The Cidofovir Controversy

Abstract

Recurrent respiratory papillomatosis (RRP) is a disease of viral etiology and is caused by the human papilloma virus (HPV). Although it is a benign disease process, there are very serious sequelae because of its involvement in the tracheobronchial tree. Multiple treatment modalities have emerged to control aerodigestive tract proliferation, ranging from surgery to immunomodulating medications, including antiviral drugs such as cidofovir. Cidofovir is an adjunct therapy employed as an intralesional injection. While cidofovir has historically been employed without long-term consequences, there are concerns associated with its use as a papilloma treatment, including potential malignant transformation of lesions, renal failure, and neutropenia. This chapter will focus on the benefits and risks of employing cidofovir in the RRP patient population as well as suggested treatment algorithms. A summary table of clinical reports of other adjuvant therapies is provided as an appendix at the end of the chapter.

Summary of Clinical Studies of Adjuvant Therapies (Excluding Cidofovir) used in the Management of Recurrent Respiratory Papillomatosis Reported between 2000 and 2017 (Prepared by P. Campisi)

Study	Design	Cohort	Outcomes
Bevacizumab
Mohr et al. (2014)	Case series Intravenous: 5–15 mg/kg per dose q 2–3 weeks initially, then increase interval	N = 5 4 adults 1 child, 8 years of age	Immediate response Very good partial remission or partial response in all patients
Sidell et al. (2014)	Case series Intralesional injection: 5–45 mg dose × 5 doses q 4–6 weeks with 532 nm KTP laser ablation	N = 9 Median age 8 years Range 3–21 years	Median 58% improvement in Derkay score ↑ Median surgical interval time 2.05X
Rogers et al. (2013)	Case series Intralesional injection: 2.5 mg/mL × 3 doses q 2–3 weeks with 532 nm KTP laser ablation	N = 10 Range 18 months–18 years	Statistically significant: ↑ Median surgical interval by 5.9 weeks ↓ Median number of procedures by 4 per year ↓ Derkay score by 6 ↑ Median total PVRQOL score by 25.5 ↑ Median emotional PVRQOL score by 11.3 ↑ Median physical PVRQOL score by 14.3
Zeitels et al. 2011	Prospective open-label trial Intralesional injection: 7.5–12.5 mg in × 4 doses q 6 weeks into vocal fold with worse disease Opposite vocal fold sham injection with saline ± 532 nm KTP laser as needed	N = 20 adults with bilateral vocal fold disease	3/20—No disease in either vocal fold 16/17—Less disease in treated vocal fold 1/17—More disease in treated vocal fold 20/20 Improved: Vocal function, acoustic and aerodynamic measures of voice, VRQOL scores
Interferon
Suter-Montano et al. (2013)	Case series Peg-IFNα-2a at 180 mcg weekly × 6 months In 3rd month, +GM-CSF 400 mcg weekly × 2 months	N = 11 adults	3 patients had tracheostomy removed Mean improvement in VRQOL measures ↓ Number of surgical interventions required
Nodarse-Cuni et al. (2004)	Case series IM injection IFNα-2b Induction: 105 IU/Kg in children 6 × 106 IU in adults Maintenance (up to 2 years): 5 × 104 IU/Kg in children 3 × 106 IU in adults	N = 169 84 adults 85 children	Relapse frequency: ↓ 74% in children ↓ 79% in adults Complete resolution in 1st presentation patients: 45% of children 88% of adults At study completion: 58% of children in remission 82% of adults in remission
Interferon and BCG
Avramov et al. (2014)	3 Parallel case series Series 1: CO2 laser ablation + 6–12 transdermal applications of BCG Series 2: CO2 laser ablation + α-Interferon 3 million IU 5 times per week for 1 month, then 3 million IU 3 times per week for 1 month, then 3 million IU once per week Series 3: Surgery alone	(No mention of how patients were allocated) N = 16 adults N = 11 adults N = 16 adults	2/16 had a relapse (follow-up 36 months) 3/11 had a relapse (follow-up 45 months) 6/16 had a relapse (follow-up 48 months)
Interferon and Cidofovir
Armbruster et al. (2001)	Case report Interferon α-2b 5 × 106 Units 3 times per week x 6 months combined with Cidofovir 5 mg/Kg per week × 2 weeks then 5 mg/Kg q 2 weeks for total 6 months	N = 1 adult	Regression of laryngeal and intrapulmonary disease
Indole 3 Carbinol
Rosen and Bryson (2004)	Prospective open-label trial I3C 200 mg orally twice daily	N = 33 24 adults 9 children	Mean follow-up 4.8 years All patients: 33% remission 30% ↓ need for surgery 36% no response Children: 1/9—complete response 3/9—partial response 5/9—no response
Acyclovir
Chaturvedi et al. (2014)	Case series Post-surgical oral acyclovir 800 mg 5 times per day × 5 days	N = 3 adults	2/3—remission at end of 1 year follow-up
Vaccination and Immune Therapy
Meacham and Thompson (2017)	4 Parallel case series Series 1: Debridement and cidofovir Series 2: Debridement and MMR Series 3: Exposure to cidofovir and MMR Series 4: Debridement only	N = 15 children Range 1–16 years N = 5 N = 6 N = 3 N = 1	No significant difference in number and frequency of required treatments or rates of remission across series
Beaumanis and Elmaraghy (2016)	Case report Quadrivalent HPV vaccine	N = 1 child 4 year old	Improved clinical course
Hermann et al. (2016)	Uncontrolled intervention study 3 Doses of quadrivalent HPV vaccine	N = 9 children Range 9–17 years	No significant difference in clinical course, anatomical score, inter-surgical interval or number of surgeries needed at 1-year follow-up
Young et al. (2015)	Case series Quadrivalent HPV vaccine	N = 20	Significant increase in inter-surgical interval 8/20—Complete remission 5/20—Partial remission
Chirila and Bolboaca (2014)	Case series Quadrivalent HPV vaccine	N = 13 Patients with recurrences after failed treatment with cidofovir	85% had no recurrence at 1-year follow-up
Lei et al. (2012)	Randomized prospective trial Arm 1: Topical MMR vaccine at site of excised lesions Arm 2: Excision only	N = 26 children	Longer period of remission in MMR but difference was not significant
Derkay et al. (2005)	Open-label, single arm intervention study Surgery followed by HspE7 500 mcg subcutaneously monthly × 3 doses	N = 27 children Range 2–18 years	At 60-weeks follow-up: Median inter-surgical interval increased 93% Stronger treatment effect in females