Cidofovir: to use or not to use?
Marlene A. Soma and David M. Albert

Great Ormond St Hospital for Children, London, UK Correspondence to David M. Albert, Clinical Lead,
Department of Otolaryngology Head and Neck Surgery, Great Ormond St Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK Tel: +44 207 405 9200;
e-mail: [email protected]

Current Opinion in Otolaryngology & Head and Neck Surgery 2008, 16:86–90
Purpose of review
Cidofovir is an antiviral agent that has been used increasingly in the last decade as an adjuvant therapy for recurrent respiratory papillomatosis. It has been used in patients with moderate to severe recurrent respiratory papillomatosis requiring frequent surgical intervention or if there is evidence of distal spread. Intralesional administration after surgical debulking delivers the medication directly to the site of disease and is thought to have fewer systemic side effects than intravenous infusion. This review examines recent publications for evidence of safety and efficacy.
Recent findings
Despite its growing popularity, the potential risks related to cidofovir use in recurrent respiratory papillomatosis have not been well documented. It is known to be nephrotoxic when administered intravenously and there remains concern that cidofovir has carcinogenic potential based on animal studies (mammary adenocarcinoma in rats). A review of the literature reveals no randomized controlled trials, one case–control study, multiple case series and case reports only. Study populations are small, however complete response rates have consistently been reported in approximately 60%. Summary
Based on current opinion and research, it is likely that intralesional cidofovir will continue to have a role in the management of moderate to severe recurrent respiratory papillomatosis. Further studies are required to assess long-term outcomes.

Keywords
cidofovir, human papilloma virus, laryngeal papillomatosis, recurrent respiratory papillomatosis, Vistide

Curr Opin Otolaryngol Head Neck Surg 16:86–90
ti 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1068-9508

Introduction
Recurrent respiratory papillomatosis (RRP) is a chal- lenging and potentially life-threatening benign neo- plastic condition caused by human papillomavirus (HPV). A cure has yet to be found and surgery remains the mainstay of treatment. The use of intralesional cido- fovir to treat severe laryngeal papillomatosis was first described by Snoeck et al. in 1998 [1]. Since that initial study, it has been adopted as an adjuvant therapy in many centres around the world. In this paper, we exam- ine how cidofovir works, risks associated with treatment, indications for its use, surgical techniques and cidofovir administration, current experience in the literature and recommendations for the future.

Historical context
The successful use of cidofovir (Vistide; Gilead Sciences, Foster City, California, USA) to interfere with the growth of tumours induced by papillomavirus was initially demonstrated in the rabbit population [2]. Reports of intralesional cidofovir administration to treat papilloma-

tous disease in humans emerged thereafter from Belgium in the late 1990s [1,3]. A spectacular response was seen with complete disappearance of a refractory papilloma in the oesophagus [3], and in 14 out of 17 patients with laryngeal papillomatosis [1]. Pransky et al. [4] published the first case series of intralesional cidofovir use in paediatric patients with severe RRP, observing a dramatic response though not complete eradication in four out of five patients.

A Cochrane review of antivirals (including cidofovir) as adjuvant therapy for the treatment of RRP was unable to identify any randomized controlled trials and concluded that that there was insufficient evidence about the efficacy of their use [5]. Few papers have addressed the risk profile of cidofovir, especially potential implica- tions for the paediatric population.

Despite this, cidofovir is currently the most commonly used adjuvant therapy in the treatment of paediatric RRP according to surveyed respondents of the American Society of Pediatric Otolaryngology (ASPO) [6] and

1068-9508 ti 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins

the British Association of Paediatric Otolaryngology (BAPO) [7]. Approximately 10% of patients treated for RRP are now receiving intralesional cidofovir as an adjunct to surgical therapy [6,7].

Mechanism of action
Cidofovir is a cytosine nucleoside analogue that is incor- porated into the growing DNA chain of both viruses and mammals. It inhibits the viral DNA polymerization process [8] and has potent antiviral activity against a broad spectrum of herpes viruses (cytomegalovirus, herpes simplex types 1 and 2, varicella zoster, Epstein– Barr virus, human herpesvirus types 6 and 8, adenovirus and human papillomavirus) [9,10]. The antiviral effect lasts for several days to weeks due to the long intracellular half life of the active metabolite cidofovir dihydrate. This allows for infrequent dosing every 1–2 weeks.

Ofthe100-plusidentifiedtypesof HPV, themost common subtypes found in RRP are HPV-6 and HPV-11 [11]. Patients with HPV-11 tend to have more aggressive clinical disease with higher likelihood of developing pulmonary or tracheal disease and requiring tracheostomy [12]. It is not known whether cidofovir is more effective against a particular subtype of HPV infection.

Risks
At present, the US Food and Drug Administration has only approved cidofovir’s use for the treatment of cytomegalo- virus retinitis in patients with AIDS. It is moderately effective for this indication compared with other antivirals, with the advantage of a 2-weekly dosing schedule instead ofdaily.Itspharmacokineticshasbeenextensively studied in this population following intravenous administration. Cidofovir is cleared by the kidney and excreted relatively unchanged in the urine. Nephrotoxicity, characterized by tubular dysfunction with proteinuria, glucosuria, bicarbonaturia, polyuria, and increased serum creatinine is a potential complication, reduced by concomitant vigorous hydration and oral probenicid [13]. Renal func- tion should be monitored during intravenous therapy and parameters tend to return to baseline after its discon- tinuation [8].

The use of cidofovir for any alternative indication is considered an ‘off label’ use of the medication. In spite of this, cidofovir has been used successfully to treat other viral infections including HPV (e.g. recalcitrant condyloma in HIV-infected patients and grade III cervical intraepithelial neoplasia) both as a topical gel and direct intralesional injection [14]. Centres using cidofovir as an adjuvant treatment for RRP have mostly adopted intralesional administration [15titi ]. This is well tolerated and has a relatively low toxicity profile, however

variable diffusion rates from the site may result in plasma concentrations approaching the nephrotoxic range [16]. Three case reports of intravenous administration of cidofovir for RRP reinforce the need for renal precautions [15titi ], with one report also describing neutropenia that required cessation of concurrent interferon a-2a treat- ment and reduction of the cidofovir dose [17].

Cidofovir has also been shown to be carcinogenic in rodent studies [18]. A 26-week toxicology study evaluating once weekly subcutaneous injections of cidofovir was termi- nated at 19weeks due to the development of mammary adenocarcinoma in female rats. This finding was also seen with intravenous administration, as well as a significant incidence of Zymbal’s gland carcinomas in both male and female rats at dosage regimens equivalent to 1.1 times the recommended human systemic exposure [19]. Even though mammary adenocarcinoma development is a frequent occurrence in rat pharmacologic studies, some of these tumours arose early and at much lower doses of cidofovir than recommended human levels [19]. Reassur- ingly, no tumours were detected in primate studies after intravenous cidofovir administration, however the dosing was at 0.7 times the human systemic exposure, the duration of treatment was short and the study population was small [19].

Death related to RRP is usually due to progressive pulmonary failure (pneumonia or cavitating pulmonary disease), or rarely, malignant transformation to squamous cell carcinoma. The incidence of squamous cell carci- noma in RRP is thought to be between 2 and 3%, with particular predisposition in those individuals exposed to radiation, bleomycin therapy or tobacco, those with onco- genic subtypes of HPV (particularly HPV-16 or HPV-18) or those with an increasing degree of cellular atypia in resected specimens. The progression of dysplasia to malignant degeneration has been less well defined in the larynx compared with the cervix.

The risk of cidofovir-induced malignancy and prema- lignancy is unknown in humans. Long-term follow up to date is at most 10years and there is a lack of well controlled studies examining its safety [15titi ]. There have been no reports of malignant transformation of RRP following cidofovir use, nor the development of any other distant malignancy. A case of progressive dysplasia concomitant with intralesional administration for laryngeal disease, however, has been described [20].

Given the uncertain risks of cidofovir and its use in a paediatric population, one needs to counsel parents about its ‘off label’ use and the potential complications associated with the drug before obtaining consent and embarking upon therapy.

Indications
There are no definitive guidelines to recommend when to commence cidofovir use. Adjuvant therapy is often initiated in patients requiring more than four surgical procedures per year, distal multisite spread of disease or rapid regrowth of papillomas, especially with airway com- promise [21]. Scoring systems have been developed to assess severity of disease and response to treatment [22]. Deterioration of Derkay score balanced with overall pattern of progression may guide when to institute adjuvant treatment.

The authors recommend the use of cidofovir be reserved for moderate to severe cases of RRP; that is, aggressive, recalcitrant disease requiring increasingly frequent surgical intervention. The unknown long-term safety profile of cidofovir at this point in time precludes its recommendation for mild cases or as a first-line treatment in newly diagnosed cases.

Surgical treatment of recurrent respiratory papillomatosis
Goals of surgical ablation should be to reduce tumour burden, decrease disease spread, create a safe and patent airway, improve voice quality, preserve anatomy and increase time between surgical intervals [21]. HPV is known to exist in normal appearing tissue adjacent to papillomas, hence complete eradication is usually not possible [23]. Adjuvant use of cidofovir at the site of excised papilloma aims to inhibit recurrence and address subclinical disease. It is also used as a tumoricidal agent in areasdifficulttoaddresssurgically,forexampletheanterior commissure.

The authors’ preference is to use the microdebrider for surgical removal of RRP. The technique is relatively fast, safe, well tolerated and avoids potential problems associ- ated with the carbon dioxide laser [24,25]. It has also been shown to cause equivalent immediate postoperative pain, greater improvement in voice quality and the overall procedure cost is lower in some centres [26]. Intralesional cidofovir is used after surgical debulking with the microdebrider in those patients with moderate to severe disease. Interestingly, microdebrider use has superseded the carbon dioxide laser since the mid-1990s amongst surveyed American Society of Pediatric Otolaryngology (ASPO) members [6], whereas the laser remains the most popular technique for surveyed British Association of Paediatric Otolaryngology (BAPO) members [7]. It is not known whether cidofovir is more effective with cold steel or laser techniques.

Administration and technique
Due to the systemic side effects and renal monitoring required with intravenous administration, intralesional

application is the preferred method of adjuvant admin- istration of cidofovir for RRP, especially in children. There has been no consensus reached regarding the optimal concentration or overall dosage of cidofovir. It has been suggested that the intralesional dose should be less than that reported to lead to toxicity in intravenous infusion (3 mg/kg) [16].

Preparation of the surgical field prior to cidofovir admin- istration is important to help define the limits of the disease and identify sites for excision and injection. Adrenaline (1 : 10 000) soaked pledgets placed in the larynx for a few minutes blanches the mucosa and assists with haemostasis. After ablation of the papillomas, a Storz needle is used to inject cidofovir at the base of the removed lesion. An alternative disposable needle is a 22 gauge ti 7.00 in. spinal needle (BD Medical, New Jersey, USA). Concern about airway compromise, particu- larly when injecting at the level of the vocal cords, can be bypassed by temporary intubation with an endotracheal tube for a few minutes. This technique is favoured by the senior author to ensure adequate exposure to cidofovir and spread of the depot.

The incidence of papillomatous disease in the distal airways (trachea, bronchi and pulmonary parenchyma) is thought to be between 13 and 30% in children and 16% of adults with RRP [6,7,27]. Lung extension is associated with a poor prognosis as no treatment is available to cure this complication. It usually progresses to respiratory failure and death. The use of cidofovir in this situation is even less studied. Intravenous administration has been used [17,28] and there have been reports of delivery to the distal trachea using flexible variceal injectors [29]. The effects of direct instillation and inhalational admin- istration of cidofovir have not been formally examined.

Current experience
As with most viruses, the manifestations of HPV infection vary for each individual and its course is unpredictable. RRP is particularly aggressive in the younger age group, however it may plateau and enter remission, or may even recur after years of remission in others. The response to cidofovir also appears variable and its benefits difficult to predict.

Chadha and James [15titi ] have recently systematically reviewed antiviral use for RRP in the English literature. Most studies using cidofovir were case reports or case series, with the largest sample size being a modest 19 patients spanning both the adult and paediatric populations. There was only one case controlled series identified, however the small sample numbers (seven patients) reduce its validity [30]. Seventeen studies of intralesional cidofovir administration showed wide

variability of mean initial Derkay score (5–23), mean total cidofovir dosage (5.6–143 mg), mean total injection number (3–28), mean total therapy period (2– 25 months), and mean follow-up period (7–51 months). The median treatment protocol was 2.5–5 mg/ml mostly every 2–4 weeks, though some centres described use every 2 months.

Despite the obvious difficulties comparing these studies, the results were combined to estimate the overall efficacy of intralesional cidofovir in 158 patients: 57% demon- strated complete resolution, 35% had a partial response and 8% showed no improvement [15titi ].

Seventy-four members of ASPO serving approximately 700 paediatric patients with RRP were surveyed regard- ing response to cidofovir. The median age at first intra- lesional injection was 5.5 years, with a median of five injections. Sixty-one percent of children were reported as being much improved or free of disease, 35% as not improved and 4% were worse after treatment with cidofovir [6]. This higher percentage of nonresponders may be a reflection of the well documented aggressive disease pattern seen in the paediatric age group.

At this point in time, there is no evidence to guide which patients will be more likely to respond to adjuvant treatment with cidofovir.

Recommendations
Recommendations from the RRP Task Force meeting in Las Vegas, Nevada in May 2005 [19] regarding the use of cidofovir include the following:

(1)Cidofovir should be routinely presented as a treat- ment option in moderately to severely afflicted RRP patients; that is, those patients who require frequent surgery, have worsening airway compromise or severely impaired communication or who may other- wise be considered for tracheostomy.
(2)Use of cidofovir should be discouraged in patients with more mild disease until long-term results from its use have been established.
(3)Informed consent should be obtained prior to use of cidofovir, documenting risks of nephrotoxicity, potential carcinogenicity and other unknown long- term implications.
(4)Adverse responses to the use of cidofovir, especially evidence of dysplasia or malignant transformation to squamous cell carcinoma should be reported.

Based on a current review of the literature, the authors

Conclusion
RRP remains a challenging and frustrating disease for both patients and their otolaryngologists. Intralesional cidofovir is the most promising adjuvant therapy currently available for this condition, with complete response rates seen in approximately 60% of patients. Its use, however, is still in its infancy and the long-term safety profile has yet to be determined. Until a multicentre randomized controlled trial has been established to assess its impact and potential complications, its use should be reserved for moderate to severe disease. Patients and parents should be counselled about these concerns.

References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
ti of special interest
titi of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 101).
1Snoeck R, Wellens W, Desloovere C, et al. Treatment of severe laryngeal papillomatosis with intralesional cidofovir [(S)-1-(3-hydroxy-2-phosphonyl- methoxypropyl) cytosine]. J Med Virol 1998; 54:219–225.
2Kurtzman G, Pickel M, Christensen N, Kreider J. Phosphonate nucleoside analogs are potent antipapillomavirus agents in animal models [abstract]. In: Program and Abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 17–20 October 1993; New Orleans, USA. Abstract No. 1593.
3VanCutsem E, Snoeck R, Van Ranst, et al. Successful treatment of a squamous papilloma of the hypopharynx-esophagus by local injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. J Med Virol 1995; 45:230–235.
4Pransky SM, Magit AE, Kearns DB, et al. Intralesional cidofovir for recurrent respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg 1999; 125:1143–1148.
5Chadha NK, James AL. Adjuvant antiviral therapy for recurrent respiratory papillomatosis. Cochrane Database Syst Rev 2005; (4):CD005053.
6Schraff S, Derkay CS, Burke B, Lawson L. American Society of Pediatric Otolaryngology members’ experience with recurrent respiratory papillomato- sis and the use of adjuvant therapy. Arch Otolaryngol Head Neck Surg 2004; 130:1039–1042.
7Tasca RA, McCormick M, Clarke R. British Association of Paediatric Otolar- yngology members experience with recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol 2006; 20:1183–1187.
8Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet 1999; 36:127–143.
9De Clercq E. Therapeutic potential of cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections. Verh K Acad Geneesk Belg 1996; 58:19–47.
10De Clercq E, Holy A, Rosenberg I, et al. A novel selective broad-spectrum anti- DNA virus agent. Nature 1986; 323:464–467.
11MajorT,SzarkaK,SziklaiI, etal. Thecharacteristic ofhuman papillomavirusDNA in head and neck cancers and papillomas. J Clin Pathol 2005; 58:51–55.
12Wiatrak BJ, Wiatrak DW, Broker TR, et al. Recurrent respiratory papilloma- tosis: a longitudinal study comparing severity associated with human papilloma viral types 6 and 11 and other risk factors in a pediatric population. Laryngoscope 2004; 114:1–23.
13Wachsman M, Petty BG, Cundy KC, et al. Pharmacokinetics safety and bioavailability of cidofovir in HIV-infected subjects. Antiviral Res 1996; 29:153–161.
14De Clercq E. Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections. Clin Microbiol Rev 2003; 16:569–596.

agree with the above recommendations and advocate the institution of a multicentre randomized controlled trial to
15
titi
Chadha NK, James AL. Antiviral agents for the treatment of recurrent respira- tory papillomatosis: a systematic review of the English-language literature. Otolaryngol Head Neck Surg 2007; 136:863–869.

assess the efficacy and long-term impact of cidofovir. Excellent summary of current publications regarding cidofovir use.

16Naiman AN, Roger G, Gagnieu MC, et al. Cidofovir plasma assays after local injection in respiratory papillomatosis. Laryngoscope 2004; 114:1151–1156.
17Dancey DR, Chamberlain DW,Krajden M, et al. Successful treatment of juvenile laryngeal papillomatosis-related multicystic lung disease with cidofovir: case report and review of the literature. Chest 2000; 118: 1210–1214.
18Gilead Sciences, Inc., Physician’s desk reference. Montvale, New Jersey: Thomson; 2003; pp. 1428–1432.
19Derkay C. Multi-Disciplinary Task Force on Recurrent Respiratory Papillomas. Cidofovir for recurrent respiratory papillomatosis (RRP): a reassessment of risks. Int J Pediatr Otorhinolaryngol 2005; 69:1465–1467.
20Wemer RD, Lee JH, Hoffman HT, et al. Case of progressive dysplasia concomitant with intralesional cidofovir administration for recurrent respira- tory papillomatosis. Ann Otol Rhinol Laryngol 2005; 114:836–839.
21Derkay CS, Darrow DH. Recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 2006; 115:1–11.
22Derkay CS, Malis DJ, Zalzal G, et al. A staging system for assessing severity of disease and response to therapy in recurrent respiratory papillomatosis. Laryngoscope 1998; 108:935–937.
23Pignatari S, Smith EM, Gray SD, et al. Detection of human papillomavirus infection in diseased and nondiseased sites of the respiratory tract in recurrent respiratory papillomatosis patients by DNA hybridization. Ann Otol Rhinol Laryngol 1992; 101:408–412.

24El-Bitar MA, Zalzal GH. Powered instrumentation in the treatment of recurrent respiratory papillomatosis: an alternative to the carbon dioxide laser. Arch Otolaryngol Head Neck Surg 2002; 128:425–428.

25Patel RS, Mackenzie K. Powered laryngeal shavers and laryngeal papilloma- tosis: a preliminary report. Clin Otolaryngol 2000; 25:358–360.

26Pasquale K, Wiatrak B, Woolley A, Lewis L. Microdebrider versus CO2 laser removal of recurrent respiratory papillomas: a prospective analysis. Laryngoscope 2003; 113:139–143.

27Derkay CS. Task force on recurrent respiratory papillomatosis: a preliminary report. Arch Otolaryngol Head Neck Surg 1995; 121:1386–1391.

28De Bilderling G, Bodart E, Lawson G, et al. Successful use of intralesional and intravenous cidofovir in association with indole-3-carbinol in an 8-year-old girl with pulmonary papillomatosis. J Med Virol 2005; 75:332–335.

29Cullen RD, Zdanski C. Delivery of cidofovir to respiratory papillomas of the distal trachea. Laryngoscope 2005; 115:552–554.

30Mandell DL, Arjmand EM, Kay DJ, et al. Intralesional cidofovir for pediatric recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg 2004; 130:1319–1323.