NIH guideline for people with HIV: alternative therapy and its rating

“IV cidofovir is a potential alternative (CIII).” (opens the source at this quote in a new tab)
“IV cidofovir 5 mg/kg once weekly for 2 weeks, then every other week (CIII)” (opens the source at this quote in a new tab)
“Administer probenecid 2 g PO 3 hours before each cidofovir dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g).” (opens the source at this quote in a new tab)
“Administer 1 L of normal saline before and, if additional fluid load can be tolerated, administer another 1 L of normal saline after each cidofovir infusion.” (opens the source at this quote in a new tab)
“Cidofovir should be avoided in patients with sulfonamide allergy because of cross-hypersensitivity with probenecid.” (opens the source at this quote in a new tab)

NIH guideline for people with HIV: specialist consultation and laboratory monitoring during cidofovir

“Systemic foscarnet and cidofovir are nephrotoxic medications; treatment should be given in consultation with an infectious diseases specialist (AIII) and with frequent laboratory monitoring (see Table 5).” (opens the source at this quote in a new tab)
“However, for people receiving IV acyclovir, cidofovir, or foscarnet, monitoring of renal function and dose adjustment as necessary is recommended at initiation of treatment and at least once or twice weekly for the duration of treatment, if stable” (opens the source at this quote in a new tab)

CDC sexually transmitted infections guideline: weekly intravenous cidofovir

“Intravenous cidofovir 5 mg/kg body weight once weekly might also be effective.” (opens the source at this quote in a new tab)
“Foscarnet and cidofovir are nephrotoxic medications that require intensive laboratory monitoring and infectious disease specialist consultation.” (opens the source at this quote in a new tab)

Hematopoietic cell transplantation guideline: alternative to foscarnet

“Foscarnet is the treatment of choice for resistant disease (BI); cidofovir may serve as an alternative (CIII).” (opens the source at this quote in a new tab)

European Conference on Infections in Leukemia: regimen for resistance to foscarnet

“Cidofovir 5 mg/kg once a week for 2 weeks, then once every 2 weeks* (BIII)” (opens the source at this quote in a new tab)
“Combined with probenecide and iv hydration” (opens the source at this quote in a new tab)
“In several cases, multidrug-resistant HSV strains causing disease have been documented (III).” (opens the source at this quote in a new tab)

British Association for Sexual Health and HIV guideline: regimen and grade

“Systemic therapy with either foscarnet or cidofovir is generally preferred to treat drug resistant herpes in those living with HIV.” (opens the source at this quote in a new tab)
“cidofovir 5 mg/kg body weight weekly IV infusion (2,D)” (opens the source at this quote in a new tab)
“for 2 weeks then every fortnight, administered with oral probenecid and adequate pre-hydration to reduce the risk of nephrotoxicity.” (opens the source at this quote in a new tab)
“Alternating courses of treatment with aciclovir and cidofovir for subsequent recurrences has been advocated as a strategy that may reduce the development of cidofovir-resistant strains.” (opens the source at this quote in a new tab)
“The efficacy, safety, and durability of the therapeutic response of these agents has yet to be determined in prospective controlled trials.” (opens the source at this quote in a new tab)

European guideline for genital herpes: systemic therapy and alternating courses

“Systemic therapy with either foscarnet or cidofovir is generally preferred to treat drug‐resistant herpes in those living with HIV.” (opens the source at this quote in a new tab)
“There is evidence for alternating courses of treatment with aciclovir and cidofovir for subsequent recurrences as a strategy that may reduce the development of cidofovir‐resistant strains.” (opens the source at this quote in a new tab)
“The efficacy, safety and durability of the therapeutic response of these agents have yet to be determined in prospective controlled trials.” (opens the source at this quote in a new tab)

Position after foscarnet as summarized in reviews

“i.v. CDV is the alternative therapy when FOS resistance is suspected.” (opens the source at this quote in a new tab)
“Off-label CDV use for R/R HSV infection has been described in observational studies and case series” (opens the source at this quote in a new tab)
“mainly for patients with FOS intolerance or suspected FOS resistance.” (opens the source at this quote in a new tab)

“Lesions that fail to respond to FOS could be treated with cidofovir (5 mg/kg once a week for 3 to 4 weeks).” (opens the source at this quote in a new tab)

Cidofovir regimen, monitoring, and regulatory status as tabulated in a review

Field	Quoted entry
Dose	“5 mg/kg i.v. weekly for 3 weeks and then once every 2 weeks for 3 doses.”“Co-administered with probenecid and i.v. hydration.”
Clinically significant adverse reactions	“Nephrotoxicity: renal insufficiency. (U.S. boxed warning).”“Contraindicated if serum creatinine >1.5 mg/dL, CrCl ≤55 mL/min, or urine protein ≥100 mg/dL.”“Haematological toxicity: neutropenia (U.S. boxed warning)”
Monitoring	“Serum creatinine”“Electrolytes”“Urine protein”“Complete blood count”
FDA approval or off-label use	“Off-label use”

Labeled indication: cytomegalovirus retinitis in AIDS

“Cidofovir is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS).” (opens the source at this quote in a new tab)
“THE SAFETY AND EFFICACY OF CIDOFOVIR INJECTION HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (SUCH AS PNEUMONITIS OR GASTROENTERITIS), CONGENITAL OR NEONATAL CMV DISEASE, OR CMV DISEASE IN NON-HIV-INFECTED INDIVIDUALS.” (opens the source at this quote in a new tab)
“CIDOFOVIR INJECTION IS INDICATED ONLY FOR THE TREATMENT OF CMV RETINITIS IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME.” (opens the source at this quote in a new tab)
“Controlled clinical studies of efficacy have been limited to patients with AIDS and CMV retinitis.” (opens the source at this quote in a new tab)

Use for HSV infection outside the labeled indication

“Cidofovir is approved for treatment of HCMV retinitis in AIDS patients and is available as an intravenous formulation.” (opens the source at this quote in a new tab)
“Cidofovir has proven to be effective in the treatment of progressive mucocutaneous infections due to ACV- and/or FOS-resistant HSV in immunocompromised patients” (opens the source at this quote in a new tab)
“but it is not approved for this indication.” (opens the source at this quote in a new tab)

In vitro activity against herpes simplex virus in the prescribing information

“Cidofovir is active in vitro against a variety of laboratory and clinical isolates of CMV and other herpesviruses” (opens the source at this quote in a new tab)

Virus	IC50 (μM)
Wild-type CMV isolates	“0.5 to 2.8”
HSV-1, HSV-2	“12.7 to 31.7”

Labeled dose for the approved indication

“The recommended induction dose of cidofovir injection for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks.” (opens the source at this quote in a new tab)
“The recommended maintenance dose of cidofovir injection is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over one hr), administered once every 2 weeks.” (opens the source at this quote in a new tab)
“THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED.” (opens the source at this quote in a new tab)

Required probenecid with each dose

“TO MINIMIZE POTENTIAL NEPHROTOXICITY, PROBENECID AND INTRAVENOUS SALINE PREHYDRATION MUST BE ADMINISTERED WITH EACH CIDOFOVIR INJECTION INFUSION.” (opens the source at this quote in a new tab)
“Probenecid must be administered orally with each cidofovir injection dose. Two grams must be administered 3 hr prior to the cidofovir injection dose and one gram administered at 2 and again at 8 hr after completion of the one hr cidofovir injection infusion (for a total of 4 grams).” (opens the source at this quote in a new tab)
“Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting.” (opens the source at this quote in a new tab)

Required saline hydration with each dose

“Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of cidofovir injection.” (opens the source at this quote in a new tab)
“The saline solution should be infused over a 1 to 2 hr period immediately before the cidofovir injection infusion.” (opens the source at this quote in a new tab)
“Patients who can tolerate the additional fluid load should receive a second liter.” (opens the source at this quote in a new tab)

Dose adjustment and discontinuation for changes in renal function

“The maintenance dose of cidofovir injection must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 to 0.4 mg/dL above baseline.” (opens the source at this quote in a new tab)
“Cidofovir injection therapy must be discontinued for an increase in serum creatinine of ≥ 0.5 mg/dL above baseline or development of ≥ 3+ proteinuria.” (opens the source at this quote in a new tab)

Real-world cohort of 125 hematopoietic cell transplant recipients: intravenous cidofovir in 6 participants

“Ninety-four patients received foscarnet, 6 received IV cidofovir, and 21 received topical antivirals for a total of 109 foscarnet courses, 6 IV cidofovir courses, and 28 topical antiviral courses.” (opens the source at this quote in a new tab)
“The treatment duration was a mean (SD) of 21.8 (13.8), 20.3 (10.1), and 41.0 (37.5) days for foscarnet, IV cidofovir, and topical antivirals, respectively.” (opens the source at this quote in a new tab)
“Among 6 IV cidofovir courses, renal function abnormalities were reported during 3 courses (50%).” (opens the source at this quote in a new tab)
“One of 6 courses of IV cidofovir was discontinued because of the renal function abnormalities.” (opens the source at this quote in a new tab)
“Systemic cidofovir requires weekly IV administration and, although it could theoretically be given in the outpatient setting, concerns for nephrotoxicity and limited efficacy data hinder its applicability for refractory HSV.” (opens the source at this quote in a new tab)

Allogeneic stem cell transplant recipients in France: cidofovir after foscarnet in 8 participants

“Fourteen cases of severe acyclovir-resistant herpes simplex virus type 1 (HSV-1) infection, 7 of which showed resistance to foscarnet, were diagnosed among 196 allogeneic stem cell transplant recipients within a 29-month period.” (opens the source at this quote in a new tab)
“All patients received foscarnet; 8 subsequently received cidofovir.” (opens the source at this quote in a new tab)
“No strain from any of the 7 patients was resistant in vitro to cidofovir; however, only 3 of 7 patients achieved complete response.” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: intravenous cidofovir after foscarnet

“All patients were initially treated with high-dose oral valacyclovir (1000 mg every 8 hours) or intravenous acyclovir (5–10 mg/kg every 8 hours) without a response and then were transitioned to foscarnet and/or cidofovir (topical or intravenous).” (opens the source at this quote in a new tab)
“IV cidofovir dose used at 5mg/kg weekly” (opens the source at this quote in a new tab)
“Recurrent HSV infection occurred in four patients (22%), all of whom had foscarnet-resistant HSV infection, an underlying diagnosis of GvHD, and were treated with parenteral or topical cidofovir therapy.” (opens the source at this quote in a new tab)

Single-center cohort of 18 allogeneic transplant recipients: renal toxicity with intravenous cidofovir as tabulated in a review

“five patients received i.v. CDV, and four of them experienced renal toxicity (concurrently exposed to FOS).” (opens the source at this quote in a new tab)
“Four out of five patients who received i.v. FOS and i.v. CDV required haemodialysis.” (opens the source at this quote in a new tab)

Single-center series of 5 allogeneic transplant recipients: cidofovir as step-down therapy in 2 participants

“Foscarnet was used in all patients as initial therapy, whereas intravenous cidofovir was used as step-down therapy in two patients.” (opens the source at this quote in a new tab)
“Protracted courses of antivirals (foscarnet followed by cidofovir, or foscarnet alone) were required, with a median duration of therapy of five weeks (range: two to nine weeks); and although clinical improvement was noted in all the patients, complete healing and resolution of the infection were achieved in none.” (opens the source at this quote in a new tab)

Case report after haploidentical transplantation: healing with cidofovir after foscarnet toxicity

“We describe a 67-year-old female patient with multiple ulcers and erosions of the periocular, perioral, and oral mucosa after haploidentical allo-HSCT.” (opens the source at this quote in a new tab)
“In particular, an adverse effect of low potassium and renal damage has been observed with foscarnet.” (opens the source at this quote in a new tab)
“From Day +98, the treatment was switched to i.v. cidofovir (5 mg/kg) once a week for 2 weeks and then every other week for one month” (opens the source at this quote in a new tab)
“The patient showed significant improvement after 2 injections of cidofovir” (opens the source at this quote in a new tab)
“Cidofovir may be effective for acyclovir-resistant patients; however, the efficacy of systemic cidofovir administration for acyclovir-resistant patients after allo-HSCT remains unknown.” (opens the source at this quote in a new tab)

Case from a transplant series: response followed by acute renal failure and neutropenia

“After 5 doses of CID 5 mg/kg per week, significant improvement was noted; however, the treatment course was complicated by acute renal failure and neutropenia, which recurred after rechallenge with CID.” (opens the source at this quote in a new tab)

In vitro susceptibility of isolates from allogeneic transplant recipients

“All the isolates were sensitive to cidofovir, for which the IC(50) values correlated inversely with those for acyclovir (P=.01).” (opens the source at this quote in a new tab)

Boxed warning for cidofovir

“RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF CIDOFOVIR INJECTION. CASES OF ACUTE RENAL FAILURE RESULTING IN DIALYSIS AND/OR CONTRIBUTING TO DEATH HAVE OCCURRED WITH AS FEW AS ONE OR TWO DOSES OF CIDOFOVIR INJECTION.” (opens the source at this quote in a new tab)
“TO REDUCE POSSIBLE NEPHROTOXICITY, INTRAVENOUS PREHYDRATION WITH NORMAL SALINE AND ADMINISTRATION OF PROBENECID MUST BE USED WITH EACH CIDOFOVIR INJECTION INFUSION.” (opens the source at this quote in a new tab)
“RENAL FUNCTION (SERUM CREATININE AND URINE PROTEIN) MUST BE MONITORED WITHIN 48 HOURS PRIOR TO EACH DOSE OF CIDOFOVIR INJECTION AND THE DOSE OF CIDOFOVIR INJECTION MODIFIED FOR CHANGES IN RENAL FUNCTION AS APPROPRIATE” (opens the source at this quote in a new tab)
“CIDOFOVIR INJECTION IS CONTRAINDICATED IN PATIENTS WHO ARE RECEIVING OTHER NEPHROTOXIC AGENTS.” (opens the source at this quote in a new tab)
“NEUTROPENIA HAS BEEN OBSERVED IN ASSOCIATION WITH CIDOFOVIR INJECTION TREATMENT. THEREFORE, NEUTROPHIL COUNTS SHOULD BE MONITORED DURING CIDOFOVIR INJECTION THERAPY.” (opens the source at this quote in a new tab)
“IN ANIMAL STUDIES CIDOFOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED HYPOSPERMIA” (opens the source at this quote in a new tab)

Contraindications

“Initiation of therapy with cidofovir injection is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).” (opens the source at this quote in a new tab)
“Cidofovir injection is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.” (opens the source at this quote in a new tab)
“Cidofovir injection is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.” (opens the source at this quote in a new tab)

Nephrotoxicity: label warnings

“Dose dependent nephrotoxicity is the major dose-limiting toxicity related to cidofovir injection administration.” (opens the source at this quote in a new tab)
“Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of cidofovir injection-related nephrotoxicity.” (opens the source at this quote in a new tab)
“Continued administration of cidofovir injection may lead to additional proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis.” (opens the source at this quote in a new tab)
“Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of cidofovir injection.” (opens the source at this quote in a new tab)
“The safety of cidofovir injection has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents” (opens the source at this quote in a new tab)

Nephrotoxicity: incidence in clinical trials in cytomegalovirus retinitis

“Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creatinine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving cidofovir injection at a maintenance dose of 5 mg/kg every other week.” (opens the source at this quote in a new tab)
“Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107).” (opens the source at this quote in a new tab)
“Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely” (opens the source at this quote in a new tab)
“In clinical trials, cidofovir injection was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.” (opens the source at this quote in a new tab)

Neutropenia, ocular hypotony, uveitis, and metabolic acidosis

“In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm3 occurred in 24% of patients.” (opens the source at this quote in a new tab)
“Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.” (opens the source at this quote in a new tab)
“Among the subset of patients monitored for intraocular pressure changes, a ≥ 50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose.” (opens the source at this quote in a new tab)
“Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing.” (opens the source at this quote in a new tab)
“A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients.” (opens the source at this quote in a new tab)
“Decreases in serum bicarbonate to ≤ 16 mEq/L occurred in 16% of cidofovir-treated patients.” (opens the source at this quote in a new tab)
“Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving cidofovir injection.” (opens the source at this quote in a new tab)

Serious adverse events or laboratory abnormalities in more than 5% of patients

Event	Patients, number (%) of 135
Proteinuria (≥ 100 mg/dL)	“68 (50)”
Neutropenia (≤ 500 cells/mm3)	“33 (24)”
Decreased intraocular pressure	“17 (24)”
Decreased serum bicarbonate (≤ 16 mEq/L)	“21 (16)”
Fever	“19 (14)”
Infection	“16 (12)”
Creatinine elevation (≥ 2.0 mg/dL)	“16 (12)”
Pneumonia	“12 (9)”
Dyspnea	“11 (8)”
Nausea with vomiting	“10 (7)”

Adverse events, laboratory abnormalities, or intercurrent illnesses of any severity in more than 15% of patients

Event	Patients, number (%) of 115
Any adverse event	“115 (100)”
Proteinuria (≥ 30 mg/dL)	“101 (88)”
Nausea with or without vomiting	“79 (69)”
Fever	“67 (58)”
Neutropenia (< 750 cells/mm3)	“50 (43)”
Asthenia	“50 (43)”
Headache	“34 (30)”
Rash	“34 (30)”
Infection	“32 (28)”
Alopecia	“31 (27)”
Diarrhea	“30 (26)”
Pain	“29 (25)”
Creatinine elevation (> 1.5 mg/dL)	“28 (24)”
Anemia	“28 (24)”
Anorexia	“26 (23)”
Dyspnea	“26 (23)”
Chills	“25 (22)”
Increased cough	“22 (19)”
Oral moniliasis	“21 (18)”

Laboratory monitoring before each dose

“Serum creatinine and urine protein must be monitored within 48 hours prior to each dose.” (opens the source at this quote in a new tab)
“White blood cell counts with differential should be monitored prior to each dose.” (opens the source at this quote in a new tab)
“Intraocular pressure should be monitored during cidofovir injection therapy.” (opens the source at this quote in a new tab)

Nephrotoxicity and myelosuppression as summarized in reviews

“Nephrotoxicity is the most common side effect of CDV” (opens the source at this quote in a new tab)
“even when administered with probenecid; myelosuppression, including neutropenia, is also of concern” (opens the source at this quote in a new tab)
“The limited available data and the severe toxicity of CDV underscore the need for further investigation into the optimal conditions and patient profiles for successful CDV intervention for HCT recipients with R/R HSV infections.” (opens the source at this quote in a new tab)

“Because of its nephrotoxicity, cidofovir is routinely administered with probenecid and requires intravenous hydration.” (opens the source at this quote in a new tab)