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Cidofovir

A Review of its Use in Cytomegalovirus Retinitis in Patients with AIDS

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Summary

Abstract

Cidofovir is an antiviral nucleotide analogue with significant activity against cytomegalovirus (CMV) and other herpesviruses. The drug is indicated for the treatment of CMV retinitis, a sight-threatening condition, in patients with AIDS. Cidofovir has a long intracellular half-life which allows for a prolonged interval (2 weeks) between maintenance doses. In contrast, other intravenous treatment options for patients with CMV retinitis (i.e. ganciclovir and foscarnet) must be administered on a daily basis.

The efficacy of intravenous cidofovir has been demonstrated in patients with AIDS and previously untreated CMV retinitis in multicentre randomised trials, and in a dose-finding study of cidofovir in patients with AIDS and previously treated relapsing CMV retinitis. Clinical trials have been relatively small (n ≤ 100 patients) and no studies have been conducted directly comparing intravenous cidofovir with the more established intravenous agents, ganciclovir or foscarnet. Indirect comparisons of clinical trial data suggest that intravenous cidofovir may have similar efficacy to intravenous ganciclovir or foscarnet in delaying progression of CMV retinitis. However, such comparisons must be made with caution because of potential differences in patient populations, data analysis techniques and interobserver variability in the masked assessment of retinal photographs.

Nevertheless, intravenous cidofovir offers a less intrusive administration regimen than intravenous ganciclovir or foscarnet because of its prolonged dosage interval. Since therapy is life-long, patients receiving daily intravenous ganciclovir or foscarnet (but not cidofovir) usually require an indwelling central venous catheter and are therefore at increased risk of serious infection. The relatively long dosage interval for cidofovir may also have favourable implications in terms of overall treatment costs and patient quality of life, although specificdata are very limited.

Potentially irreversible nephrotoxicity is the major treatment-limiting adverse event associated with intravenous cidofovir in patients with AIDS-related CMV retinitis. Anterior uveitis/iritis has been reported frequently with intravenous cidofovir in postmarketing reports and a small number of patients have developed hypotony. Other treatment options for CMV retinitis are also associated with serious adverse events, and selection of pharmacotherapy will depend on a number of factors including retinitis lesion characteristics, patient quality-of-life issues and efficacy and tolerability profiles of available therapies.

Conclusion: Although the extent of its use may be limited by its adverse event profile, cidofovir offers a useful addition to the limited number of drugs available for the treatment of CMV retinitis in patients with AIDS.

Pharmacodynamic Properties

Cidofovir undergoes activation to its diphosphate metabolite by intracellular kinases which are present in both cytomegalovirus (CMV)-infected and uninfected cells. Cidofovir diphosphate selectively inhibits CMV DNA polymerase and reduces the rate of viral DNA synthesis. Ganciclovir also requires activation by phosphorylation but, unlike cidofovir, requires initial virus-encoded activation by a CMV kinase (an enzyme product of the CMV UL97 gene) which can occur only in CMV-infected cells. In general, in vitro studies have demonstrated that the susceptibility of CMV clinical isolates to cidofovir and the safety margin of cidofovir (selectivity index) are at least comparable to those for ganciclovir. Cidofovir is active against some, but not all, foscarnet-resistant clinical isolates of CMV.

Most ganciclovir-resistant isolates of CMV appear to be UL97 gene product mutants and therefore remain susceptible to cidofovir unless mutations in the DNA polymerase gene are also present. Cross resistance between cidofovir and ganciclovir has been documented in clinical isolates of CMV or strains of CMV selected for resistance in vitro.

There is no ideal animal model of human CMV retinitis because of the species specificity of the virus; however, studies with cidofovir have been conducted in rabbits with experimentally induced herpes simplex virus (HSV)-1 infection of the retina. In this model, pretreatment of eyes with intravitreal injection of cidofovir up to 1 month (or liposome-encapsulated cidofovir up to 8 months) before HSV-1 inoculation prevented or delayed development of retinitis.

Pharmacokinetic Properties

Cidofovir has poor oral bioavailability (<5%) and is therefore administered intravenously. After single dose intravenous administration of cidofovir 3 or 5 mg/kg to individuals with HIV infection (with or without CMV retinitis), peak serum drug concentrations (Cmax) and area under the serum concentration-time curve values (AUC) increased proportionally with dose. Cmax and AUC values were higher when the same cidofovir dose was administered with concomitant oral probenecid (as per cidofovir dosage and administration recommendations) than when administered without probenecid. Binding of cidofovir to plasma proteins is negligible (<7%). Elimination half-life (t½β), renal clearance (CLr) and volume of distribution at steady-state (Vss) were independent of cidofovir dose. Both CLr and Vss were lower when oral probenecid was administered concomitantly, presumably as a result of decreased active tubular secretion of cidofovir. Approximately 90% of an administered dose of cidofovir is eliminated in the urine unchanged. The t½β of cidofovir in serum is approximately 2.5 hours; however, the intracellular half-life of the active metabolite cidofovir diphosphate is ≈65 hours, which may explain the prolonged antiviral effect of the drug.

Therapeutic Use

A significantly longer median time to progression of CMV retinitis (primary end-point of studies) was demonstrated with cidofovir (standard regimen) than with deferred treatment (≥120 vs ≈20 days) in patients with AIDS and previously untreated CMV retinitis in 2 small multicentre randomised trials. Patients in the cidofovir group started treatment immediately after randomisation, whereas patients in the deferred treatment groups received treatment only after progression of CMV retinitis occurred.

The standard regimen of cidofovir achieved a significantly longer median time to progression of CMV retinitis than a lower dosage (>280 vs 49 days) in a dose-finding study of patients with AIDS and CMV retinitis who had previously received anti-CMV treatment with ganciclovir, foscarnet or both drugs. In 1 of the 2 studies comparing immediate cidofovir treatment versus deferred treatment, the monthly rate of increase in retinal area affected was significantly greater with deferred treatment (1.8 or 2.2%) than with immediate treatment with the lower (0.8%) or standard (0.3%) dosage of cidofovir. None of the 3 studies demonstrated a significant difference in visual acuity or survival between the various treatment groups, although the studies were not designed with these as primary end-points.

For the 3 trials described, the standard cidofovir dosage regimen was as follows: induction dosage 5 mg/kg every week for 2 weeks; maintenance dosage 5 mg/kg every 2 weeks. The lower dosage of cidofovir included the same induction regimen followed by a maintenance dosage of 3 mg/kg every 2 weeks. Cidofovir was administered intravenously with concomitant oral probenecid and intravenous hydration to reduce the risk of nephrotoxicity.

Intraocular administration of cidofovir has been evaluated in small numbers of patients. However, it is contraindicated by the manufacturer because of a poor risk-benefit profile (see Tolerability summary section below).

Tolerability

Adverse events associated with intravenous cidofovir lead to discontinuation of therapy in approximately 20 to 25% of patients, most frequently because of nephrotoxicity. Cidofovir-induced renal impairment is dose-related and is at least partially reversible after discontinuation or interruption of therapy in most patients. Pooled tolerability data are now available from >800 patients with HIV infection, most of whom also had a diagnosis of CMV retinitis. These patients received the recommended regimen of cidofovir along with saline hydration and concomitant high dose oral probenecid to reduce the risk of dose-limiting nephrotoxicity. The most frequently reported adverse events were nephrotoxicity (22.4% of patients), uveitis/iritis (10.1%), haematological abnormalities (9.7%), nausea and/or vomiting (9.1%), fever (6.2%) and skin rash or pruritus (4.2%). It is noteworthy that postmarketing data suggest a somewhat higher incidence of anterior uveitis/iritis (occasionally with hypotony) associated with intravenous cidofovir than that reported in the pooled analysis above. In addition, concomitant administration of probenecid is frequently associated with various adverse events (e.g. nausea, emesis, fever and rash), leading to discontinuation of study treatment in about 4% of patients. Cidofovir is thought to be concentrated in renal proximal tubule cells via active transport, and probenecid is thought to reduce the concentration of cidofovir within the renal compartment.

The efficacy and tolerability profile of intraocular cidofovir was generally favourable in single centre case series of small numbers of patients with AIDS and CMV retinitis. In contrast, results of a multicentre trial showed poor efficacy. Moreover, uveitis/iritis was reported in the majority of patients and a significant proportion of patients developed clinically significant hypotony. As a result, the manufacturer abandoned further study of intraocular cidofovir and this route of administration is listed as a contraindication in the manufacturer’s product labelling for the drug.

Dosage and Administration

The recommended regimen of intravenous cidofovir in patients with CMV retinitis and AIDS who have adequate renal function is an induction dosage of 5 mg/kg weekly for 2 weeks followed by a maintenance dosage of 5 mg/kg every 2 weeks. Cidofovir is administered as a 1-hour infusion with saline hydration and concomitant oral probenecid to reduce the risk of dose-limiting nephrotoxicity. The drug is not recommended for use in patients with significantly compromised renal function. Other potentially nephrotoxic drugs (e.g. amphotericin, amino-glycosides, foscarnet, intravenous pentamidine, NSAIDs, vancomycin) should not be administered within 7 days of cidofovir treatment. Dosage adjustments or discontinuation of the drug are necessary in patients who have deterioration in renal function during cidofovir treatment. Monitoring of serum creatinine levels and urine protein is mandatory prior to each cidofovir dose; monitoring of white blood cell counts with differential, as well as intraocular pressure is also recommended during therapy with intravenous cidofovir.

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Authors and Affiliations

  1. Adis International Limited, Private Bag 65901, 41 Centorian Drive, Mairangi Bay, Auckland, 10, New Zealand

    Greg L. Plosker & Stuart Noble

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  1. Greg L. Plosker
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  2. Stuart Noble
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Correspondence to Greg L. Plosker.

Additional information

Various sections of the manuscript reviewed by: B.G. Gazzard, Chelsea & Westminster Healthcare National Health Service Trust, Chelsea & Westminster Hospital, London, England; M.A. Jacobson, UCSF AIDS Program, San Francisco General Hospital, San Francisco, California, USA; Y. Khaliq, Clinical Investigation Unit, The Ottawa Hospital, Ottawa, Ontario, Canada; J.P. Lalezari, University of California, Mt Zion Medical Center, San Francisco, California, USA; M.A. Polis, Intramural AIDS Program, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA; J. Rockstroh, Department of Medicine, University of Bonn, Bonn, Germany; G.J. van den Horn, Department of Ophthalmology, University of Amsterdam, Amsterdam, The Netherlands; R.J. Whitley, The University of Alabama at Birmingham, Department of Pediatrics, Division of Clinical Virology, Children’s Hospital, Birmingham, Alabama, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on cidofovir, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Cidofovir’ or ‘GS-0502’ or ‘GS-504’ or ‘HPMPC’. Medline search terms were ‘Cidofovir’ or ‘GS-0502’ or ‘GS-504’ or ‘HPMPC’. EMBASE search terms were ‘Cidofovir’ or ‘GS-0502’ or ‘GS-504’ ‘HPMPC’. Searches were last updated 5 July 1999.

Selection: Studies in patients with cytomegalovirus retinitis who received cidofovir. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Cidofovir, cytomegalovirus retinitis, antiviral, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, dosage and administration.

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Plosker, G.L., Noble, S. Cidofovir. Drugs 58, 325–345 (1999). https://doi.org/10.2165/00003495-199958020-00015

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