Cidofovir

Introduction

Cidofovir (Gilead Sciences; California, USA) is a potent antiviral drug that has been approved for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) due to infection with human immunodeficiency virus (HIV).

Several small studies and case reports describe the successful use of cidofovir applied either topically or by intralesional injection in virally-induced skin diseases.

Cidofovir is not marketed in New Zealand.

Off-label indications of cidofovir in dermatology

Non-approved reported uses of cidofovir in dermatology include:

• Viral warts, including anogenital warts
• Kaposi sarcoma
• Herpes simplex
• Molluscum contagiosum

Human papillomavirus infections

Anogenital warts

Viral warts in anogenital skin are caused by human papillomavirus (HPV) Types 6 and 8, and at times, Types 16 and 18.

• There are several case reports and results from a phase I/II clinical trial that was undertaken in immunocompetent and immunocompromised patients, where cidofovir topical gel 0.3%, 1% or 3% applied daily for 5 to 14 days resulted in complete or partial resolution of anogenital warts.
• No systemic toxicities were reported but dose-related mild to moderate application site reactions were noted.
• Cidofovir appears to offer an effective therapeutic alternative option for lesions that are unresponsive to conventional treatment methods.
• Appropriate clinical trials are required to confirm the true efficacy and safety of topical cidofovir in the treatment of anogenital warts.

Laryngeal papillomatosis

Recurrent respiratory papillomatosis is a condition characterised by viral warts in the upper airway.

• In most cases, the disease affects the larynx, other commonly affected organs include the oral cavity, the trachea, and the bronchi. Less commonly, the disease can involve the lungs or the oesophagus.
• It can affect both adults and children, causing airway obstruction and voice change.
• Several agents have been proposed as adjuvants to surgical debulking, including antivirals, administered systemically or injected into the lesions.
• There are several case reports and small studies describing the successful use of intralesional cidofovir as an adjuvant treatment for recurrent laryngeal papillomatosis associated with human papillomavirus 6 and/or 11.
• Cidofovir was injected intralesionally at concentrations varying from 2.5 to 15 mg/ml at the time of debulking.
• Therapeutic response ranged from 56.25% to 82.3% and relapse-free time from 10.05 to 49 months.
• Further research is necessary to define the most adequate dose, frequency of administration and duration of therapy.

Common warts

Common warts (also known as verrucae) are also due to infection with subtypes of HPV. The plantar area (the sole of the foot) is one of the most frequent locations.

• Treatment of common warts can present a challenge, particularly in immunosuppressed patients, and those who fail or cannot tolerate salicylic acid preparations and cryotherapy. Several case reports and case series have described the successful use of topical cidofovir in the treatment of plantar warts.
• Most published cases have reported lesion improvement within 10–12 weeks of starting treatment with 3% cidofovir cream applied once or twice daily.
• As no controlled double-blind clinical trials exist, there is no consensus about the most suitable concentration to use (generally 1–3%), its application scheme (1–2 times daily, with or without occlusion), or the optimal duration of treatment.

Herpes virus infections

HIV- associated Kaposi sarcoma

Kaposi sarcoma is associated with infection with Kaposi sarcoma herpesvirus (KSHV) also called human herpesvirus type 8.

• It presents as red to purplish macules, papules and nodules anywhere on the skin or mucous membranes and can ulcerate and become painful.
• In vitro studies using cell lines infected with KSHV have shown that cidofovir is a potent inhibitor of KSHV replication.
• A case report from the USA has described a patient with AIDS and cytomegalovirus (CMV) retinitis who was treated with cidofovir resulting in an improvement in a localised KS lesion.
• Other published case reports have failed to confirm the therapeutic benefit of IV cidofovir in the treatment of Kaposi sarcoma.

Herpes simplex infections

Herpes simplex presents with localised blistering. Type 1 herpes simplex virus is mainly associated with facial infections (cold sores or fever blisters) while type 2 causes genital herpes.

• A Canadian A multicenter phase I/II dose-escalation study of single-dose cidofovir gel for the treatment of recurrent genital herpes has described the successful use of cidofovir topical gel in otherwise healthy patients with recurrent genital herpes infection.
• Ninety-six patients were randomised in a double-blind, placebo-controlled fashion. Treatment was a single application of cidofovir gel 1%, 3%, 5% or placebo applied within 12 hours of an outbreak.
• All patients treated with cidofovir showed a decrease both in median time for cultures to become negative and in the number of days to complete healing.
• The relationship of application site reactions following the use of different doses of the study drug suggested that the optimal dose of cidofovir gel for this indication may be 1%.
• In a separate study from the USA, the safety and efficacy of cidofovir gel for the treatment of aciclovir-unresponsive genital herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial in 30 patients. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days.
• 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (p = 0.031). The median time to complete or good response was 21 days, and the median time to negative viral culture was 2 days (P 0.025, P 0.0001, respectively).
• Larger trials with topical cidofovir are warranted to further assess antiviral and clinical efficacies.
• An application to approve the use of topical cidofovir for aciclovir-resistant herpesvirus infections was denied by the United States Food and Drug Administration (FDA), citing the need for phase three data.

Poxvirus infections

Molluscum contagiosum

Molluscum contagiosum is a common viral skin infection of infants and young children. Adolescents and adults are less often infected.

• Molluscum contagiosum presents as clusters of small round papules in the face, torso, arms and perianal area.
• Several case reports in immunocompetent children have described complete clearance of molluscum contagiosum within 2–4 weeks with 1% or 3% topical cidofovir applied once or twice daily.
• In a case report published in the year 2000, topical cidofovir was effective in the treatment of generalised molluscum contagiosum in 2 children with AIDS. The lesions were treated with topical application of 3% cidofovir once a day, 5 days a week, for 8 weeks. After 2 months of treatment, all the lesions that were treated showed complete clinical resolution. There was no evidence of recurrence at the 3-, 6-, and 18-month follow-up visits.
• Cidofovir has also been reported to induce clearing of molluscum contagiosum lesions in 3 adults with AIDS, 2 of whom were receiving the drug intravenously for cytomegalovirus retinitis, and 1 was receiving topical cidofovir.

Mechanism of action of cidofovir

Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis.

• Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite.
• Cidofovir diphosphate interferes with viral DNA synthesis and inhibits viral replication by competitive inhibition with viral DNA polymerase.
• The inhibitory activity of cidofovir diphosphate is highly selective because of its greater affinity for viral DNA polymerases than for human DNA polymerases.

Drug interactions with cidofovir

Concomitant use of other nephrotoxic drugs (e.g. aminoglycosides, amphotericin B, foscarnet, IV pentamidine, vancomycin, nonsteroidal anti-inflammatory agents) is contraindicated since it may result in an increased risk of nephrotoxicity

There is no evidence of pharmacokinetic interactions of cidofovir with probenecid.

Adverse effects with cidofovir

In humans, systemic adverse reactions after topical or intralesional administration of cidofovir have been reported in a single patient with laryngeal papillomatosis who experienced chest pain after treatment with intralesional cidofovir.

Other potentially serious adverse effects with parenteral cidofovir include:

• neutropenia (reduced neutrophil white cells)
• nephrotoxicity
• ocular effects
• metabolic acidosis

Use of cidofovir in special populations

Pregnancy and lactation

• No studies regarding the administration of cidofovir by any route to pregnant women are available.
• The use of cidofovir in pregnant women should be avoided unless the benefit clearly outweighs the risk to the fetus.
• Women of childbearing potential should use effective contraception during and for 1 month following cidofovir treatment.
• It is not known whether cidofovir is distributed into milk; discontinue nursing or the drug.

Paediatric use

• The safety and efficacy of cidofovir have not been established in children <18 years of age.
• Because of the risk of potential long-term carcinogenic and reproductive toxicity, cidofovir should be used with caution in children and only when potential benefits outweigh risks.

Geriatric use

The safety and efficacy of cidofovir have not been evaluated in adults >60 years of age.

Precautions when using cidofovir

Precautions include:

• Hypersensitivity to cidofovir
• History of severe hypersensitivity to probenecid or other sulfonamide derivatives
• Preexisting renal impairment
• Concomitant use of other nephrotoxic drugs (eg aminoglycosides, amphotericin B, foscarnet, IV pentamidine, vancomycin, nonsteroidal anti-inflammatory agents) which may result in an increased risk of nephrotoxicity.

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We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).