This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the effectiveness and safety of imiquimod for the treatment of anogenital warts in non-immunocompromised adults.
Description of the condition
Human papillomavirus (HPV) is an nonenveloped, double-stranded DNA virus with an 8 kbp-long genome, comprised of eight Open Reading Frames that encodes early and late genes involved in the expression of nonstructural (Early: E1, E2, E5, E6 and E7) and structural (Late: L1 and L2) proteins during the viral life cycle. HPVs are classified as “types” on the basis of their genetic similarities (Grillo 2008). Currently, 180 different HPV types have been classified, approximately 30 of which have been found to infect genital epithelium. They are named “oncogenic” or “high risk” when they are associated with genital cancers (e.g. HPV 16, 18, 31-37). The other types are named “non-oncogenic” or “low risk” and they are associated with genital warts (HPV 6 and 11) (Wiley 2002).
HPV specifically infects and replicates in the lower levels of stratified epithelium. The spectrum of the infection includes the acquisition of the virus without pathological changes at the cellular level to Intraepithelial Neoplasia(Mayeaux 2008). Dysplastic changes begin with minor cytological changes such as koilocytes and warts to malignant changes. The natural history of disease goes from spontaneous clearance of the virus, a few months after acquisition, to the development of carcinoma of the genital tract (Wiley 2002). In genital warts, no studies specifically show the time and the percentage of virus clearance from lesions.
It is estimated that up to 75% of sexually active adults have been exposed to the virus (as detected by HPV antibodies) and around 15% to 20% carry the virus (detected as HPV DNA by polymerase chain reaction) (Garland 2002). An estimated 1% of sexually active adults have genital warts (Weinstock 2004). The incidence of genital HPV infections decreases with age, thus detection of HPV infection among older women is more likely to reflect persistent infection, whereas detection among younger women more often represents recently acquired and probably transient infection (Ho 1998).
Anogenital warts (AGW) occur on the penis, scrotum, vagina, vulva, anus and perineal areas and inguinal folds; areas that are traumatized during intercourse. Condylomas may be solitary but generally comprise from five to more than 15 lesions of 1 mm to 10 mm diameter. Warts may coalesce into large plaques (von Krogh 2000). The warts can be macular or flat, keratotic, pedunculated, and acuminate or cauliflower-shaped. Symptoms may include inflammation, pain, fissuring, itching, bleeding, or dyspareunia (von Krogh 2000). Diagnoses of AGW are primarily clinical (Garland 2002) and visual examination supported by a magnifying glass if it is necessary; this is the only recommended test for diagnosis and cure evaluation (Maw 2000). The acetic acid test is not a specific test for HPV infection and it should not be used for screening; nor is a biopsy, with or without viral typing, recommended for patients with typical lesions (Kodner 2004; Mayeaux 2008) because it doesn't modify the treatment of the condition (von Krogh 2000).
The differential diagnosis includes pearly penile papules and vulvars papillomatosis (normal variants), condyloma latum, seborrhoeic keratoses, dysplastic and benign nevi, molluscum contagiosum, and neoplasms (Mayeaux 2008).
Description of the intervention
Although 30% of AGW spontaneously regress without treatment, there is no way to determine whether a specific lesion will regress, remain unchanged, or increase in size (Berman 2012). Treatment should be offered to all patients with AGW.
There are several treatments available for the management of genital warts. The treatment aims to reduce symptoms and visible lesions, but doesn't eliminate HPV infection directly. Therapies such as interferon (IFN) and imiquimod treat the infection by stimulating immune responses (Dockrell 2001); the catechins has been involved in the regression of genital warts through the cell cycle arrest, apoptosis induction and the inhibition of HPV gene expression (Stockfleth 2012). In addition, cidofovir, an acyclic nucleoside phosphonate, directly affects viral replication and has been tested for treatment of HPV lesions (Ho 1998).
Treatment should be guided by the morphology, size, number and localization of the wart (Kodner 2004). Treatments are divided into provider and patient-applied therapy groups. Also, there are surgical and medical managements. Surgical treatments include electrosurgery, surgical excision, cryotherapy, and laser surgery. Nonsurgical therapies, such as podophylin resin, IFN, and bi- and tri-chloroacetic acid (BCA, TCA) can be provider-applied. Patient-applied medications include podophyllotoxin, imiquimod, catechins and 5-fluorouracil (5-FU) cream (Ho 1998) (Workowski 2010). Imiquimod is indicated for the treatment of external AGW, superficial basal cell carcinoma and actinic keratoses (Wagstaff 2007). It has potential to treat other human papillomavirus associated conditions such as flat warts, plantar warts and common warts (verruca vulgaris) (Marini 2002).
Imiquimod is used topically in cream with concentrations from 1% to 5%, by application daily or three times per week for 8 to 16 weeks. Patients must be advised to wash the affected area with soap and water 6 to 10 hours after the application (Garland 2002; Weinstock 2004). Systemic absorption is minimal (Miller 1999). The drug is retained in the skin for prolonged periods, resulting in an elimination half-life of one day. Imiquimod and its active metabolites (S26704 and S27700) are excreted in urine and feces (Wagstaff 2007).
The application of imiquimod could to produce local skin reactions; the most frequent ones are local pruritus, erythema, excoriation or flaking, erosion, edema, and scabbing or crusting. Systemic events are rare and include headache, fatigue, myalgia and nausea. Other adverse events are decreases in hemoglobin, white blood cells and platelets. Reactions have been reported in skin at distant sites, such as erythema multiform, Steven Johnson syndrome and cutaneous lupus erythematosus (Wagstaff 2007).
How the intervention might work
Imiquimod is a novel synthetic imidazoquinolines(1-[2-methylpropyl]-1H-imidazo[4,5-c]quinolin-4-amine) (Marini 2002). HPV is non-cytolytic, has no systemic phase and its replication is not accompanied by inflammation (Garland 2002) with the consequent evasion of antigen presentation, delaying the immune system activation. The clinical efficacy of topical imiquimod is secondary to the stimulation of both innate and cell-mediated immune responses to tumor and viral antigens. The monocytes, keratinocytes, Langerhan’s cells and T-lymphocytes are stimulated to produce cytokines (INF-α and IL 1, 6, 8, 10 and 12); also B-lymphocytes proliferate to produce immunoglobulins (Dockrell 2001). This drug produce inhibition of associated pathological angiogenesis via stimulated apoptosis (Buck 1998; Schon 2007).
In the US and Europe, Imiquimod is indicated for external genital and perianal warts treatment and its efficacy in immunocompetent patients has been assessed in several studies. Complete clearance of the warts occurred in 40% to 70% of imiquimod recipients after three-times weekly or daily administration for 8 to 16 weeks. Imiquimod has also been used in superficial basal cell carcinoma, demonstrating superiority to placebo, with complete resolution of lesions in 79% to 87% of patients (Wagstaff 2007).
Why it is important to do this review
Currently, the available therapies for treating AGW include a wide range of therapeutic options. The selection of therapy is based on the experience of the healthcare provider, patient preference, cost of treatment, adverse effects and the feasibility of a given procedure (Maw 2004), in addition to the absence of definitive evidence which suggests that any of the therapies are superior to any other (Workowski 2010).
Traditionally, patient-applied treatment, such as Podofilox and Catechins (green tea), is frequently associated with local reactions like irritation, induration, erosion, pruritus, pain and edema. Provider-administered treatments (Podophyllin resin, BCA, TCA, cryotherapy and surgical removal) require substantial clinical training, additional equipment, local or general anesthesia and longer office visits with some risk of systemic absorption and toxicity(Workowski 2010), all of which limit applicability in clinical practice.
Currently, there are no systematic reviews comparing the effectiveness and safety of imiquimod with other available therapies for treating anogenital warts in non-immunocompromised adults. Imiquimod could offer the advantages of patient-applied therapies with a low local reaction rate, without incurring the limitations of provider-administered treatments. All this makes it necessary to assess the effectiveness and safety of imiquimod for treating anogenital warts in non-immunocompromised adults.
To assess the effectiveness and safety of imiquimod for the treatment of anogenital warts in non-immunocompromised adults.
Criteria for considering studies for this review
Types of studies
We will include all published and unpublished randomized clinical trials, where the majority of participants used imiquimod as first line therapy compared with placebo, expectant management, any other patient-applied treatment or any other provider-administered therapy for the treatment of anogenital warts in non-immunocompromised adults. We will not include quasi-randomized or cross-over trials.
Types of participants
We will include men and nonpregnant women with immunocompetence over 16 years of age who have been clinically diagnosed with anogenital warts regardless of biopsy confirmation. We will not include participants without clinically visible lesions.
Types of interventions
Imiquimod (any concentration, frequency, and duration of treatment) versus placebo.
Imiquimod (any concentration, frequency, and duration of treatment) versus expectant management.
Imiquimod (any concentration, frequency, and duration of treatment) versus any other patient-applied treatment (any concentration, frequency, and duration of treatment) (such as Podofilox and Catechins).
Imiquimod (any concentration, frequency, and duration of treatment) versus any other provider-administered treatment (any concentration, frequency, and duration of treatment) (such as podophyllin resin, TCA, BCA, cryotherapy and surgical removal).
We will not include interferon and 5-fluorouracil in order to avoid overlapping with other Cochrane Collaboration systematic reviews.
Types of outcome measures
1. Complete regression after treatment.
2. Partial regression after treatment.
3. Dyspareunia after treatment.
1. Time to complete regression.
2. Relief of symptoms during treatment.
3. Recurrence during follow-up (from 0 to 6 and from 6 to 12 months)
4. Appearance of new warts during treatment.
5. Excessive scarring at application site.
6. Time to resumption of intercourse.
7. Pain during therapy.
8. Pigmentary changes at application site.
9. Any local reactions during therapy (erythema, irritation, ulceration, erosion, edema, flaking, induration).
10. Any systemic reactions during therapy (headache, fatigue, myalgia, nausea, decrease of hemoglobin or white blood cells or platelets, erythema multiform, Steven Johnson syndrome or cutaneous lupus erythematosus).
11. Requirement of any additional patient-applied or provider-administered treatment at the end of the therapy.
12. Patient's satisfaction with treatment.
13. Cost effectiveness of intervention.
Search methods for identification of studies
We will attempt to identify as much relevant Randomized Controlled Trials (RCTs) as possible of “imiquimod” for “anogenital warts”, irrespective of their language of publication, publication date and publication status (published, unpublished, in press, and in progress). We will use both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will contact with the Trials Search Coordinator (TSC) of the Sexually Transmitted Infections Cochrane Review Group in order to implement a comprehensive search strategy to capture as many relevant RCTs as possible in electronic databases. For this purpose, we will use a combination of controlled vocabulary (MeSH, Emtree, DeCS, including exploded terms) and free-text terms (considering spelling variants, synonyms, acronyms and truncation) for “anogenital warts” and “imiquimod”, with field labels, proximity operators and boolean operators. The search strategies can be found in Appendix 1 (Electronic search strategies).
Specifically, we will search in the following electronic databases:
- MEDLINE®, Ovid platform (1946 to present).
- MEDLINE® In-Process & Other Non-Indexed Citations, Ovid platform (1946 to present).
- MEDLINE® Daily Update, Ovid platform (1946 to present).
- EMBASE.com (1947 to present).
- The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to present).
- LILACS, IAHx interface (1982 to present).
We will use for MEDLINE, Cochrane highly sensitive search strategy for identifying RCTs: sensitivity and precision maximizing version (2008 revision), Ovid format (Higgins 2011). The LILACS search strategy will be combined with RCTs filter of IAHx interface.
These searches will be updated within 6 months before publication of the review.
Searching other resources
We will attempt to identify additional relevant RCTs by using of the following methods:
1. Searching in the Sexually Transmitted Infections Cochrane Review Group’s Specialized Register, which includes RCTs and controlled clinical trials, from 1944 to 2008, located through electronic searching (MEDLINE, EMBASE and CENTRAL) and handsearching.
2. Searching in trials registers:
- WHO International Clinical Trials Registry Platform ICTRP portal (http://apps.who.int/trialsearch/).
- ClinicalTrials.gov (http://clinicaltrials.gov/).
3. Searching in Web of Science® (2001 to present).
4. Searching for grey literature in System for Information on Grey Literature in Europe “OpenGrey” (http://www.opengrey.eu/): 1990, 1992, 1995, 1996 and 1997.
5. Searching by contacting with authors of all RCTs identified by others methods.
6. Searching by contacting with pharmaceutical companies producing “imiquimod” for “anogenital warts”.
7. Handsearching in the following journals: Anatolian Journal of Obstetrics & Gynecology, Current Medical Literature Gynecology & Obstetrics, Current Obstetrics and Gynecology Reports, ISRN Obstetrics and Gynecology, Journal of South Asian Federation of Obstetrics & Gynecology, Obstetrics and Gynecology International, Obstetrics Gynaecology and Reproductive Medicine, Sexual Science: the newsletter of the Society for the Scientific Study of Sexuality and Sexualities.
8. Handsearching of conference proceeding abstracts in the following events:
- The International Society for Sexually Transmitted Diseases Research (ISSTDR) (http://www.isstdr.org/): 2007, 2009 and 2011.
- The British Association for Sexual Health and HIV (BASHH) (http://www.bashh.org/): 2004, 2006, 2007 and 2009.
- International Congress on Infectious Diseases (ICID) (http://www.isid.org/): 2010 and 2012.
- The International Union against Sexually Transmitted Infections (IUSTI) (http://www.iusti.org/): 2011 and 2012.
- International Society for Infectious Diseases (ISID) (http://www.isid.org/): 2011.
- International Meeting on Emerging Diseases and Surveillance (IMED) (http://www.isid.org/): 2007, 2009 and 2011.
- Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (http://www.icaac.org/): 2011 and 2012.
- The International Federation of Gynecology and Obstetrics (FIGO) (http://www.figo2012.org/home/): 2012.
9. Handsearching within previous systematic reviews and other relevant publications on the same topic.
10. Handsearching within reference lists of all RCTs identified by others methods.
Data collection and analysis
Selection of studies
Two review authors will independently assess for inclusion all the titles and abstracts of records retrieved from the search strategy. The final selection of studies to be included into the review will be undertaken independently by two of the review authors and any disagreements will be resolved through discussion or, if required, a third author will be consulted.
Data extraction and management
We will design a form to extract data. For eligible studies, two authors will extract the data independently using the agreed form; those authors will be area and methodology experts. Any disagreement about extracted data will be resolved through discussion or, if required, we will consult a third author. If this is unsuccessful, the discrepancies will be reported in the review.
We will extract data on the following:
location of the study and setting;
power calculation performed;
inclusion and exclusion criteria;
baseline information of the participants in order to have comparable intervention groups at entry (number of women, number of men, site, size, number and shape of lesions, number of participants who received imiquimod as first line therapy or as second line therapy);
total number of intervention groups;
types of interventions: imiquimod any concentration, frequency, and duration of treatment;
types of comparison: Any patient-applied treatment (any concentration, frequency, and duration of treatment) or any other provider-administered treatment (any concentration, frequency, and duration of treatment);
methods used to generate random allocation;
methods used to maintain allocation concealment;
number of subjects enrolled, randomized, excluded after randomization, and analyzed;
use of any method of blinding of the researchers or patients in order to evaluate outcomes;
adherence to the planned intervention and other interventions in the groups under evaluation;
number of participants lost to follow up in the groups;
outcomes stated in methods versus outcomes reported in results;
how secondary outcomes were deﬁned;
differences between groups for outcome assessment;
time of follow-up of participants to measure outcomes;
how adverse event reports were validated;
use of intention-to-treat analysis;
funding sources, reported;
ethical issues: use of signed informed consent and ethics approval.
We will enter data into Review Manager (RevMan) and check them for accuracy. When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to ask for further details. For a single randomized controlled clinical trial report, we will extract data directly onto a data collection form and in case of multiple reports, we will extract data from each report separately, then we will combine information across data collection forms.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by consensus or by involving a third assessor. Those assessing risk of bias will be theme and methodology experts. For collecting missing information, we will contact the study investigators using open ended questions.
(1) Random sequence generation (checking for possible selection bias)
We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the method as:
low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number); or
unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess methods used to blind outcome assessment as:
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.
We will assess methods as:
low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
unclear risk of bias.
We will use a cut-off point of 20% to consider that a study is at low or high risk of bias according to the level of missing data.
(5) Selective reporting (checking for reporting bias)
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We will assess the methods as:
low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We will describe for each included study any important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis'.
We will use the GRADE approach in order to produce a Summary of Findings Table (Higgins 2011). We will downgrade the quality of evidence depending on the presence of the following factors:
1. study limitations;
2. inconsistency of results;
3. indirectness of evidence;
5. publication bias.
Measures of treatment effect
For dichotomous data, we will present results as summary risk ratio (RR) with 95% confidence intervals (CI). The RR as a relative effect measure has consistency, works well with a low or high rate of events, and it is easy to interpret and use in clinical practice.
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardized mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Where a clinical trial is identified that randomized participants to several intervention groups, we will determine which intervention groups are relevant. To avoid confusion for the reader, we will include all intervention groups of the study in the table of “Characteristics of Included Studies” in the notes cell, providing a detailed description only of the intervention groups relevant to the review, and only these groups will be used in analyses.
Finally, in order to overcome a unit-of-analysis error for a study that could contribute multiple, correlated comparisons, we will combine all relevant experimental intervention groups of the studies into a single group and also combine all relevant control intervention groups into a single control group, in order to create a single pair-wise comparison (Higgins 2011). We will explore the approach to including a study with multiple intervention groups through undertaking sensitivity analyses - see 'Sensitivity analysis'.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effects by using sensitivity analysis.
For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomized to each group in the analyses, and all participants will be analyzed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomized minus any participants whose outcomes are known to be missing. We will contact the study investigators in order to obtain the missing data.
Assessment of heterogeneity
We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 40% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.
Assessment of reporting biases
If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by (Egger 1997), and for dichotomous outcomes we will use the test proposed by (Harbord 2006). If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.
We will carry out statistical analysis using Review Manager (RevMan). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful we will not combine trials.
If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
We will explore the following potential sources of heterogeneity using subgroup analyses:
Concentration of imiquimod (less than 5%; 5% or more).
Duration of therapy (less than 8 weeks; 8 or more weeks).
Times per week (Once daily; any other frequency per week).
Lesion site (perineal or perianal skin).
Sex of the patient.
Severity of the disease (Area major or minor of 1cm2).
The following outcomes will be used in subgroup analysis:
Complete regression after treatment.
Partial regression at the end of the treatment.
Dyspareunia after treatment.
For fixed-effect inverse variance meta-analyses we will assess differences between subgroups by interaction tests. For random-effects and fixed-effect meta-analyses using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.
We plan to perform sensitivity analyses for aspects of the review that might have affected the results, for example, where there was risk of bias associated with the quality of some of the included trials, the approach used to include a study with multiple intervention groups (combining groups to create a single pair-wise comparison versus splitting the "share" group into two or more groups), or the inclusion of studies with patients that had been previously treated. We also plan to carry out sensitivity analysis to explore inclusion of the effects of ﬁxed-effect or random-effects analysis for outcomes with statistical heterogeneity.
Dr. Martinez-Velasquez MY revised the first draft of the protocol providing a clinical perspective.
Dr. Salazar LC contributed to organizing the references and commented on the first draft protocol.
Appendix 1. Electronic search strategies
MEDLINE and CENTRAL (Ovid platform)
1 exp Condylomata Acuminata/
5 exp Warts/
9 (papilloma adj5 virus).tw.
13 randomized controlled trial.pt.
14 controlled clinical trial.pt.
17 clinical trials as topic.sh.
21 exp animals/ not humans.sh.
22 20 not 21
23 11 and 12 and 22
Note: the CENTRAL search strategy doesn’t include the terms #13 - #22.
#1.1 'condyloma acuminatum'/exp
#1.5 'condyloma latum'/exp
#1.6 'verruca vulgaris'/exp
#1.9 'wart virus'/exp
#1.11 (papilloma NEAR/5 virus):ab,ti
#1.13 #1.1 OR #1.2 OR #1.3 OR #1.4 OR #1.5 OR #1.6 OR #1.7 OR #1.8 OR #1.9 OR #1.10 OR #1.11 OR #1.12
#1.16 #1.14 OR #1.15
#1.17 'randomized controlled trial'/exp
#1.18 'single blind procedure'/exp
#1.19 'double blind procedure'/exp
#1.20 'crossover procedure'/exp
#1.21 #1.17 OR #1.18 OR #1.19 OR #1.20
#1.26 'cross over':ab,ti
#1.28 (doubl* NEXT/1 blind*):ab,ti
#1.29 #1.22 OR #1.23 OR #1.24 OR #1.25 OR #1.26 OR #1.27 OR #1.28
#1.30 #1.21 OR #1.29
#1.32 'animal experiment'/de
#1.34 #1.31 OR #1.32 OR #1.33
#1.36 #1.34 AND #1.35
#1.37 #1.34 NOT #1.36
#1.38 #1.30 NOT #1.37
#1.39 #1.13 AND #1.16 AND #1.38 AND [embase]/lim
Sexually Transmitted Infections Cochrane Review Group’s Specialized Register
Using the terms “imiquimod” and “wart” in title, abstract and keywords.
Contributions of authors
Grillo-Ardila CF conceived and will coordinate the review, contributed to writing the first draft of the protocol, provided a methodological and clinical perspective. Gaitán-Duarte HG commented on and revised the first draft of the protocol providing a methodological and clinical perspective. Angel-Muller E contributed to writing, commented on and revised the first draft of the protocol providing a clinical perspective. Ruiz-Parra AI commented on and revised the first draft of the protocol providing a methodological and clinical perspective. Lethaby A commented on and revised the first draft of the protocol providing a methodological perspective.
Declarations of interest
None known. None of review authors have studies that might potentially be included in this review.