Cidofovir: An overview

INTRODUCTION — Cidofovir was the first nucleotide analog approved for clinical use. The drug has been employed almost exclusively to treat cytomegalovirus (CMV) infections in patients with the acquired immunodeficiency syndrome (AIDS) and transplant recipients. However, cidofovir is also used as a therapeutic option against other viral infections. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)

MECHANISM OF ACTION — Cidofovir is a monophosphate nucleotide analog. After undergoing cellular phosphorylation to its diphosphate form, it competitively inhibits the incorporation of deoxycytidine triphosphate (dCTP) into viral DNA by viral DNA polymerase. Incorporation of the drug disrupts further chain elongation [1]. Unlike nucleoside analogs such as acyclovir or ganciclovir, cidofovir is not phosphorylated (and hence activated) by a viral kinase.

SPECTRUM OF ACTIVITY — Cidofovir demonstrates in vitro activity against a number of DNA viruses, including the herpesviruses, adenovirus, polyomavirus, papillomavirus, and poxvirus [2]. Cidofovir also retains activity against thymidine kinase-negative herpes simplex virus (HSV) and UL97 phosphotransferase-negative CMV, which are mutant viruses resistant to acyclovir and ganciclovir. Clinical efficacy has been demonstrated rigorously only against CMV. Its clinical utility in infections caused by other viral pathogens remains to be determined [1,2].

MECHANISM OF RESISTANCE — Reduced susceptibility of CMV to cidofovir has been associated with mutations in the viral DNA polymerase gene [3,4]. Since its mechanism of action does not require phosphorylation, cidofovir is unaffected by mutations in CMV phosphotransferase which confer resistance to ganciclovir. However, prolonged therapy with ganciclovir in patients with CMV infections has been associated with the emergence of viral DNA polymerase mutations which confer cross-resistance to cidofovir [4-8].

BASIC PHARMACOKINETICS — Administration of a single dose of cidofovir (3 to 5 mg/kg intravenous [IV]) yields peak plasma concentrations of 7.3 to 11.5 mg/L. Over 80 percent of the drug is excreted unchanged in the urine within 24 hours, with a half-life of 2.4 to 3.2 hours [1]. However, cidofovir diphosphate, an active metabolite, is eliminated more slowly with first and second phase intracellular half-lives of 24 and 65 hours, respectively [1]. This property permits the drug to be dosed every two weeks.

The most important toxicity of the drug is renal, which can be reduced by coadministration with saline and probenecid; probenecid blocks active renal tubular secretion (see 'Toxicity' below). Dosing probenecid prior to, two hours after, and eight hours after cidofovir infusion may result in the doubling of serum concentrations [1]. The fact that probenecid protects against nephrotoxicity and yet decreases renal clearance of the drug may seem paradoxical. However, the drug appears to prevent damage to proximal renal tubular epithelial cells by preventing the uptake of cidofovir into these cells; at the same time, drug concentrations can decrease more slowly since these same renal cells are responsible for secreting the drug into the urine.

TOXICITY — As noted above, the most important toxicity of cidofovir is dose-dependent nephrotoxicity; the drug is contraindicated in persons with proteinuria (2+ or greater) or baseline serum creatinine greater than 1.5 mg/dL. Cidofovir has been associated with decreased renal function and the emergence of a Fanconi-type syndrome, with proteinuria, glucosuria, and bicarbonate wasting [9,10]. Alternative formulations, such as brincidofovir (CMX001), an oral prodrug of cidofovir, may have less nephrotoxicity, though studies of prophylaxis against CMV showed suboptimal results [11,12].

To monitor for nephrotoxicity, serum creatinine and urine protein (dipstick is acceptable) should be checked within 48 hours prior to each dose of cidofovir, and dose reduction or discontinuation is required for evidence of renal dysfunction. Approximately 50 percent of patients receiving cidofovir in clinical trials developed either proteinuria (2+ or greater), increased serum creatinine (rise of at least 0.4 mg/dL), or decreased creatinine clearance (55 mL/min or less) [9].

Renal dysfunction is usually reversible with discontinuation of the drug. However, a few cases of end-stage kidney disease associated with the use of cidofovir in HIV-positive individuals have been reported [13,14]. Topical or intralesional use of cidofovir may also be rarely associated with renal dysfunction and monitoring may be necessary [15,16]. The systemic absorption of cidofovir after topical application is probably higher if applied to nonintact skin.

Patients should receive 1 liter of normal saline over one to two hours immediately preceding the cidofovir dose and, if they can tolerate the fluid load, a second liter either during or immediately following the drug [9]. Patients must also receive probenecid (2 g orally three hours prior and 1 g two and eight hours following cidofovir) [9].

Nausea and vomiting are common side effects of probenecid and may be reduced by giving the drug with food or by administration of antiemetics. Rash is also common and management with an antihistamine and/or acetaminophen may be appropriate [9].

Neutropenia has been observed in approximately 20 percent of patients receiving cidofovir [9], though it is difficult to establish causality for this finding given its common appearance in advanced AIDS. In rats, cidofovir has been associated with mammary adenocarcinoma and thus it should be regarded as a potential human carcinogen [9].

Acute iritis and ocular hypotony, which have precluded intravitreal administration, have also been associated with IV cidofovir [17,18]. However, when evaluating a patient with ocular inflammation who is receiving both cidofovir for CMV retinitis and antiretroviral therapy for HIV, one must also consider the possibility of vitritis associated with an immune reconstitution inflammatory syndrome. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'CMV immune reconstitution inflammatory syndromes'.)

USE IN PREGNANCY — Cidofovir is embryotoxic in rats and rabbits, and there are no adequate studies in pregnant females. Females of childbearing potential should use contraception during and for one month following treatment with cidofovir, and males who have sex with females of childbearing potential should use barrier contraception during and for three months after treatment [9].

Cidofovir should be used in pregnant females only if the potential benefits outweigh the risk to the fetus.

CLINICAL USE OF CIDOFOVIR — IV cidofovir has only been rigorously studied in patients with AIDS for treatment of CMV retinitis. Although IV cidofovir is sometimes used in the treatment of other viral infections, data are limited to case reports or case series. There have also been case reports and small series describing the use of topical cidofovir for the treatment of infections such as acyclovir-resistant herpes simplex virus (HSV) [19], human papillomavirus-related warts [20], and molluscum contagiosum [20,21]. However, no US Food and Drug Administration-approved topical formulation of cidofovir is available.

Guidance on the use of cidofovir for treatment of specific infections is presented separately. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Relapsed infection' and "AIDS-related cytomegalovirus neurologic disease", section on 'Cidofovir' and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Cidofovir' and "Treatment of drug-resistant genital herpes simplex virus infection in patients with HIV", section on 'Topical therapies' and "Common causes of hoarseness in children", section on 'Papillomatosis' and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Antiviral agents' and "Kidney transplantation in adults: BK polyomavirus-associated nephropathy", section on 'Adjunctive therapies' and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Antiviral selection' and "Treatment and prevention of mpox (monkeypox)", section on 'Specific agents'.)

SUMMARY AND RECOMMENDATIONS

●Mechanism of action – Cidofovir is a monophosphate nucleotide analog of deoxycytidine triphosphate (dCTP). After undergoing cellular phosphorylation, cidofovir competitively inhibits the incorporation of dCTP into viral DNA by viral DNA polymerase. Incorporation of the drug disrupts further chain elongation. (See 'Mechanism of action' above.)

●Spectrum of activity – Cidofovir demonstrates in vitro activity against a number of DNA viruses, including adenovirus, polyomavirus, papillomavirus, poxvirus, and the herpesviruses (including acyclovir-resistant strains of herpes simplex virus [HSV]). Clinical efficacy has been demonstrated rigorously only against cytomegalovirus (CMV) infection. (See 'Spectrum of activity' above.)

●Mechanism of resistance – Reduced susceptibility of CMV to cidofovir has been associated with mutations in the viral DNA polymerase gene. (See 'Mechanism of resistance' above.)

●Basic pharmacokinetics – Over 80 percent of cidofovir is excreted unchanged in the urine within 24 hours, with a half-life of 2.4 to 3.2 hours. However, its active metabolite is eliminated more slowly, which permits drug dosing every two weeks. (See 'Basic pharmacokinetics' above.)

●Toxicity

•The most important toxicity of cidofovir is dose-dependent nephrotoxicity; cidofovir has been associated with decreased renal function and the emergence of a Fanconi-type syndrome, with proteinuria, glucosuria, and bicarbonate wasting. Cidofovir is contraindicated in persons with significant proteinuria or with a baseline serum creatinine greater than 1.5 mg/dL. (See 'Toxicity' above.)

•Patients should receive 1 liter of normal saline over one to two hours immediately preceding cidofovir dosing. If they can tolerate the fluid load, a second liter should be given either during or immediately following cidofovir administration. Patients must also receive probenecid (2 g orally three hours prior and 1 g two and eight hours following cidofovir), which may prevent damage to proximal renal tubular epithelial cells by preventing the uptake of cidofovir into these cells. (See 'Toxicity' above.)

●Use in pregnancy – Cidofovir should be used in pregnant females only if the potential benefits outweigh the risk to the fetus. (See 'Use in pregnancy' above.)