Otolaryngology–Head and Neck Surgery (2007) 136, 863-869
LITERATURE REVIEW
Antiviral agents for the treatment of recurrent
respiratory papillomatosis: A systematic review
of the English-language literature
Neil K. Chadha, MB ChB(Hons), BSc(Hons), MRCS(Eng), DOHNS, and
Adrian L. James, MA, Torquay, Devon, United Kingdom; and Toronto, Ontario,
Canada
OBJECTIVE: To determine the efficacy of antiviral agents for
recurrent respiratory papillomatosis (RRP) in children and adults.
STUDY DESIGN: Systematic review to include randomized
controlled trials (RCTs), comparative studies (historical and/or
nonrandomized), case series, and case reports.
RESULTS: Twenty-six original studies were included (one casecontrol series, 21 noncomparative trials, four case reports, and no
RCTs). Meta-analysis was not possible. The antiviral modalities included acyclovir, ribavirin, intravenous cidofovir, and intralesional
cidofovir injections. The strongest evidence was for intralesional
cidofovir, with 17 studies including 158 patients. Of these, 90 patients
(57%) demonstrated complete resolution, 55 patients (35%) a partial
response, and 13 patients (8%) showed no improvement.
CONCLUSIONS: Insufficient evidence from controlled trials exists for reliable conclusions, but several series indicate intralesional
cidofovir may have some efficacy. A well-designed placebo-controlled, double-blinded, randomized controlled trial is needed.
SIGNIFICANCE: This study provides the background for future
study design and a comprehensive review of the available evidence.
© 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
R
ecurrent respiratory papillomatosis (RRP) is characterized by papillomatous growths of the airway predominantly affecting the larynx and trachea. It is the most
common benign laryngeal neoplasm in children1 and these
papillomata may cause life-threatening airway obstruction
From the Department of ENT Otolaryngology–Head and Neck Surgery, Torbay Hospital, Torquay (Dr Chadha) and the Department of Otolaryngology–Head and Neck Surgery, The Hospital for Sick Children,
Toronto (Dr James).
Presented at the Annual Meeting of the American Academy of Otolaryngology–Head and Neck Surgery, Toronto, ON, Canada, September 1720, 2006.
or voice change.2 Malignant transformation can also occur
in 3% to 5% of patients.3 RRP has a bi-modal age distribution,
commonly presenting in children below five years or in adults
in the third decade.4 Incidence in the US has been reported as
4.3 per 100,000 per year in children (“juvenile-onset RRP”)
and 1.8 per 100,000 in adults (“adult-onset RRP”).4
The condition is caused by the human papilloma virus
(HPV), a small, nonenveloped, 20-sided, capsid virus with
double-stranded circular DNA, also associated with skin
warts, genital condyloma, and cervical cancer in humans. Of
the 90-plus identified types of HPV,5 the two sub-types
causing the majority of RRP are HPV-6 and HPV-11.6 Type
11 appears to be the more virulent, associated with earlier
presentation, longer disease activity, higher mortality rate,
and more frequent malignant transformation.7 Co-infection
with other viruses has been demonstrated, including herpes
simplex virus, cytomegalovirus, and Epstein-Barr virus, and
can be predictive of an aggressive course.8 Transmission in
juvenile-onset RRP may be secondary to direct contact with
papillomata in an infected birth canal,9 and in adults through
activation of latent virus present from birth, or infection
through oral or sexual contact.10
RRP commonly presents with progressive hoarseness, stridor, and respiratory distress, and less often with a chronic
cough, recurrent pneumonia, failure to thrive, dyspnea, and
dysphagia.2 Diagnosis is made by visualization of the papilloReprint requests: Neil K. Chadha, Specialist Registrar in ENT Otolaryngology–Head and Neck Surgery, Torbay Hospital, Lawes Bridge, Torquay, Devon, UK TQ2 7AA.
E-mail address: [email protected].
0194-5998/$32.00 © 2007 American Academy of Otolaryngology–Head and Neck Surgery Foundation. All rights reserved.
doi:10.1016/j.otohns.2006.09.007
864
Otolaryngology–Head and Neck Surgery, Vol 136, No 6, June 2007
mata via flexible naso-laryngoscopy or direct laryngo-bronchoscopy, with biopsies useful for histologic confirmation and
exclusion of malignant transformation. A staging system has
been established based on area of involvement, severity, and
observed characteristics including the patient’s voice quality
and extent of any respiratory distress.11
Management of RRP usually involves repeated surgical
debulking of the papillomata, and affected children can
require several procedures over their lifetimes. As there is
no therapeutic regimen for eradicating HPV from the airway, the aims of treatment are to relieve airway obstruction,
improve voice quality, reduce the spread of the disease, and
facilitate remission.12 A number of therapies have been
proposed as adjunctive therapy to surgical debulking, such
as antiviral agents, ␣-interferon, indole 3-carbinol, retinoids, and photodynamic therapy. Antiviral agents for RRP
include systemic acyclovir, systemic ribavirin, and intralesional cidofovir. The mechanism of action of antivirals is
predominantly inhibition of viral nucleic acid synthesis, and
therefore direct action against HPV (or the other viruses
involved) is the likely mechanism for any antiviral therapy
efficacy. The usage of antiviral agents in humans has been
associated with nausea, vomiting, abdominal pain, acute
renal impairment, hepatitis, and neutropenia.13
Adjuvant antiviral therapy has been used in many centers
in the US and UK. A web-based survey of American Society of Pediatric Otolaryngology members found that 10% of
current RRP patients were receiving antiviral adjuvant therapy and 34 of 62 practices had tried using intralesional
cidofovir.14 A postal survey of the British Association of
Pediatric Otolaryngologists found that 10% of RRP patients
were receiving intralesional cidofovir.15 Although an RRP
is an uncommon condition, it carries significant morbidity
and any antiviral therapy with proven benefits could be
usefully applied to this population. The Cochrane review of
antivirals as adjuvant therapy in the treatment of RRP has
identified no randomized controlled trials.16 Consequently,
there is a need for a systematic review of other available
evidence, including any nonrandomized studies and caseseries to guide practice. The aim of this study is to perform
a systematic review of the literature and assess the current
evidence for the efficacy of antiviral agents in the management of RRP in children and adults.
rin,” “aciclovir,” and “acyclovir.” These terms were combined using Boolean operators. Reference lists from relevant articles including other reviews were searched and
leading experts in the field were contacted for information
on any relevant unpublished data. Pharmaceutical companies manufacturing relevant antiviral agents were contacted
to seek unpublished trial data. Searches were restricted to
the English language.
Inclusion Criteria
The included studies comprised peer-reviewed randomized
controlled trials (RCTs), comparative studies (historical
and/or nonrandomized), case series, and case reports. Only
human studies, on patients diagnosed with recurrent respiratory papillomatosis, using antiviral agents as sole or adjuvant treatment, were included. Studies of therapeutic
agents with antiviral properties but not themselves antiviral
agents (eg, ␣-interferon, vaccination, indole-3-carbinol)
were excluded.
Assessment of Quality
The evidence presented in the selected studies was categorized by level of evidence as defined by the Oxford Centre
for Evidence-Based Medicine (see Table 1).17 The appraisal
of case-series study quality was undertaken using the checklist developed by Young et al,18 giving a quality score (QS)
of zero to three.
Data Extraction and Analysis
Data were extracted from the included articles by the first
author, and confirmed independently by the second author,
using data forms and outcome measures developed a priori.
Descriptive statistics were extracted or calculated for outcomes (where possible), and a qualitative synthesis of the
results undertaken. Differences in the frequency of each
variable before and after treatment were calculated using
McNemar’s ␹2 test, with P ⬍ 0.05 considered statistically
Table 1
Designation of levels of evidence, adapted from the
Oxford Centre for Evidence-Based Medicine17
Level
Studies of a therapy
Search Strategy
1a
Original published studies on RRP and antivirals were identified by using a comprehensive search strategy in MEDLINE
(from 1966 to April 2006), EMBASE (from 1974 to April
2006), and the Cochrane Central Register of Controlled
Trials (CENTRAL) in Issue 4, 2006 of the Cochrane Library. The search terms used for RRP were “recurrent respiratory papilloma*,” “laryngeal papilloma*,” and “RRP.”
The search terms used for antivirals were “antiviral agents
[MeSH],” “antiviral*,” “anti-viral*,” “cidofovir,” “ribavi-
1b
1c
2a
2b
2c
3a
3b
4
5
Systematic review (SR) of randomized
controlled trials (RCTs)
Individual RCT
All-or-none study
SR of cohort studies
Individual cohort study
Outcomes research or ecological studies
SR of case-control studies
Individual case-control study
Case-series
Expert opinion
METHODS
Chadha and James
Antiviral agents for the treatment of recurrent . . .
significant. A meta-analysis was not possible due to the
design of the identified studies.
865
DISCUSSION
Evidence for Acyclovir
RESULTS
Twenty-six original studies met the inclusion criteria. These
studies were reviewed and their evidence level17 determined
(see Table 1). They comprised one case-control series, 21
case series or noncomparative trials, four case reports, and
no randomized controlled trials. The ages of the participants
were extracted from the studies and used to determine
ranges and means. The articles are summarized in Table 2.
For the studies using intralesional cidofovir the participants’ disease severity (using the RRP staging system developed by Derkay et al11), treatment regimen (including
total dosage, injection frequency, and length of treatment),
follow-up period, and outcomes are detailed in Table 3.
Combining the 17 studies of intralesional cidofovir gives a
total patient number of 158. Of these, 90 patients (57%)
demonstrated complete resolution of the disease in response
to the intralesional cidofovir (within the follow-up periods),
55 patients (35%) a partial response, and 13 patients (8%)
showed no improvement.
Efficacy. The activity of acyclovir is dependent on the presence of virally-encoded thymidine kinase. This enzyme is
known not to be encoded by papillomavirus, so any beneficial effects in RRP patients would likely be due to action
on co-infectors, including with herpes simplex type 1, cytomegalovirus, and Epstein-Barr virus.12 These co-infections are more common in those with clinically aggressive
RRP.8 Only three small case-series report the use of acyclovir as adjuvant treatment for RRP.41,42,44 In the caseseries by Kiroglu et al,41 12 patients with aggressive RRP
were treated with six months of daily oral acyclovir, and
nine of these patients were disease-free throughout followup, ranging from 14 to 25 months. The other three were said
to have taken the drug inadequately. Endres et al42 tried
acyclovir in seven patients with severe recalcitrant RRP,
and found five had improved after a short follow-up. The
study by Lopez Aguado et al44 included three patients,
treated with acyclovir postoperatively, who had no papilloma recurrence for between 18 and 42 months. The
lack of controlled studies severely limits the ability to
assess the efficacy of acyclovir.
Table 2
Summary of reviewed studies
Study and year
Naiman (2006)19
Dikkers (2005)20
Lee (2005)21
Co (2004)22
Mandell (2004)23
Peyton Shirley (2004)24
Naiman (2003)25
Chhetri (2003)26
Pransky (2003)27
Akst (2003)28
Milczuk (2003)29
El Hakim (2002)30
Bielamowicz (2002)31
Chhetri (2002)32
Armbruster (2001)33
Balauff (2001)34
Van Valckenborgh (2001)35
Pransky (2000)36
Wilson (2000)37
Dancey (2000)38
Pransky (1999)39
Snoeck (1998)40
Kiroglu (1994)41
Endres (1994)42
McGlennen (1993)43
Lopez Aguado (1991)44
Design
Case series
Case series
Case series
Case series
Case-control
series
Case series
Case series
Case series
Case series
Case series
Case series
Case series
Case series
Case series
Case report
Case report
Case report
Case series
Case series
Case report
Case series
Case series
Case series
Case series
Case series
Case series
Level of
evidence17
No. of
participants
4
4
4
4
3b
19
9
13
5
4 subjects
3 controls
11
26
5
1
11
4
2
13
5
1
1
1
5[*]
3
1
5
17
12
6
4
3
4
4
4
4
4
4
4
4
4
5
5
5
4
4
5
4
4
4
4
4
4
Mean age years
(range in
parentheses)
32 (22-44)
N/A (adults)
33 (9-68)
36 (30-43)
6 (1-14)
2 (1-3)
28 (5-56)
5 (1-11)
6
7 (2-14)
4 (3-7)
4 (3-5)
47 (19-85)
44 (21-62)
34
3
8
7 (6-10)
41 (30-63)
35
2 (1-3)
38 (11-77)
12 (3-25)
N/A
28 (2-49)
8 (5-11)
Antiviral used
Intralesional
Intralesional
Intralesional
Intralesional
Intralesional
cidofovir
cidofovir
cidofovir
cidofovir
cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intravenous cidofovir
Ribavirin
Intravenous cidofovir
Intralesional cidofovir
Intralesional cidofovir
Intravenous cidofovir
Intralesional cidofovir
Intralesional cidofovir
Acyclovir
Acyclovir
Ribavirin
Acyclovir
866
Otolaryngology–Head and Neck Surgery, Vol 136, No 6, June 2007
Table 3
Summary of reviewed studies on intralesional cidofovir for RRP
Mean value (range in parentheses)
Study
Naiman (2006)19
Dikkers (2005)20
Lee (2005)21
Co (2004)22
Mandell (2004)23
Peyton Shirley (2004)24
Naiman (2003)25
Chhetri (2003)26
Pransky (2003)27
Pransky (1999-2003)b,27,36,39
Akst (2003)28
Milczuk (2003)29
El Hakim (2002)30
Bielamo-wicz (2002)31
Chhetri (2002)32
Wilson (2000)37
Snoeck (1998)40
Follow-up
No. of Initial Derkay Total cidofovir Total injection Total therapy
dosage mg
number
period months period months
patients
score11
19
9
13
5
4
11
26a 16
10
5
1
10
11a 6
5
4
2
13
5
3
17
5 (1-14)
N/A
12 (8-15)
N/A
6 (3-8)
N/A
5 (2-14)
10 (2-33)
9 (3-16)
20
18c (N/A)
12 (8-20)
16 (8-25)
23 (0-53)
23 (21,25)
10 (2-29)
N/A
N/A
N/A
N/A
64 (11-128)
143 (40-284)
75 (45-113)
N/A
N/A
N/A
N/A
N/A
N/A
N/A (3-20)c
5.6 (1-15)
18.5 (10-30)
8.3 (2-15)
N/A
22.5 (3-4)
47 (38-57)
N/A (21-42)
17.9 (3-43)
5
9
4
5
4
6
4
6
13
(1-11)
(6-17)
(1-9)
(3-7)
(2-7)
(4-16)
(1-7)
(2-20)
(8-22)
⬎28
8 (4-13)c
4 (N/A)
8 (N/A)
6 (6-7)
3
6 (1-19)
7 (2-12)
N/A
7 (2-15)
N/A (1-47)
25 (8-54)
N/A
4 (2-6)
10 (4-18)
N/A
9 (N/A)
14 (N/A)
15 (8-29)
51
8 (3-14)c
4 (N/A)
4 (N/A)
8 (7-8)
2 (1-2)
13 (1-48)
12 (7-16)
N/A
5 (1-13)
24 (8-57)
20 (6-36)
25 (11-48)
N/A (2-10)
27 (N/A)
min. 24
9 (1-32)
7 (1-35)
15 (N/A)
51
40 (7-66)
N/A
N/A
33 (29-40)
12
N/A
12 (7-16)
N/A
16 (2-32)
a
data split by 2 differing treatment protocols.
3 publications following the same patients.
c
data available for 9 of 10 patients only.
b
Safety. The three studies on acyclovir for RRP describe no
adverse events in any of the 22 patients included, and
adverse effects of the drug are generally considered uncommon.
Evidence for Ribavirin
Efficacy. After animal studies demonstrated ribavirin inhibited the cutaneous warts in rabbits infected with cottontail
rabbit papillomavirus,45 oral ribavirin was trialed as an
adjunct to laser surgery for RRP by McGlennen et al.43 This
uncontrolled trial of four patients described complete remission after two months’ follow-up in two patients, and minimal recurrence in the other two after four months’ followup. A case report34 described a 5-year improvement in RRP
in a 3-year-old child after liver transplantation, who had
severe RRP resistant to other treatments which required
tracheostomy. Again, the lack of controlled studies severely
limits the ability to assess the efficacy of ribavirin.
Safety. All of McGlennen’s patients suffered a moderate or
severe decrease in hemoglobin with a reticulocytosis. Other
side effects included transient headache and fatigue.43
Evidence for Intralesional Cidofovir
Efficacy. Cidofovir has activity against a range of viruses
including cytomegalovirus, varicella zoster virus, herpes
simplex virus types 1 and 2, Epstein-Barr virus, adenovirus,
and HPV. There have been several uncontrolled series in
which intralesional cidofovir has been administered for
RRP.19-32,36,37,39,40 All except one of these studies were
uncontrolled, and they have used a variety of treatment
protocols. Mandell et al attempted a small-scale controlled
series, with four children treated and three controls.23 The
treatment group had two-monthly CO2 laser debulking procedures with injection of cidofovir into the center of affected areas (at a concentration of 5 mg/mL), on up to six
occasions. The controls were essentially treated the same,
but no injection (or placebo injection) was performed with
the laser debulking. The groups’ prestudy mean Derkay
scores were similar (controls: 6.8, cidofovir: 5.9; P value:
4.8), but final scores at 27 months were significantly different (controls: 5.2, cidofovir: 0.6; P value: 0.04). The study
validity was reduced, though, by the lack of randomization,
group demographic differences, lack of blinding, lack of
placebo, and very small sample size.
Across all the case series, treatment frequency varied
from two-weekly to two-monthly, total injection numbers
from one to 22, total treatment period from one to 54
months, and follow-up from two to 57 months. The median
treatment protocol would be intralesional injections of 2.5
to 5 mg/mL cidofovir, every two to four weeks, over a
12-month period. If the results of all the case-series are
combined to provide an estimate of the overall efficacy of
intralesional cidofovir in the 158 patients, 90 patients (57%)
Chadha and James
Antiviral agents for the treatment of recurrent . . .
867
Table 3
(continued)
No. of patients (% in parentheses)
Injection freq.
Every
Every
Every
Every
Every
Every
Every
Every
Every
N/A
Every
Every
Every
Every
Every
Every
Every
Every
Every
2-4 weeks
2-4 weeks
3 weeks
month
2 months
2 weeks
month
month
2 weeks
2-3 weeks
month
month
6-8 weeks
2 weeks
month
2-4 weeks
2-4 weeks
2-4 weeks
Resolved (Derkay score ⫽ 0)
17
7
10
0
3
3
6
2
1
1
5
6
3
1
0
13
0
3
9
(89)
(78)
(77)
(0)
(75)
(27)
(37)
(20)
(20)
(100)
(50)
(100)
(60)
(25)
(0)
(100)
(0)
(100)
(53)
demonstrated complete resolution, 55 patients (35%) a partial response, and 13 patients (8%) showed no improvement.
Although these results are promising, their uncontrolled
nature creates the potential for considerable bias and prevents analysis of the role of disease severity in response. In
many of these studies, other adjuvant therapies and a range
of surgical treatments were used, hindering the ability to
confidently attribute benefits to the cidofovir.
There is a need for a well-designed randomized controlled trial to further assess the potential efficacy of adjuvant intralesional cidofovir for RRP. One such trial was
attempted by the NIAID Collaborative Antiviral Study
Group in the late 1990s, but this effort was unsuccessful due
to poor accrual of patients.3 The study was further hindered
by FDA restrictions on the cidofovir concentration to 0.3
mg/mL, as opposed to the 5 mg/mL used in the majority of
the uncontrolled trials described above. As the condition is
relatively uncommon, it is likely that a multi-center randomized controlled trial will be required for adequate patient
numbers to obtain appropriate study power. Long term follow-up is necessary to sufficiently assess the impact of these
treatments and potential complications. A placebo-controlled,
double-blinded study should be possible. The Cochrane review
on the subject by Chadha et al16 provides the basis for an RCT
protocol, including appropriate outcome measures.
Safety. Intravenous cidofovir has previously shown nephrotoxicity with proteinuria, glucosuria, bicarbonaturia, poly-
Partial response
2
2
2
5
1
2
10
7
4
0
5
0
0
2
2
0
5
0
6
No response
(11)
(22)
(15)
(100)
(25)
(18)
(63)
(70)
(80)
(0)
(50)
(0)
(0)
(50)
(100)
(0)
(100)
(0)
(35)
0
0
1
0
0
6
0
1
0
0
0
0
2
1
0
0
0
0
2
(0)
(0)
(8)
(0)
(0)
(55)
(0)
(10)
(0)
(0)
(0)
(0)
(40)
(25)
(0)
(0)
(0)
(0)
(12)
uria, and increased serum creatinine.46 Renal function
returns to baseline after discontinuing cidofovir, and administration of probenecid decreases its clearance, leading to
reduction in nephrotoxicity.47 In a study of cidofovir plasma
levels after intralesional injections, Naiman et al48 demonstrated these remained below those expected to result in
toxicity. The levels were dose-dependent in children, but
not in adults where diffusion from the injected sites was
unpredictable. This led to the recommendation that intralesional cidofovir be used at less than the recommended
intravenous dose (5 mg/kg) to prevent any risk of systemic
toxicity. Rodent studies of subcutaneous cidofovir have
demonstrated that it has a carcinogenic potential in these
animals, causing mammary adenocarcinomas.49 The potential for carcinogenesis in humans is unknown. The MultiDisciplinary Task Force on RRP49 has recommended that until
more is known about the long-term safety of cidofovir in
humans, it should only be routinely used as adjuvant therapy in
those with moderate to severe RRP, not responding to surgery
alone. They also suggest the nephrotoxic and potential carcinogenic nature of the drug should be discussed in consenttaking and any adverse responses reported to the Task Force.
Evidence for Intravenous Cidofovir
Efficacy. Three case reports describe the use of intravenous cidofovir for RRP. One adult RRP patient, who had
previously undergone over 200 surgical procedures, had
868
Otolaryngology–Head and Neck Surgery, Vol 136, No 6, June 2007
complete remission, with 1-year follow-up, after two
months intravenous cidofovir combined with interferon
␣-2b.33 In another case a 12-month treatment regimen,
combined with surgery and indole-3-carbinol, saw improvement in a child with laryngeal, tracheal, and lung
papillomatosis.35 The third case described an adult with
laryngeal and lung papillomatosis who had 24 months of
intravenous cidofovir in combination with interferon
␣-2b and was considerably improved 18 months after
cessation.38 The lack of controlled studies, and use of
other agents, severely limits the ability to assess the
efficacy of intravenous cidofovir.
Safety. As described above, systemic cidofovir can be associated with nephrotoxicity requiring careful monitoring of
renal function during treatment. Neutropenia occurred in
one of the patients, requiring cessation of the co-administered interferon ␣-2b and a reduction in the dosage of
cidofovir.38
CONCLUSIONS
The most promising of the adjuvant antiviral therapies for
RRP is intralesional cidofovir, with several case series and
one case-controlled series demonstrating positive outcomes.
However, as case series do not provide a comparison group,
conclusions about treatment effects should be made cautiously. Interpretation is also limited by small population
sizes, lack of blinding, variations in disease severity, and
inconsistency of treatment protocols. There are also concerns about the safety of intralesional cidofovir, particularly
if used in concentrations that result in high plasma levels.
With current evidence, the guidelines for intralesional cidofovir usage recommended by the Multi-Disciplinary Task
Force on RRP49 seem very appropriate. Namely, it should
only be routinely used as adjuvant therapy in those with
moderate to severe RRP, not responding to surgery alone.
They also suggest the nephrotoxic and potential carcinogenic nature of the drug should be discussed in obtaining
informed consent.
A major role of case series and case reports is to generate
questions and theories for assessment by other methodologies. There is clearly a need for a well-designed placebocontrolled, double-blinded, randomized controlled trial assessing the efficacy of intralesional cidofovir therapy for
RRP. A power calculation for study size can be based on the
population data from the largest series available (standard
deviation of Derkay stage ⫽ 3.2)19 and the treatment effect
of the comparative trial (Derkay stage posttreatment minus
pretreatment difference ⫽ 3.7).23 To demonstrate a significant difference between intralesional cidofovir and placebo, the estimated sample size required is 34 (ie, 17 in each
group) (power ⫽ 90%; ␣ ⫽ 0.05; unpaired two-sample
Student t test). It is likely that a multi-center trial will be
required for adequate patient numbers to obtain appropriate
study power. A North American registry of patients with
RRP has been created,50 and this should assist identification
and recruitment of suitable patients. Long-term follow-up
will be required to sufficiently assess the impact of these
treatments and potential complications. This comprehensive
systemic review provides the background needed for future
study design.
REFERENCES
1. Morgan AH, Zitsch RP. Recurrent respiratory papillomatosis in children: a retrospective study of management and complications. Ear
Nose Throat J 1986;65(9):19 –28.
2. Derkay CS. Recurrent respiratory papillomatosis. Laryngoscope 2001;
111(1):57– 69.
3. Kimberlin DW. Current status of antiviral therapy for juvenile-onset
recurrent respiratory papillomatosis. Antiviral Res 2004;63(3):141–51.
4. Shykhon M, Kuo M, Pearman K. Recurrent respiratory papillomatosis.
Clin Otolaryngol Allied Sci 2002;27(4):237– 43.
5. Menzo S, Monachetti A, Trozzi C, et al. Identification of six putative
novel human papillomaviruses (HPV) and characterization of candidate HPV type 87. J Virol 2001;75(23):11913–9.
6. Corbitt G, Zarod AP, Arrand JR, et al. Human papillomavirus (HPV)
genotypes associated with laryngeal papilloma. J Clin Pathol 1988;
41(3):284 – 8.
7. Rabah R, Lancaster WD, Thomas R, et al. Human papillomavirus-11associated recurrent respiratory papillomatosis is more aggressive than
human papillomavirus-6-associated disease. Pediatr Dev Pathol 2001;
4(1):68 –72.
8. Pou AM, Rimell FL, Jordan JA, et al. Adult respiratory papillomatosis:
human papillomavirus type and viral coinfections as predictors of
prognosis. Ann Otol Rhinol Laryngol 1995;104(10 Pt 1):758 – 62.
9. Silverberg MJ, Thorsen P, Lindeberg H, et al. Condyloma in pregnancy is strongly predictive of juvenile-onset recurrent respiratory
papillomatosis. Obstet Gynecol 2003;101(4):645–52.
10. Kashima HK, Shah F, Lyles A, et al. A comparison of risk factors in
juvenile-onset and adult-onset recurrent respiratory papillomatosis.
Laryngoscope 1992;102(1):9 –13.
11. Derkay 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(6):935–7.
12. Derkay CS, Darrow DH. Recurrent respiratory papillomatosis. Ann
Otol Rhinol Laryngol 2006;115(1):1–11.
13. Mehta DK. British National Formulary. 46th Edition. British Medical
Association and Royal Pharmaceutical Society of Great Britain, London; September 2005.
14. Schraff S, Derkay CS, Burke B, et al. American Society of Pediatric
Otolaryngology members’ experience with recurrent respiratory papillomatosis and the use of adjuvant therapy. Arch Otolaryngol Head
Neck Surg 2004;130(9):1039 – 42.
15. Tasca RA, McCormick M, Clarke RW. British Association of Paediatric Otorhinolaryngology members experience with recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol 2006;70(7):
1183–7.
16. Chadha NK, James AL. Adjuvant antiviral therapy for recurrent
respiratory papillomatosis. Cochrane Database Syst Rev 2005(4):
CD005053.
17. Oxford Centre for Evidence-based Medicine. Levels of evidence. May
2001. http://www.cebm.net/levels_of_evidence.asp#levels (accessed
17/3/2006).
18. Young J, Fry-Smith A, Hyde C. Lung volume reduction surgery
(LVRS) for chronic obstructive pulmonary disease (COPD) with underlying severe emphysema. Thorax 1999;54(9):779 – 89.
Chadha and James
Antiviral agents for the treatment of recurrent . . .
19. Naiman AN, Abedipour D, Ayari S, et al. Natural history of adultonset laryngeal papillomatosis following multiple cidofovir injections.
Ann Otol Rhinol Laryngol 2006;115(3):175– 81.
20. Dikkers FG. Treatment of recurrent respiratory papillomatosis with
microsurgery in combination with intralesional cidofovir—a prospective study. Eur Arch Otorhinolaryngol 2006;263(5):440 –3.
21. Lee AS, Rosen CA. Efficacy of cidofovir injection for the treatment of
recurrent respiratory papillomatosis. J Voice 2004;18(4):551– 6.
22. Co J, Woo P. Serial office-based intralesional injection of cidofovir in
adult-onset recurrent respiratory papillomatosis. Ann Otol Rhinol
Laryngol 2004;113(11):859 – 62.
23. Mandell DL, Arjmand EM, Kay DJ, et al. Intralesional cidofovir for
pediatric recurrent respiratory papillomatosis. Arch Otolaryngol Head
Neck Surg 2004;130(11):1319 –23.
24. Peyton Shirley W, Wiatrak B. Is cidofovir a useful adjunctive therapy
for recurrent respiratory papillomatosis in children? Int J Pediatr Otorhinolaryngol 2004;68(4):413– 8.
25. Naiman AN, Ceruse P, Coulombeau B, et al. Intralesional cidofovir
and surgical excision for laryngeal papillomatosis. Laryngoscope
2003;113(12):2174 – 81.
26. Chhetri DK, Shapiro NL. A scheduled protocol for the treatment of
juvenile recurrent respiratory papillomatosis with intralesional cidofovir. Arch Otolaryngol Head Neck Surg 2003;129(10):1081–5.
27. Pransky SM, Albright JT, Magit AE. Long-term follow-up of pediatric
recurrent respiratory papillomatosis managed with intralesional cidofovir. Laryngoscope 2003;113(9):1583–7.
28. Akst LM, Lee W, Discolo C, et al. Stepped-dose protocol of cidofovir
therapy in recurrent respiratory papillomatosis in children. Arch Otolaryngol Head Neck Surg 2003;129(8):841– 6.
29. Milczuk HA. Intralesional cidofovir for the treatment of severe juvenile recurrent respiratory papillomatosis: long-term results in 4 children. Otolaryngol Head Neck Surg 2003;128(6):788 –94.
30. El Hakim H, Waddell AN, Crysdale WS. Observations on the early
results of treatment of recurrent respiratory papillomatosis using cidofovir. J Otolaryngol 2002;31(6):333–5.
31. Bielamowicz S, Villagomez V, Stager SV, et al. Intralesional cidofovir
therapy for laryngeal papilloma in an adult cohort. Laryngoscope
2002;112(4):696 –9.
32. Chhetri DK, Blumin JH, Shapiro NL, et al. Office-based treatment of
laryngeal papillomatosis with percutaneous injection of cidofovir. Otolaryngol Head Neck Surg 2002;126(6):642– 8.
33. Armbruster C, Kreuzer A, Vorbach H, et al. Successful treatment of
severe respiratory papillomatosis with intravenous cidofovir and interferon ␣-2b. Eur Respir J 2001;17(4):830 –1.
34. Balauff A, Sira J, Pearman K, et al. Successful ribavirin therapy for
life-threatening laryngeal papillomatosis post liver transplantation. Pediatr Transplant 2001;5(2):142– 4.
35. Van Valckenborgh I, Wellens W, De Boeck K, et al. Systemic cidofovir in papillomatosis. Clin Infect Dis 2001;32(3):E62– 4.
869
36. Pransky SM, Brewster DF, Magit AE, et al. Clinical update on 10
children treated with intralesional cidofovir injections for severe recurrent respiratory papillomatosis. Arch Otolaryngol Head Neck Surg
2000;126(10):1239 – 43.
37. Wilson WR, Hashemiyoon R, Hawrych A. Intralesional cidofovir for
recurrent laryngeal papillomas: preliminary report. Ear Nose Throat J
2000;79(4):236 – 8.240.
38. Dancey 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(4):1210 – 4.
39. Pransky SM, Magit AE, Kearns DB, et al. Intralesional cidofovir for
recurrent respiratory papillomatosis in children. Arch Otolaryngol
Head Neck Surg 1999;125(10):1143– 8.
40. Snoeck R, Wellens W, Desloovere C, et al. Treatment of severe
laryngeal papillomatosis with intralesional injections of cidofovir [(S)1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine]. J Med Virol
1998;54(3):219 –25.
41. Kiroglu M, Cetik F, Soylu L, et al. Acyclovir in the treatment of
recurrent respiratory papillomatosis: a preliminary report. Am J Otolaryngol 1994;15(3):212– 4.
42. Endres DR, Bauman NM, Burke D, et al. Acyclovir in the treatment of
recurrent respiratory papillomatosis. A pilot study. Ann Otol Rhinol
Laryngol 1994;103(4 Pt 1):301–5.
43. McGlennen RC, Adams GL, Lewis CM, Faras AJ, Ostrow RS. Pilot
trial of ribavirin for the treatment of laryngeal papillomatosis. Head
Neck 1993;15(6):504 –12; discussion 512–3.
44. Lopez Aguado D, Perez Pinero B, Betancor L, et al. Acyclovir in the
treatment of laryngeal papillomatosis. Int J Pediatr Otorhinolaryngol
1991;21(3):269 –74.
45. Ostrow RS, Forslund KM, McGlennen RC, et al. Ribavirin mitigates
wart growth in rabbits at early stages of infection with cottontail rabbit
papillomavirus. Antiviral Res 1992;17(2):99 –113.
46. Wachsman M, Petty BG, Cundy KC, et al. Pharmacokinetics, safety
and bioavailability of HPMPC (cidofovir) in human immunodeficiency virus–infected subjects. Antiviral Res 1996;29(2–3):
153– 61.
47. Cundy KC, Lynch G, Lee WA. Bioavailability and metabolism of
cidofovir following topical administration to rabbits. Antiviral Res
1997;35(2):113–22.
48. Naiman AN, Roger G, Gagnieu MC, et al. Cidofovir plasma assays
after local injection in respiratory papillomatosis. Laryngoscope 2004;
114(7):1151– 6.
49. Derkay C. Cidofovir for recurrent respiratory papillomatosis (RRP): a
re-assessment of risks. Int J Pediatr Otorhinolaryngol 2005;69(11):
1465–7.
50. Armstrong LR, Derkay CS, Reeves WC. Initial results from the national registry for juvenile-onset recurrent respiratory papillomatosis.
RRP Task Force. Arch Otolaryngol Head Neck Surg 1999;125(7):
743– 8.