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Intralesional injection of the antiviral agent cidofovir (Vistide™, Gilead Sciences, Foster City, CA, US) has recently been advocated for the adjuvant treatment of severe cases of recurrent respiratory papillomatosis (RRP) in children [1, 2]. Cidofovir is a cytosine nucleotide analog with activity against DNA viruses. Reports indicated both short- and long-term benefit when intralesional cidofovir injections are combined with surgical excision. This report presents the results in four patients treated in this manner.

Four children, two boys and two girls, with RRP requiring more than six surgical excisions per year for over 2 years were offered treatment with intralesional cidofovir. Average age at initial diagnosis of RRP was 15 months. Average age when cidofovir was first used was 51 months, though three of the patients were less than or equal to 3.5 years old (42 months). Patient information is provided in Table 1.

Cidofovir (5 mg/ml) was injected into sites in the airway where papillomas had just been excised. Each patient had six treatments performed 6–8 weeks apart. Biopsies confirmed benign papilloma lesions in all cases. Excision of papillomas was performed using sharp technique. At each surgical session, the status of the airway was recorded and the extent of papillomatosis was staged using the ASPO Otobase staging system for RRP [3]. Three patients (1–3) responded by the third injection series to cidofovir with overall lower severity scores. Only the patient who ultimately had complete response, patient 3, continued to experience diminishing scores. Patients 1 and 2, who responded initially to cidofovir, both had "rebound" by the fifth injection series. Patient 4 did not see any benefit from cidofovir injection based on severity scores. He continues to have scattered papillomas in the supraglottis, posterior glottis, subglottis, and trachea. Cidofovir did not appear to help with the tracheal papillomas, though the papilloma at the carina did resolve once cidofovir therapy was complete.

This series contained one patient who had a complete response to intralesional cidofovir. The other three patients continue to suffer from papilloma growth in their larynges. None of the patients in this series demonstrated any adverse effects of cidofovir. Subsequent biopsies at sites previously injected with cidofovir indicate no malignant transformation. Other case series using intralesional cidofovir as adjuvant treatment for RRP have been more promising. Pransky et al. [1] report on 10 children treated with cidofovir (5 mg/ml) injections. One group of five patients received between 8 and 18 injections then followed for up to 22 months. No more than three additional procedures were needed for these five patients, and four of the five are disease free. An additional five patients were treated using a different protocol: four injections every 2 weeks. Of these five patients, only one is disease free, three have had an important decrease in frequency of treatment and severity, and one continued to have severe disease. Recently, Bielamowicz et al. [2] described 13 adults treated with intralesional cidofovir injections. Repeated injections were given monthly until no further papillomas were seen on endoscopy. An average of six injections were required to achieve remission. The clinical severity in these 13 adults was less than that seen in children reported in other studies.

The potential tumorgenicity of cidofovir and HPV in humans remains a concern. Intralesional cidofovir has caused malignant transformation in rats. Intravenous cidofovir did not induce tumors in cynomolgus monkeys (Gilead Sciences Investigator's Brochure). Whether intralesional cidofovir is carcinogenic in humans is unknown. Although no study has demonstrated neoplasia at a site of cidofovir injection in children, injecting a potential carcinogen into an area where the potential for malignant transformation is higher than otherwise should be considered carefully. Moreover, there is no consensus regarding how to use intralesional cidofovir or how frequently it should be administered.

Intralesional cidofovir may provide benefit in reducing the rate of RRP growth while under treatment, but RRP severity returned to pre-treatment levels once cidofovir treatment was stopped. Because adenocarcinomas have been reported with repeated subcutaneous injections of cidofovir in rats, intralesional cidofovir for treatment of RRP in children should be viewed with caution. Additional multi-centered studies should be organized to determine safety, efficacy, and proper regimen before intralesional injection of cidofovir can be recommended.