Background: Contovir is a mixture of herbal extracts (Tanacetum vulgare, Rossa canina, Urtica dioica) that is supplemented with selenium. Objectives: This study aimed to add Contovir to the classic treatment of recurrent respiratory papillomatosis (RRP) in order to decrease the severity and extent of the disease, elongate the surgical intervals and improve the sense of patient well-being. Furthermore, we had to adjust the prescribed drug dosage, since there were no previous findings available. Patients and Methods: This is a case study of RRP patients treated with Contovir as an adjuvant to the classic treatment, from March 2011 to February 2013, at an academic tertiary hospital (Rasoul-e-Akram hospital). All patients underwent surgical removal of papilloma and then were prescribed Contovir. Disease severity was quantified based on Derkayâ��s staging system. Results: Eight patients were enrolled in this study. The extent and severity of the disease improved in six cases. One had no response, and the severity of disease increased in one patient. Patients with supraglottic lesions had better responses to Contovir adjuvant therapy. No immediate or long-term side effects were reported. Conclusions: Although Contovir has been found to be an advantageous adjuvant for RRP treatment, further studies are called for to verify these findings. Â© 2016, Iranian Red Crescent Medical Journal

Ahmadi, A.

Bahri, M.

Derakhshandeh, V.

Farhadi, M.

Izadi, F.

Khorram Khorshid, H.R.

Madani, H.

Shahrivar, R.

Tavakoli, M.M.

eprints Iran University of Medical Sciences

Iran Red Crescent Med J. 2017 December; 19(12):e21577.Published online 2016 February 20.doi: 10.5812/ircmj.21577.Rapid CommunicationContovir - A New Adjuvant Therapy in Recurrent RespiratoryPapillomatosis: A Case StudyMohammad Farhadi,1 Farzad Izadi,1,* Maryam Bahri,1 Vitta Derakhshandeh,1 Mohammad MoeinTavakoli,1 Hamid Reza Khorram Khorshid,1 Hessamodin Madani,1 Roya Shahrivar,1 and Aslan Ahmadi11ENT-Head and Neck Surgery Research Center and Department, Rasool Akram Hospital, Iran University of Medical Sciences, Tehran, IR Iran*Corresponding author: Farzad Izadi, ENT-Head and Neck Surgery Research Center and Department, Rasool Akram Hospital, Iran University of Medical Sciences, Tehran, IRIran., E-mail: farzadizadi@dr.comReceived 2014 July 05; Revised 2015 April 07; Accepted 2015 May 04.AbstractBackground: Contovir is a mixture of herbal extracts (Tanacetum vulgare, Rossa canina, Urtica dioica) that is supplemented withselenium.Objectives: This study aimed to add Contovir to the classic treatment of recurrent respiratory papillomatosis (RRP) in order todecrease the severity and extent of the disease, elongate the surgical intervals and improve the sense of patient well-being. Further-more, we had to adjust the prescribed drug dosage, since there were no previous findings available.Patients and Methods: This is a case study of RRP patients treated with Contovir as an adjuvant to the classic treatment, fromMarch 2011 to February 2013, at an academic tertiary hospital (Rasoul-e-Akram hospital). All patients underwent surgical removal ofpapilloma and then were prescribed Contovir. Disease severity was quantified based on Derkay’s staging system.Results: Eight patients were enrolled in this study. The extent and severity of the disease improved in six cases. One had no response,and the severity of disease increased in one patient. Patients with supraglottic lesions had better responses to Contovir adjuvanttherapy. No immediate or long-term side effects were reported.Conclusions: Although Contovir has been found to be an advantageous adjuvant for RRP treatment, further studies are called forto verify these findings.Keywords: Recurrent Respiratory Papillomatosis (RRP), Adjuvant Therapy, Contovir1. BackgroundRecurrent respiratory papillomatosis (RRP) is a recur-rent benign tumor of the respiratory tract. It is causedby genital tract human papillomaviruses (type 6 and 11are the most common causes). This disease is transmit-ted during normal vaginal delivery from the infected birthcanal to the respiratory tract of the child (1). The incidenceof RRP in children is 1 - 4 per 100,000 and among adultsis 1.8 - 3.9 per 100,000 (2). The major treatment modal-ity for RRP is surgical de-bulking of papilloma by meansof laser ablation or microdebridment. RRP does not curethe disease, due to papilloma regrowth after surgical re-moval. Studies have shown that approximately 4.4 pro-cedures per year are needed for each patient with severeRRP (3). The frequent surgery requirement brings emo-tional and economic burdens on the patients and theirfamilies. Accordingly, laryngologists attempt to reducethe frequency of procedures by using non-invasive modali-ties including supplementation with an antiviral adjuvant.The criterion for adjuvant therapy is the need for surgerymore than four times per year (4). Clinical trials haveshown some controlling effect of adjuvants such as inter-feron alfa, cidofovir, indole-3-carbinol, acyclovir, ribavirin,isotretinoin, methotrexate, the mumps vaccine, and pho-todynamic therapy on RRP treatment. Interferon alfa andcidofovir have antiviral activities, and they also modulatethe host immune response to HPV (4). Contovir, as a newversion of an IMOD (immuno-modulatory drug), is a mix-ture of herbal extracts (Tanacetum vulgare, Rossa canina,Urtica dioica) supplemented with selenium, carotene andflavonoids (5, 6). The anti-inflammatory and antioxida-tive effects of IMODs have been shown on colitis, type 1diabetes, pancreatic Langerhans islet transplantation andpolycystic ovary syndrome. Previous studies showed theimmunostimulation and antiviral effect of IMODs in HIV-infected patients (7, 8). Safety and potential mutagenic andgenotoxic studies in the preclinical and clinical phase havedemonstrated that IMODs are safe and non-mutagenic (6).Copyright © 2016, Iranian Red Crescent Medical Journal. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided theoriginal work is properly cited.Farhadi M et al.2. ObjectivesBased on the requirement for a new, safe and cost-effective adjuvant, this study evaluates Contovir as a sup-plement to the classic treatment of RRP.3. Patients and Methods3.1. MethodsThis is a case study regarding patients with RRP, whichwere enrolled in a prospective follow-up using Contovirfor the treatment of RRP from March 2011 to February 2013in Rasoul-e-Akram hospital; a tertiary referral hospital inTehran, Iran affiliated with Iran University of Medical Sci-ences. Prior to beginning the treatment with Contovir, pa-tients underwent endoscopic evaluation in the operatingroom to locate and quantify the extent of the disease. Therate of recurrence was determined by reviewing the last 12months of surgical history. To standardize the treatment,the surgeon discontinued all other adjuvant therapies in-cluding I3C and INF.Disease severity was quantified based on the stagingsystem described by Derkay et al. (9) The initial dose of Con-tovir was 1.5 mg/kg IV. Since it causes phlebitis in children,it was administered orally. Contovir dosing was continuedas: 3 mg/kg, 6 mg/kg (10th study month), 20 g/kg (16th studymonth).3.2. PatientsPretreatment laboratory tests were performed on allpatients, including CBC diff, FBS, BUN, Cr, Na, K, liver func-tion tests, and urinalysis. These tests were repeated beforeeach surgery. Patients, or their parents, consented to thedrug administration. In each surgery, the patient’s voiceand airway condition was documented. Patients were alsoasked about experienced side effects.This study was approved by the institutional reviewboard of Tehran University of Medical Sciences ethics com-mittee. Written informed consent was obtained from thepatients, and the study protocol conformed to the ethicalguidelines of the 1975 declaration of Helsinki, as reflectedin a prior approval by the institution’s human research de-partment.4. ResultsTo evaluate the efficacy of Contovir in the treatment ofRRP, nine patients were enrolled in this study. One patientdropped out during follow-up, due to noncompliance withthe medication.Demographic data for the patients are shown in Table1. Average age at initial treatment of RRP was 3.6 years.Patients were between 2 and 56 years old. Seven patientswere≤ 15 years old. Case 1 had glottic stenosis secondary tomalpractice and multiple surgeries for RRP in another cen-ter. Due to this patient’s weak responses to surgery and themedication used in this trial, we had to administer INF andI3C, and after all four surgeries, his Derkay’s scores were notchanged.This study included six patients who responded to Con-tovir as adjuvant therapy. The score remained constant forone patient (case 3) and was increased for another (case 1).The response appeared after the second surgery onContovir (P = 0.042) and two patients showed more signif-icant response to Contovir (cases two and six).In cases two and eight papilloma disappeared in thesupraglottis, and in cases four and seven the lesion’s exten-sion decreased in the supraglottis. This change was morevisible after the second surgery on Contovir. In addition,the glottic lesions responded on the third surgery.Tracheal and subglottic papilloma did not respond toContovir, demonstrating that only two of five patients withtracheal involvement had a decreasing tracheal score.5. DiscussionNumerous studies have been designed to evaluate therole of different adjuvants for improvement of the courseof RRP. Interferon alfa is the most common adjuvant ther-apy for RRP. In one study of 60 RRP patients, Leventhal et al.reported a 78% response rate to interferon (10). Rosen et al.showed, in a study of 21 RRP patients treated with indole-3-carbinol, a complete response in 33%, a partial responsein 30% and no response in 37% of patients (11). In a reviewof the intra lesional effect of cidofovir on RRP patients byChadha et al., patients demonstrated 57% complete resolu-tion, 35% partial response and 8% no improvement (12).Despite the positive responses to these medications,their adverse effects are mentioned. Neuropsychiatriccomplications and bone marrow suppression are two ma-jor complications of interferon. One of its limitations is arebound phenomenon after a primary positive response(4). In addition, intravenous cidofovir has nephrotoxicside effects and it is potentially carcinogenic in animals(12).In our study, six of eight patients responded to Con-tovir. It is not understood why some patients experiencednear complete remission of papilloma, whereas others hadpartial responses or none at all. HPV11 and tracheal lesionsare two predictors of severe RRP (13). Case 1 had laryngealcomorbidity, and this patient’s HPV type was HPV11. Case 32 Iran Red Crescent Med J. 2017; 19(12):e21577.Farhadi M et al.had only tracheal involvement. These are important char-acteristics to define the lack of response to Contovir. It isimportant to note that the response to Contovir was rapidand occurred after the second surgery.Both cases 2 and 6, who had good responses, had foursurgeries in the last year . These cases showed a decrease indisease scores on the supraglottis and glottis. They werefollowed for one year, and their score did not increase.Supraglottic and glottic lesions showed better and moresignificant responses compared to subglottic and trachealpapilloma. No adverse effect (clinical and laboratory) wasdetected in this study.There are no previous studies of Contovir administra-tion for treatment of RRP. Our findings provide beneficialevidence of Contovir as an adjuvant for RRP treatment thatis efficacious, well-tolerated and a noninvasive oral drug.The limitations of the present study include lack of a con-trol group, unknown HPV typing and short-term follow-up.Therefore, additional studies are recommended.5.1. ConclusionOur results show that Contovir can be a safe and ef-fective adjuvant therapy for patients with RRP, but furtherclinical trials are necessary before it can be recommendedfor widespread use.FootnotesAuthors’ Contribution: All authors have contributedequally in all parts of the manuscript preparation processincluding: 1, study concept and design; 2, acquisition ofdata; 3, analysis and interpretation of data; 4, drafting ofthe manuscript; 5, critical revision of the manuscript forimportant intellectual content; 6, statistical analysis; 7, ad-ministrative, technical, and material support; 8, study su-pervision.Funding/Support: Iran University of Medical Sciences.References1. Shah K, Kashima HK, Polk BF, Shah F, Abbey H, Abramson A. Rarity ofcesarean delivery in cases of juvenile-onset respiratory papillomato-sis. Obstetrics & Gynecology. 1986;68(6):795–9.2. Bielecki I, Mniszek J, Cofala M. Intralesional injection of cidofovirfor recurrent respiratory papillomatosis in children. Int J PediatrOtorhinolaryngol. 2009;73(5):681–4. doi: 10.1016/j.ijporl.2009.01.002.[PubMed: 19193450].3. Omland T, Lie KA, Akre H, Sandlie LE, Jebsen P, Sandvik L, et al.Recurrent respiratory papillomatosis: HPV genotypes and risk ofhigh-grade laryngeal neoplasia. PLoS One. 2014;9(6). eee99114. doi:10.1371/journal.pone.0099114. [PubMed: 24918765].4. Kimberlin DW. Current status of antiviral therapy for juvenile-onsetrecurrent respiratory papillomatosis. Antiviral Res. 2004;63(3):141–51.doi: 10.1016/j.antiviral.2004.06.013. [PubMed: 15451182].5. Azonov JA, Khorshid HRK, Novitsky YA, Farhadi M, Ghorbanoghli Z,Shahhosseiny MH. Protective effects of setarud (IMODTM) on develop-ment of diet-induced hypercholesterolemia in rabbits. Daru J Pharm.Sci. 2008;16(4):218–22.6. Khorshid HRK, Novitsky YA, Abdollahi M, Shahhosseiny MH, SadeghiB, Madani H, et al. Studies on potential mutagenic and genotoxic ac-tivity of Setarud. Daru J Pharm Sci. 2008;16(4):223–8.7. Rezvanfar MA, Rezvanfar MA, Ahmadi A, Shojaei-Saadi HA, BaeeriM, Abdollahi M. Molecular mechanisms of a novel selenium-based complementary medicine which confers protectionagainst hyperandrogenism-induced polycystic ovary. Theriogenol-ogy. 2012;78(3):620–31. doi: 10.1016/j.theriogenology.2012.03.008.[PubMed: 22541319].8. Baghaei A, Esmaily H, Abdolghaffari AH, Baeeri M, Gharibdoost F, Ab-dollahi M. Efficacy of Setarud (IMod), a novel drug with potent anti-toxic stress potential in rat inflammatory bowel disease and compar-ison with dexamethasone and infliximab. Indian J Biochem Biophys.2010;47(4):219–26. [PubMed: 21174949].9. Derkay CS, Malis DJ, Zalzal G, Wiatrak BJ, Kashima HK, Coltrera MD.A staging system for assessing severity of disease and response totherapy in recurrent respiratory papillomatosis. The Laryngoscope.1998;108(6):935–7.10. Leventhal BG, Kashima HK, Mounts P, Thurmond L, Chapman S,Buckley S, et al. Long-term response of recurrent respiratory pa-pillomatosis to treatment with lymphoblastoid interferon alfa-N1. Papilloma Study Group. N Engl J Med. 1991;325(9):613–7. doi:10.1056/NEJM199108293250904. [PubMed: 1861694].11. Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratorypapillomatosis: long-term results. J Voice. 2004;18(2):248–53. doi:10.1016/j.jvoice.2003.05.005. [PubMed: 15193659].12. Chadha NK, James AL. Antiviral agents for the treatment of recur-rent respiratory papillomatosis: a systematic review of the English-language literature. Otolaryngol Head Neck Surg. 2007;136(6):863–9.doi: 10.1016/j.otohns.2006.09.007. [PubMed: 17547971].13. Kayode A. The descriptive review, from recurrent respiratory papillo-matosis of the disease, an enigmatic. scielo. 2012;16(1):108–14.Iran Red Crescent Med J. 2017; 19(12):e21577. 3Farhadi M et al.Table 1. The patients’ Scores at Initiation and After Contovir Treatment, the Subunits Score and the Extension and Severity of PapillomaSubunits Pre Contovir Score 1th OP on Contovir 2th 3th 4th 5th 6th 7thPatient number =1; Gender = male; Age, y = 2; Age (First presentation), y = 0.5; Total Number of Opertion in Last Year = 5; Comorbidity = Glottic stenosis; Tracheotomy = +Supra glottis 22 21 6 21 12 24 6 21Glottis 12 12 9 12 12 12 12 12Sub glottis 3 3 3 3 3 3 3 3Trachea 6 9 6 6 3 9 9 9Total 43 45 24 42 30 48,(INF+I3C)63020 45Patient number =2; Gender = male; Age, y = 4; Age (First presentation), y = 1.5; Total Number of Opertion in Last Year = 4; Comorbidity = None; Tracheotomy = +Supra glottis 4 0 0 0Glottis 1 0 0 0Sub glottis 3 0 0 0Trachea 6 9 4 2Total 14 9 4 2aPatient number = 3; Gender = female; Age, y = 15; Age (First presentation), y = 5; Total Number of Opertion in Last Year = 4; Comorbidity = None; Tracheotomy = +Supra glottis 0 0 0 0Glottis 0 0 0 0Sub glottis 0 0 0 0Trachea 6 9 9 6Total 6 9 9 66Patient number = 4; Gender = male; Age, y = 11; Age (First presentation), y = 1; Total Number of Opertion in Last Year = 3; Comorbidity = None; Tracheotomy = -Supra glottis 6 3 6 1 3 6 3Glottis 5 7 6 2 9 6 4Sub glottis 0 0 1 0 1 3 0Trachea 3 0 0 0 0 0 0Total 14 10 13 3 13 15 7Patient number = 5; Gender = male; Age, y = 56; Age (First presentation), y = 3; Total Number of Opertion in Last Year = 1; Comorbidity = None; Tracheotomy = -Supra glottis 0 3 3 0 0Glottis 6 3 3 1 0Sub glottis 3 3 3 3 3Trachea 6 3 3 6 9Total 15 12 12 10 12Patient number = 6; Gender = female; Age, y = 15; Age (First presentation), y = 13; Total Number of Opertion in Last Year = 4; Comorbidity = None; Tracheotomy = -Supra glottis 0 1 0Glottis 9 2 1Sub glottis 0 0 0Trachea 0 0 0Total 9 3 1Patient number = 7; Gender = female; Age, y = 3.5; Age (First presentation), y = 3.5; Total Number of Opertion in Last Year = 0; Comorbidity = GE reflux; Tracheotomy = -Supra glottis 6 6 0 2 2 0 0Glottis 9 9 9 5 9 9 6Sub glottis 0 0 0 0 0 0 0Trachea 0 0 0 0 0 0 0Total 15 15 9 7 11 9 6Patient number = 8; Gender = female; Age, y = 9; Age (First presentation), y = 4; Total Number of Opertion in Last Year = 0; Comorbidity = None; Tracheotomy = -Supra glottis 3 0 0 1Glottis 9 9 9 8Sub glottis 0 0 0 0Trachea 0 0 0 0Total 12 9 9 9a During one year follow up, any lesion didn’t see in laryngoscopy.4 Iran Red Crescent Med J. 2017; 19(12):e21577.

Contovir - A new adjuvant therapy in recurrent respiratory papillomatosis: A case study

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Contovir - A new adjuvant therapy in recurrent respiratory papillomatosis: A case study

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