RRP Task Force ActivitiesRRP Task Force ActivitiesRRP Focus Group 2007RRP Focus Group 2007

Craig Derkay, MDCraig Derkay, MD

Professor and Vice-ChairmanProfessor and Vice-Chairman

Otolaryngology and PediatricsOtolaryngology and Pediatrics

Eastern Virginia Medical SchoolEastern Virginia Medical School

RRP Task ForceRRP Task Force

Multi-disciplinary group that meets twice yearly (September Multi-disciplinary group that meets twice yearly (September and May) in conjunction with the AAO and COSMand May) in conjunction with the AAO and COSM

No further funding from CDC to continue registryNo further funding from CDC to continue registry Coordination of research efforts and assistance to Coordination of research efforts and assistance to

investigators to disseminate information and recruit investigators to disseminate information and recruit interested centers and patientsinterested centers and patients

Formulated statement on Public Health Infection concerns Formulated statement on Public Health Infection concerns for children with RRPfor children with RRP

Formulated statement on Cidofovir safety and use Formulated statement on Cidofovir safety and use Tackling statement on HPV typingTackling statement on HPV typing Working with Merck and Sanofi to develop prospective Working with Merck and Sanofi to develop prospective

investigation of role of the vaccine in reducing the incidence investigation of role of the vaccine in reducing the incidence of RRP and treatment for existing patientsof RRP and treatment for existing patients

Post-Licensing SuggestionsPost-Licensing Suggestionsfor RRP Vaccine Trialsfor RRP Vaccine Trials

Establish the anti-HPV 6 and anti-HPV 11 Establish the anti-HPV 6 and anti-HPV 11 antibody levels in cohort of actively treated RRP antibody levels in cohort of actively treated RRP patients to determine who might benefit from patients to determine who might benefit from therapeutic administration of vaccinetherapeutic administration of vaccine

Vaccinate a cohort of children (girls and boys) Vaccinate a cohort of children (girls and boys) currently in remission and follow for several yearscurrently in remission and follow for several years

Begin surveillance study of new-onset RRP and Begin surveillance study of new-onset RRP and compare over time the incidence and prevalence compare over time the incidence and prevalence in a communityin a community

Attempt a therapeutic trial, perhaps in conjunction Attempt a therapeutic trial, perhaps in conjunction with artemisinin or another cytotoxic drugwith artemisinin or another cytotoxic drug

Children and partners of patients with RRP Children and partners of patients with RRP have no evidence of the disease during long-have no evidence of the disease during long-

term observationterm observationGerein V, Intl J Ped Oto 2006;70; 2061-2066Gerein V, Intl J Ped Oto 2006;70; 2061-2066

15 year multi-center, prospective and 15 year multi-center, prospective and retrospective German and Russian study to retrospective German and Russian study to investigate whether children and partners of investigate whether children and partners of RRP patients develop the disease and whether RRP patients develop the disease and whether there is an impact of pregnancy on the diseasethere is an impact of pregnancy on the disease

Total of 54 patients with 50 offspringTotal of 54 patients with 50 offspring All children born to RRP patients were healthy All children born to RRP patients were healthy

and RRP was never diagnosedand RRP was never diagnosed None of the sexual partners of RRP patients has None of the sexual partners of RRP patients has

developed the diseasedeveloped the disease

Children and partners of patients with RRP Children and partners of patients with RRP have no evidence of the disease during long-have no evidence of the disease during long-

term observationterm observationGerein V, Intl J Ped Oto 2006;70; 2061-2066Gerein V, Intl J Ped Oto 2006;70; 2061-2066

All pregnant women with HPV 11 had excessive All pregnant women with HPV 11 had excessive growth of papillomas while only 17% of HPV 6 growth of papillomas while only 17% of HPV 6 women demonstrated this (p<.0001)women demonstrated this (p<.0001)

Conclusions: Patients with RRP are able to Conclusions: Patients with RRP are able to have healthy children regardless of the stage of have healthy children regardless of the stage of their disease. their disease. The sexual partners of RRP patients do not The sexual partners of RRP patients do not appear to be at risk of developing RRP. appear to be at risk of developing RRP. Pregnancy has a negative impact on the course Pregnancy has a negative impact on the course of RRP that is worse with HPV 11.of RRP that is worse with HPV 11.

Toxicity issues with CidofovirToxicity issues with Cidofovir

Received expedited approval by FDA under Received expedited approval by FDA under HIV/AIDS fast-track rulesHIV/AIDS fast-track rules

Only approved for use to treat CMV-retinitis in Only approved for use to treat CMV-retinitis in AIDS patientsAIDS patients

Animal studies worrisome regarding potential for Animal studies worrisome regarding potential for carcinogenicitycarcinogenicity

Plasma assays after local injection produce Plasma assays after local injection produce levels at-risk for nephrotoxicitylevels at-risk for nephrotoxicity

Use outside of clinical protocols becoming Use outside of clinical protocols becoming widespread without systematic evaluation of widespread without systematic evaluation of adverse eventsadverse events

A case of progressive dysplasia A case of progressive dysplasia concomitant with intralesional Cidofovir concomitant with intralesional Cidofovir

administration for RRPadministration for RRPWermer, Smith, Annals Jan 2006Wermer, Smith, Annals Jan 2006

Case report of 28 year-old non-smoker Case report of 28 year-old non-smoker with RRP who experienced progressive with RRP who experienced progressive and worsening dysplasia while being and worsening dysplasia while being treated with intra-lesional Cidofovir treated with intra-lesional Cidofovir (5mg/cc x 3.5cc) on 3 occasions over 27 (5mg/cc x 3.5cc) on 3 occasions over 27 monthsmonths

Raises concern over off-label useRaises concern over off-label use

CidofovirCidofovir

Black Box warning: Annals 2005;114;834-5Black Box warning: Annals 2005;114;834-5Potent carcinogen in ratsPotent carcinogen in ratsIntra-lesional injections may achieve local and Intra-lesional injections may achieve local and systemic levels high enough to induce toxicitiessystemic levels high enough to induce toxicitiesCase reports showing progression to severe Case reports showing progression to severe dysplasiadysplasiaLiability all on the shoulders of the physicianLiability all on the shoulders of the physicianInformed consent is the keyInformed consent is the key

Cidofovir for RRP: A re-assessment of risksCidofovir for RRP: A re-assessment of risks

RRP Task Force consensus statement on CidofovirRRP Task Force consensus statement on Cidofovir Derkay et al, Int J Ped Oto 2005;69;1465-1467Derkay et al, Int J Ped Oto 2005;69;1465-1467

Given the promising results reported in pediatric and adult Given the promising results reported in pediatric and adult patients, cidofovir should be routinely presented as a patients, cidofovir should be routinely presented as a treatment treatment optionoption in in moderately-to-severely afflicted RRP patientsmoderately-to-severely afflicted RRP patients. i.e.; . i.e.; those patients whose disease is not improving on surgical those patients whose disease is not improving on surgical therapy alone or in conjunction with less potentially morbid therapy alone or in conjunction with less potentially morbid adjuvant measures and/or requiring surgical intervention greater adjuvant measures and/or requiring surgical intervention greater than 3 times a year. than 3 times a year.

With appropriate consent, cidofovir therapy should be a With appropriate consent, cidofovir therapy should be a viable viable optionoption in patents whose disease severity is resulting in a need in patents whose disease severity is resulting in a need for frequent surgery, worsening airway compromise or severely for frequent surgery, worsening airway compromise or severely impaired communication or those who otherwise may be impaired communication or those who otherwise may be considered candidates for tracheotomyconsidered candidates for tracheotomy

Cidofovir for RRP: A re-assessment of risksCidofovir for RRP: A re-assessment of risks RRP Task Force consensus statement on RRP Task Force consensus statement on

CidofovirCidofovir Derkay et al, Int J Ped Oto Oct 2005Derkay et al, Int J Ped Oto Oct 2005

Patients with more mild disease, Patients with more mild disease, particularly particularly childrenchildren, should be discouraged in most cases , should be discouraged in most cases from seeking treatment with cidofovir, until a from seeking treatment with cidofovir, until a better understanding of the long-term better understanding of the long-term implications of the use of this drug have been implications of the use of this drug have been established. established.

With appropriate informed consent, cidofovir could With appropriate informed consent, cidofovir could still be utilized on a still be utilized on a case-by-case basiscase-by-case basis, at the , at the discretion of the prescribing physician, for the discretion of the prescribing physician, for the more mildly affected patient.more mildly affected patient.

Cidofovir for RRP: A re-assessment of Cidofovir for RRP: A re-assessment of risksrisks

RRP Task Force consensus statement on RRP Task Force consensus statement on CidofovirCidofovir

Derkay et al, Int J Ped Oto Oct 2005Derkay et al, Int J Ped Oto Oct 2005

As with all surgical procedures, As with all surgical procedures, informed informed consent should be obtained and consent should be obtained and documented in the patient's recorddocumented in the patient's record. At a . At a minimum, this should include a frank minimum, this should include a frank discussion of the nephrotoxic and discussion of the nephrotoxic and carcinogenic potential of this drugcarcinogenic potential of this drug ..

Cidofovir for RRP: A re-assessment of Cidofovir for RRP: A re-assessment of risksrisks

RRP Task Force consensus statement on RRP Task Force consensus statement on CidofovirCidofovir

Derkay et al, Int J Ped Oto Oct 2005Derkay et al, Int J Ped Oto Oct 2005

Adverse responses, particularly evidence of Adverse responses, particularly evidence of dysplasia or malignant transformation to dysplasia or malignant transformation to squamous cell carcinoma, either locally or squamous cell carcinoma, either locally or remotely, remotely, should be reportedshould be reported simultaneously to simultaneously to the FDA (form 3500 or 3500A) and to the RRP the FDA (form 3500 or 3500A) and to the RRP Task Force through email communication with Task Force through email communication with its Chairman, Craig Derkay, MD its Chairman, Craig Derkay, MD (craig.derkay@chkd.org)(craig.derkay@chkd.org)

Role for HPV TestingRole for HPV Testing

Formulating a statementFormulating a statement Awaiting approval of commercially Awaiting approval of commercially

available testingavailable testing

Reasons for HPV Sub-typing Reasons for HPV Sub-typing

Prognosis for individual patients at time of Prognosis for individual patients at time of diagnosisdiagnosis Plan more frequent surgical Plan more frequent surgical

interventionsinterventions Aggressive airway surveillanceAggressive airway surveillance CT scans of chest at intervalsCT scans of chest at intervals

Risk of malignancy (HPV 16,18, Risk of malignancy (HPV 16,18, 11?11?)) Clearly, in the pediatric airway, HPV 11 Clearly, in the pediatric airway, HPV 11

is high riskis high risk

HPV subtypes causing RRP: 6,11 (16,18 rarely)HPV subtypes causing RRP: 6,11 (16,18 rarely) Previous studies, most non prospective, suggest HPV 11 has Previous studies, most non prospective, suggest HPV 11 has

more aggressive coursemore aggressive course Rimmel et al;Prognosis of viral subtyping.Rimmel et al;Prognosis of viral subtyping. Laryngoscope, 1997Laryngoscope, 1997

HPV-11 worse prognosis, frequency, tracheal spreadHPV-11 worse prognosis, frequency, tracheal spread Rabah et al; HPV subtype 11 more aggressive than HPV 6.Rabah et al; HPV subtype 11 more aggressive than HPV 6.

Archived parafin specimens.Archived parafin specimens. Pediatric & Developmental Pediatric & Developmental Pathology, 2001 Pathology, 2001

Maloney et al; Viral loads in HPV 6 and 11, antibody response Maloney et al; Viral loads in HPV 6 and 11, antibody response and clinical course and clinical course Archives Oto. July 2006Archives Oto. July 2006 Viral load constant for 6 and 11. only antibody response in Viral load constant for 6 and 11. only antibody response in

type 11 patients. Worse clinical course for type 11type 11 patients. Worse clinical course for type 11 Wiatrak et al; 10 year prospective analysis of viral subtypes.Wiatrak et al; 10 year prospective analysis of viral subtypes.

Laryngoscope, 2004.Laryngoscope, 2004.

Longitudinal measures of HPV 6 and 11 viral Longitudinal measures of HPV 6 and 11 viral loads and antibody response in children with loads and antibody response in children with

RRPRRPMaloney, Unger, Reeves et al, Arch OTOHNS 2006;132;711-715Maloney, Unger, Reeves et al, Arch OTOHNS 2006;132;711-715

Longitudinal pilot study of 15 children at Egleston Longitudinal pilot study of 15 children at Egleston Children’s with RRP to measure viral loads of HPV 6 and Children’s with RRP to measure viral loads of HPV 6 and 11 and associated clinical severity11 and associated clinical severity

4 had HPV 6; 4 HPV 11 and 7 had mixed 6/114 had HPV 6; 4 HPV 11 and 7 had mixed 6/11 Viral loads were stable over timeViral loads were stable over time HPV 11 was significantly associated with more annual HPV 11 was significantly associated with more annual

surgical procedures (p=.02)surgical procedures (p=.02) Only 3/15 children had detectable antibodies against Only 3/15 children had detectable antibodies against

viral-like particles (all HPV 11)viral-like particles (all HPV 11) Conclude: Little need to repeat HPV typing over timeConclude: Little need to repeat HPV typing over time

Age of child, more than HPV type, is Age of child, more than HPV type, is associated with clinical course in RRPassociated with clinical course in RRP

Buchinsky FJ, 2007 in pressBuchinsky FJ, 2007 in press

Interim analysis of 118 children with RRP enrolled in Interim analysis of 118 children with RRP enrolled in gene-mapping studygene-mapping study

Clinical course analyzed with respect to HPV type Clinical course analyzed with respect to HPV type and age of the patientand age of the patient

HPV 11 patients were 4x more likely to run an HPV 11 patients were 4x more likely to run an aggressive course aggressive course

Age of patient at time of surgery or age at the time Age of patient at time of surgery or age at the time of diagnosis were more closely associated with of diagnosis were more closely associated with overall clinical course than HPV type.overall clinical course than HPV type.

RRP Viral TypingRRP Viral Typing

Gerein V.Gerein V. Et al: Et al: Incidence, age at onset, and potential Incidence, age at onset, and potential reasons of malignant transformation in recurrent reasons of malignant transformation in recurrent respiratory papillomatosis patients: 20 years respiratory papillomatosis patients: 20 years experience.experience. Otolaryngology - Head & Neck Surgery. Otolaryngology - Head & Neck Surgery. 132(3):392-4, 2005 Mar.132(3):392-4, 2005 Mar. Univ. of Mainz, GermanyUniv. of Mainz, Germany

42 cases of SEVERE RRP, failed IFN therapy42 cases of SEVERE RRP, failed IFN therapy ALL pt’s with pulmonary spread had HPV type 11ALL pt’s with pulmonary spread had HPV type 11 5 of the hpv 11 pt’s developed cancer 5 of the hpv 11 pt’s developed cancer (4 of 5 smokers)(4 of 5 smokers) The results of long-term follow-up in The results of long-term follow-up in RRPRRP patients with patients with

HPVHPV 1111 underline the necessity of reanalyzing the underline the necessity of reanalyzing the current therapycurrent therapy

RRP Viral TypingRRP Viral Typing

Reidy, P.Reidy, P. Et al: Et al: Wayne St. University , Detroit, MIWayne St. University , Detroit, MI Integration of human papillomavirus type 11 in Integration of human papillomavirus type 11 in

recurrent respiratory papilloma-associated cancer.recurrent respiratory papilloma-associated cancer.Source Source Laryngoscope. 114(11):1906-9, 2004 Nov.Laryngoscope. 114(11):1906-9, 2004 Nov.

Increased incidence of HPV type 11 in laryngeal Increased incidence of HPV type 11 in laryngeal CA pt’s with prior history of RRPCA pt’s with prior history of RRP

Brian Wiatrak’s Triolgic Thesis Summary Brian Wiatrak’s Triolgic Thesis Summary Wiatrak Wiatrak et al; Laryngoscope. 2004 Nov;114 (11 Pt 2 Suppl 104):1-et al; Laryngoscope. 2004 Nov;114 (11 Pt 2 Suppl 104):1-

2323

73 patients, 10 years, standard RRP staging system73 patients, 10 years, standard RRP staging system

HPV-11 more likely to:HPV-11 more likely to: Have Higher severity scoresHave Higher severity scores More frequent surgeryMore frequent surgery Require adjuvant medical Rx.Require adjuvant medical Rx. Have higher incidence of tracheal dz.Have higher incidence of tracheal dz. Require tracheotomyRequire tracheotomy Develop pulmonary dz.Develop pulmonary dz.

HPV Sub-TypingHPV Sub-TypingDigene® Digene®

The Digene® HPV Test*, using Hybrid Capture® 2 (hc2) The Digene® HPV Test*, using Hybrid Capture® 2 (hc2) technology, is the only FDA–approved HPV DNA test and technology, is the only FDA–approved HPV DNA test and collectively detects the 13 clinically–relevant high–risk HPV collectively detects the 13 clinically–relevant high–risk HPV types. types.

The Digene HPV Test is a signal–amplified, nucleic acid test The Digene HPV Test is a signal–amplified, nucleic acid test that provides standardized, objective results upon which that provides standardized, objective results upon which healthcare providers may rely on to accurately assess patient healthcare providers may rely on to accurately assess patient risk for cervical intraepithelial neoplasia (CIN) and cancer. risk for cervical intraepithelial neoplasia (CIN) and cancer.

The Digene HPV Test is the only FDA–approved HPV test for:The Digene HPV Test is the only FDA–approved HPV test for: Primary screening, in conjunction with a Pap, of Primary screening, in conjunction with a Pap, of

women age 30 years and older; andwomen age 30 years and older; and Triage of women of any age with ASC–US Pap results.Triage of women of any age with ASC–US Pap results.

High–risk typeHigh–risk type 16,18,31,33,35,39,45,16,18,31,33,35,39,45,

51,52,56,58,59,6851,52,56,58,59,68

Low-risk typeLow-risk type 6,11,42,43,446,11,42,43,44

HPV Sub-Typing HPV Sub-Typing Digene® HPV TestDigene® HPV Test

AMPLICOR®AMPLICOR® HPV test HPV test Roche DiagnosticsRoche Diagnostics

PCR- based HPV screening testPCR- based HPV screening test Identifies 13 high risk typesIdentifies 13 high risk types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68 Therefore, HPV types 6 and 11 are termed low-risk (LR) Therefore, HPV types 6 and 11 are termed low-risk (LR)

HPV types, and HPV types involved in carcinogenesis HPV types, and HPV types involved in carcinogenesis (such as types 16 and 18) are termed high-risk (HR) (such as types 16 and 18) are termed high-risk (HR) HPV types.HPV types. Comparison of Two Commercial Assays for Detection Comparison of Two Commercial Assays for Detection

of Human Papillomavirus (HPV) in Cervical Scrape of Human Papillomavirus (HPV) in Cervical Scrape Specimens Specimens 20052005 Maaike A. P. C. van Ham et al. Maaike A. P. C. van Ham et al. Journal of Clinical Microbiology, Journal of Clinical Microbiology, June 2005, p. 2662-2667June 2005, p. 2662-2667

Linear Array KitLinear Array KitRoche DiagnosticsRoche Diagnostics

PCR-based linear array HPV product PCR-based linear array HPV product Amplification of target DNA by PCR and Amplification of target DNA by PCR and

Hybridization techniquesHybridization techniques The linear array identifies 37 HPV genotypes, The linear array identifies 37 HPV genotypes,

including all high- and low-risk genotypes. including all high- and low-risk genotypes. Provides Provides specific subtype (genotype)specific subtype (genotype) information information Currently available as Currently available as researchresearch tool only tool only Insurance reimbursement issuesInsurance reimbursement issues Plan is to make commercially available in the Plan is to make commercially available in the

future future (2007?)This is what we are waiting for!(2007?)This is what we are waiting for!

CelebrexCelebrex

Study funded by NIH.Study funded by NIH. DSMB group established with first meeting in DSMB group established with first meeting in

September. September. IND being prepared for FDA Awaiting word from Pfizer IND being prepared for FDA Awaiting word from Pfizer

for inclusion of children in the protocolfor inclusion of children in the protocol Celebrex has been approved for use in children >2 years Celebrex has been approved for use in children >2 years

with rheumatoid arthritis (protocol will allow children >4 with rheumatoid arthritis (protocol will allow children >4 years)years)

Pilot data: 3/3 patients have achieved remission in 3, 6 Pilot data: 3/3 patients have achieved remission in 3, 6 and 9 months with 1 year of follow-up. All 3 had severe and 9 months with 1 year of follow-up. All 3 had severe disease and one had tracheal involvement!disease and one had tracheal involvement!