or inadequate hydration, which dramatically increases nephrotoxicity risk 1, 2
• Never administer by intraocular injection 1
• Never initiate therapy without calculating creatinine clearance, as serum creatinine alone is insufficient 1
• Never continue therapy if proteinuria develops, as this may progress to irreversible Fanconi syndrome 1

Efficacy Data

Clinical trials demonstrate that cidofovir effectively delays progression of CMV retinitis compared to deferred treatment, with median time to progression of 64 days (low-dose) and not reached (high-dose) versus 20-21 days for deferral 5. However, no direct comparative trials with ganciclovir or foscarnet exist 6, 7. The biweekly maintenance dosing offers advantages over daily IV ganciclovir or foscarnet, eliminating the need for indwelling central venous catheters and associated infection risks 7.