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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

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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

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significant. A meta-analysis was not possible due to the design of the identified studies.

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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

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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%)

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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

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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.

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