RRP Task Force Activities
RRP Focus Group 2007
Craig Derkay, MD
Professor and Vice-Chairman
Otolaryngology and Pediatrics
Eastern Virginia Medical School
RRP Task Force
 Multi-disciplinary group that meets twice yearly
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(September and May) in conjunction with the AAO and
COSM
No further funding from CDC to continue registry
Coordination of research efforts and assistance to
investigators to disseminate information and recruit
interested centers and patients
Formulated statement on Public Health Infection
concerns for children with RRP
Formulated statement on Cidofovir safety and use
Tackling statement on HPV typing
Working with Merck and Sanofi to develop prospective
investigation of role of the vaccine in reducing the
incidence of RRP and treatment for existing patients
Post-Licensing Suggestions
for RRP Vaccine Trials
 Establish the anti-HPV 6 and anti-HPV 11
antibody levels in cohort of actively treated RRP
patients to determine who might benefit from
therapeutic administration of vaccine
 Vaccinate a cohort of children (girls and boys)
currently in remission and follow for several
years
 Begin surveillance study of new-onset RRP and
compare over time the incidence and prevalence
in a community
 Attempt a therapeutic trial, perhaps in
conjunction with artemisinin or another cytotoxic
drug
Children and partners of patients with RRP
have no evidence of the disease during longterm observation
Gerein V, Intl J Ped Oto 2006;70; 2061-2066
 15 year multi-center, prospective and
retrospective German and Russian study to
investigate whether children and partners of
RRP patients develop the disease and whether
there is an impact of pregnancy on the disease
 Total of 54 patients with 50 offspring
 All children born to RRP patients were healthy
and RRP was never diagnosed
 None of the sexual partners of RRP patients has
developed the disease
Children and partners of patients with RRP
have no evidence of the disease during longterm observation
Gerein V, Intl J Ped Oto 2006;70; 2061-2066
 All pregnant women with HPV 11 had excessive
growth of papillomas while only 17% of HPV 6
women demonstrated this (p<.0001)
 Conclusions: Patients with RRP are able to
have healthy children regardless of the stage of
their disease.
The sexual partners of RRP patients do not
appear to be at risk of developing RRP.
Pregnancy has a negative impact on the course
of RRP that is worse with HPV 11.
Toxicity issues with Cidofovir
 Received expedited approval by FDA under
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HIV/AIDS fast-track rules
Only approved for use to treat CMV-retinitis in
AIDS patients
Animal studies worrisome regarding potential for
carcinogenicity
Plasma assays after local injection produce
levels at-risk for nephrotoxicity
Use outside of clinical protocols becoming
widespread without systematic evaluation of
adverse events
A case of progressive dysplasia
concomitant with intralesional Cidofovir
administration for RRP
Wermer, Smith, Annals Jan 2006
 Case report of 28 year-old non-smoker
with RRP who experienced progressive
and worsening dysplasia while being
treated with intra-lesional Cidofovir
(5mg/cc x 3.5cc) on 3 occasions over 27
months
 Raises concern over off-label use
Cidofovir
 Black Box warning: Annals 2005;114;834-5
Potent carcinogen in rats
Intra-lesional injections may achieve local and
systemic levels high enough to induce toxicities
Case reports showing progression to severe
dysplasia
Liability all on the shoulders of the physician
Informed consent is the key
Cidofovir for RRP: A re-assessment of risks
RRP Task Force consensus statement on Cidofovir
Derkay et al, Int J Ped Oto 2005;69;1465-1467
 Given the promising results reported in pediatric and
adult patients, cidofovir should be routinely
presented as a treatment option in moderately-toseverely afflicted RRP patients. i.e.; those patients
whose disease is not improving on surgical therapy
alone or in conjunction with less potentially morbid
adjuvant measures and/or requiring surgical
intervention greater than 3 times a year.
 With appropriate consent, cidofovir therapy should
be a viable option in patents whose disease
severity is resulting in a need for frequent surgery,
worsening airway compromise or severely impaired
communication or those who otherwise may be
considered candidates for tracheotomy
Cidofovir for RRP: A re-assessment of risks
RRP Task Force consensus statement on
Cidofovir
Derkay et al, Int J Ped Oto Oct 2005
Patients with more mild disease, particularly
children, should be discouraged in most cases
from seeking treatment with cidofovir, until a
better understanding of the long-term
implications of the use of this drug have been
established.
With appropriate informed consent, cidofovir could
still be utilized on a case-by-case basis, at the
discretion of the prescribing physician, for the
more mildly affected patient.
Cidofovir for RRP: A re-assessment of
risks
RRP Task Force consensus statement on
Cidofovir
Derkay et al, Int J Ped Oto Oct 2005
As with all surgical procedures, informed
consent should be obtained and
documented in the patient's record. At a
minimum, this should include a frank
discussion of the nephrotoxic and
carcinogenic potential of this drug.
Cidofovir for RRP: A re-assessment of
risks
RRP Task Force consensus statement on
Cidofovir
Derkay et al, Int J Ped Oto Oct 2005
Adverse responses, particularly evidence of
dysplasia or malignant transformation to
squamous cell carcinoma, either locally or
remotely, should be reported simultaneously to
the FDA (form 3500 or 3500A) and to the RRP
Task Force through email communication with its
Chairman, Craig Derkay, MD
(craig.derkay@chkd.org)
Role for HPV Testing
 Formulating a statement
 Awaiting approval of commercially
available testing
Reasons for HPV Sub-typing
 Prognosis for individual patients at time of
diagnosis
 Plan more frequent surgical
interventions
 Aggressive airway surveillance
 CT scans of chest at intervals
 Risk of malignancy (HPV 16,18, 11?)
 Clearly, in the pediatric airway, HPV 11
is high risk
 HPV subtypes causing RRP: 6,11 (16,18 rarely)
 Previous studies, most non prospective, suggest HPV 11
has more aggressive course
 Rimmel et al;Prognosis of viral subtyping.
Laryngoscope, 1997
 HPV-11 worse prognosis, frequency, tracheal
spread
 Rabah et al; HPV subtype 11 more aggressive than
HPV 6. Archived parafin specimens. Pediatric &
Developmental Pathology, 2001
 Maloney et al; Viral loads in HPV 6 and 11, antibody
response and clinical course Archives Oto. July 2006
 Viral load constant for 6 and 11. only antibody
response in type 11 patients. Worse clinical
course for type 11
 Wiatrak et al; 10 year prospective analysis of viral
subtypes. Laryngoscope, 2004.
Longitudinal measures of HPV 6 and 11 viral
loads and antibody response in children with
RRP
Maloney, Unger, Reeves et al, Arch OTOHNS 2006;132;711-715
 Longitudinal pilot study of 15 children at Egleston
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Children’s with RRP to measure viral loads of HPV 6 and
11 and associated clinical severity
4 had HPV 6; 4 HPV 11 and 7 had mixed 6/11
Viral loads were stable over time
HPV 11 was significantly associated with more annual
surgical procedures (p=.02)
Only 3/15 children had detectable antibodies against
viral-like particles (all HPV 11)
Conclude: Little need to repeat HPV typing over time
Age of child, more than HPV type, is
associated with clinical course in RRP
Buchinsky FJ, 2007 in press
 Interim analysis of 118 children with RRP enrolled in
gene-mapping study
 Clinical course analyzed with respect to HPV type
and age of the patient
 HPV 11 patients were 4x more likely to run an
aggressive course
 Age of patient at time of surgery or age at the time
of diagnosis were more closely associated with
overall clinical course than HPV type.
RRP Viral Typing
 Gerein V. Et al: Incidence, age at onset, and potential
reasons of malignant transformation in recurrent
respiratory papillomatosis patients: 20 years
experience. Otolaryngology - Head & Neck Surgery.
132(3):392-4, 2005 Mar. Univ. of Mainz, Germany
 42 cases of SEVERE RRP, failed IFN therapy
 ALL pt’s with pulmonary spread had HPV type 11
 5 of the hpv 11 pt’s developed cancer (4 of 5
smokers)
 The results of long-term follow-up in RRP patients
with HPV 11 underline the necessity of reanalyzing
the current therapy
RRP Viral Typing
 Reidy, P. Et al: Wayne St. University , Detroit, MI
 Integration of human papillomavirus type 11 in
recurrent respiratory papilloma-associated cancer.
Source Laryngoscope. 114(11):1906-9, 2004 Nov.
 Increased incidence of HPV type 11 in laryngeal
CA pt’s with prior history of RRP
Brian Wiatrak’s Triolgic Thesis Summary Wiatrak
et al; Laryngoscope. 2004 Nov;114 (11 Pt 2 Suppl 104):123
 73 patients, 10 years, standard RRP staging system
 HPV-11 more likely to:
 Have Higher severity scores
 More frequent surgery
 Require adjuvant medical Rx.
 Have higher incidence of tracheal dz.
 Require tracheotomy
 Develop pulmonary dz.
HPV Sub-Typing
Digene®
 The Digene® HPV Test*, using Hybrid Capture® 2 (hc2)
technology, is the only FDA–approved HPV DNA test
and collectively detects the 13 clinically–relevant high–
risk HPV types.
 The Digene HPV Test is a signal–amplified, nucleic acid
test that provides standardized, objective results upon
which healthcare providers may rely on to accurately
assess patient risk for cervical intraepithelial neoplasia
(CIN) and cancer.
 The Digene HPV Test is the only FDA–approved HPV
test for:
 Primary screening, in conjunction with a Pap, of
women age 30 years and older; and
 Triage of women of any age with ASC–US Pap
results.
HPV Sub-Typing
Digene® HPV Test
 High–risk type
 Low-risk type
 16,18,31,33,35,39,45,  6,11,42,43,44
51,52,56,58,59,68
AMPLICOR® HPV test
Roche Diagnostics
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PCR- based HPV screening test
Identifies 13 high risk types
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)
HPV types, and HPV types involved in carcinogenesis
(such as types 16 and 18) are termed high-risk (HR)
HPV types.
 Comparison of Two Commercial Assays for Detection
of Human Papillomavirus (HPV) in Cervical Scrape
Specimens 2005 Maaike A. P. C. van Ham et al.
Journal of Clinical Microbiology, June 2005, p. 26622667
Linear Array Kit
Roche Diagnostics
 PCR-based linear array HPV product
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 Amplification of target DNA by PCR and
Hybridization techniques
The linear array identifies 37 HPV genotypes,
including all high- and low-risk genotypes.
Provides specific subtype (genotype)
information
Currently available as research tool only
Insurance reimbursement issues
Plan is to make commercially available in the
future (2007?)This is what we are waiting for!
Celebrex
 Study funded by NIH.
 DSMB group established with first meeting in
September.
 IND being prepared for FDA Awaiting word from Pfizer
for inclusion of children in the protocol
 Celebrex has been approved for use in children >2 years
with rheumatoid arthritis (protocol will allow children >4
years)
 Pilot data: 3/3 patients have achieved remission in 3, 6
and 9 months with 1 year of follow-up. All 3 had severe
disease and one had tracheal involvement!