Interferon for anogenital warts in non‐immunocompromised adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and safety of interferon for the treatment of anogenital warts in non‐immunocompromised adults.
Background
Description of the condition
Epidemiology
Anogenital warts are now the most common viral sexually transmitted disease in developed countries (George 2001). In a large study of privately insured individuals, anogenital warts were present in 1.7 cases per 1000 person‐years, with the highest prevalence occurring among women aged 20 to 24 years (6.2 cases per 1000 person‐years) and men aged 25 to 29 years (5.0 cases per 1000 person‐years) (Insinga 2003). In the United States, 5.6% of sexually active 18‐ to 59‐year olds reported that they had been diagnosed with anogenital warts between 1999 and 2004 (Dinh 2008). Anogenital warts can occur in bisexual, heterosexual, and homosexual men and women. Some studies report that the prevalence of anogenital warts is similar among men and women (Koshiol 2004; Insinga 2005), whereas other studies have found that women are more likely to have warts (Dinh 2008). The annual direct healthcare costs of anogenital warts in the United States are estimated to be US$200 million, with the average cost of an individual episode being US$436 (Insinga 2005).
Pathology and transmission
Anogenital warts are caused by human papillomaviruses (HPV). More than 120 HPV subtypes have been identified, of which more than 40 subtypes are specific to the anogenital tract. More than 90% of anogenital warts are caused by low‐risk HPV subtypes 6 and 11 (Brown 1999; Lacey 2006; Goon 2008). HPV is most commonly transmitted during sexual contact (Oriel 1971) when the virus penetrates the skin and mucosal surfaces through microscopic abrasions. However, the virus can also be transmitted by nonsexual contact such as hand‐genital transmission and sharing towels (Obalek 1990). There is no evidence that transmission can occur via fomites (Ferenczy 1989; Bergeron 1990).
HPV infects the basal layer of epithelial cells. Most infections stay subclinical or latent for months or years until the virus replicates in dividing epithelial cells to produce anogenital warts (Mayeaux 2008). The cell‐mediated immune response causes HPV containment and lesion regression (Coleman 1994). HPV infection could induce a local immune deficiency manifested by depletion of intraepithelial lymphocytes, langerhans cells, and CD4+ cells, as well as down regulation of cytokine production (Arany 1993). Immunocompromised patients, especially those with cell‐mediated immune deficits, have a higher prevalence of HPV‐related diseases and are more likely to have large, multifocal, and dysplastic lesions (Mayeaux 2008).
Anogenital warts tend to recur because of the presence of HPV deoxyribonucleic acid (DNA) sequences in the apparently normal surrounding tissue (Ferenczy 1985; Eron 1986). Risk factors for contracting anogenital warts include first intercourse at an early age, a large number of sexual partners, a high level of sexual hormones, and multiple pregnancies.
Symptoms and signs
Anogenital warts tend to occur on the vulva (most frequently), vagina, cervix, penis, scrotum, and perianal area. Warts may also be found within the rectum or mouth of individuals having anal or oral sex. Although commonly asymptomatic, the most frequent symptoms of HPV infection include pruritus, burning, pain, bleeding, odour, tenesmus, and pain during intercourse. On physical examination, warts usually have a classic cauliflower‐like appearance. Other common forms include flat‐topped papules, dome‐shaped papules, and keratotic warts. The lesions, which range in color from skin‐colour to pink, may vary in size from small nodules that are invisible to the naked eye to large cauliflower‐like masses. Single or multiple warts may be present, and some may even spread into large masses.
Diagnosis
Anogenital warts can usually be identified by their characteristic macroscopic appearance. A biopsy should be taken when the lesion is atypical. Colposcopy and a vaginal speculum can be used to identify lesions on the cervix or inside the vagina. Anoscopy and proctosigmoidoscopy are helpful for identifying internal lesions, especially in homosexual men. The polymerase chain reaction (PCR) technique could also be used to detect HPV DNA.
Treatment
The treatment regimens for external anogenital warts recommended by the United States Centers for Disease Control and Prevention in 2006 encompass patient‐applied therapies, such as podofilox and imiquimod, and provider‐administered therapies such as trichloroacetic or bichloracetic acid, surgical excision, loop electrosurgical excision, cryotherapy, and podophyllin (Mayeaux 2008). Most treatments aim to remove the visible lesions or relieve the symptoms, but the therapeutic effects do not last long and the rate of recurrence is very high (Armstrong 1996).
Description of the intervention
Interferon, which is classified as interferon‐alpha, ‐beta, or ‐gamma depending on its antigenic specificity and molecular structure, can be used systemically, intralesionally, or topically (Eron 1986; Friedman‐Kien 1988; Horowitz 1989; Fleshner 1994; Congilosi 1995; Armstrong 1996; Monsonego 1996; Trizna 1998). However, the systemic route is generally believed to be ineffective because interferon induces host cells to produce antiviral protein only when it is concentrated in a local region. The usual dose of intralesional interferon is 1 to 2 million units (George 2001). The adverse effects of interferon mainly include flu‐like symptoms (fever, chills, myalgia, headache, fatigue, etc.) and hematological toxic effects (leukopenia, thrombocytopenia, etc.) (Stone 1990). The adverse effects are usually mild and well tolerated. It is not known whether interferon has teratogenic effects or is secreted into breast milk.
How the intervention might work
Interferon belongs to the large class of glycoproteins known as cytokines. It is induced and secreted in response to challenges by foreign agents such as viruses, parasites, and tumor cells, and is associated with antiviral, antiproliferative, and immunomodulatory activities (Friedman‐Kien 1988; Cardamakis 1995). Interferon augments the immune response by inhibiting viral replication, activating natural killer cells and macrophages, increasing antigen presentation to lymphocytes, and increasing the resistance of host cells to viral infection. However, interferon is not usually considered as a first line treatment for anogenital warts because of its inconsistent therapeutic effect. Interferon could enhance the effect of other treatments, such as surgery and laser ablation, by lowering the viral burden in the surrounding "normal" tissue and reducing the likelihood of recurrence.
Why it is important to do this review
Some trials have shown interferon to be significantly more effective than placebo in treating anogenital warts (Relakis 1996; Syed 1998), while others have demonstrated modest or variable efficacy (Eron 1986; Friedman‐Kien 1988; CIC Study Group 1993; Fleshner 1994). In one trial, interferon had no effect on external anogenital warts as a primary or an adjunct therapy (Wiley 2002). Many authors have advocated the use of interferon in combination with other therapeutic modalities for extensive and refractory anogenital warts, whereas others do not recommend it as a therapy (Wiley 2002). Therefore, we aim to determine the benefits and harms of using interferon to treat anogenital warts and the effect of factors, such as preparation method, route of administration, dosage, regimen, sex of the patient, and severity of disease, on patient outcomes.
Objectives
To assess the efficacy and safety of interferon for the treatment of anogenital warts in non‐immunocompromised adults.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs), in all languages, that examine the effect of using interferon to treat anogenital warts in non‐immunocompromised adults. We will exclude studies that are published only in abstract form and have insufficient information, and for which no further information can be procured from the authors.
Types of participants
We will include men and women without immune suppression who are over 16 years of age and have been diagnosed with anogenital warts. Trials that include participants who do not fulfil the inclusion criteria will be excluded from review.
Types of interventions
1. Interferon alone versus placebo
2. Interferon combined with another therapy versus the other therapy alone
3. Interferon versus another treatment
4. Comparisons of different formulations of interferon (dosage, route of administration, schedule, etc.)
Types of outcome measures
Primary outcomes
1. Rate of lesion regression: complete regression, partial regression
2. Rate of recurrence
3. Rate of appearance of new warts
Secondary outcomes
1. Time to response
2. Time to recurrence
3. Time to appearance of new warts
4. Relief of symptoms
5. HPV test result
6. Adverse effects: increased body temperature, weakness or fatigue, headache, fever, chills, leukopenia, malaise, dizziness, depression, hair thinning, erythema, pain and hardness at the injection site, neutropenia, etc.
Search methods for identification of studies
See the Cochrane Sexually Transmitted Diseases Group review methods. We will compile detailed search strategies in consultation with the Cochrane Sexually Transmitted Diseases Group's Trials Search Coordinator. The sensitivity of the search strategies will be improved by including key words from relevant trials that were not detected by earlier searches. Searches will be run with and without key words referring to study design. There will be no language or publication restrictions.
Terms related to the treatment (interferon): interferon and IFN.
Terms related to the disease (anogenital warts): wart; anogenital wart; genital wart; perianal wart; venereal wart; condylomata acuminata; moist papule; mucous papule; pointed condyloma; pointed wart; venereal wart; verruca acuminata; flat condyloma; and condyloma latum.
Electronic searches
We will search the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue); MEDLINE (January 1966 to present); EMBASE (January 1974 to present); and the Chinese Biomedical Database (CBM) (January 1976 to present). We will also search the BIOSIS databases and the Proceedings of the International Society of STD Research (ISSTDR) for conference proceedings.
Searching other resources
We will search the following trials registers: metaRegister of Controlled Trials; ClinicalTrials.gov; the National Research Register Archive; the National Institute for Health Research (NIHR); and the World Health Organization International Clinical Trials Registry Platform.
We will search the Internet using Google Scholar and Intute, and the reference lists of relevant trials and reviews will be handsearched. We will not ask the manufacturers of interferon drugs for any unpublished trial data because of the substantial bias this may introduce into the results.
Data collection and analysis
Selection of studies
Four reviewers (HC, JL, JF, and HL) will independently examine abstracts and titles from the initial search to identify studies that meet the inclusion criteria. The full text of any potentially eligible studies, as well as studies without abstracts, will be retrieved. One reviewer (HC) will conduct telephone interviews with the authors of Chinese articles to ensure that the included studies were RCTs, and will email the authors of other articles in cases where important information is missing. If the required information is not available, the article will be added to the 'Awaiting assessment' reference section. Trials reported in more than one publication will be included in the analysis only once. Reasons for excluding trials will be detailed in the 'Characteristics of excluded studies' table.
Data extraction and management
Data on study characteristics, including methods, study quality, participants, interventions, outcomes, and duration of follow up, will be extracted independently by three reviewers (HC, JL, and JF) . Any disagreements among reviewers will be resolved by discussion or by consulting the Cochrane Sexually Transmitted Diseases Group. The reviewers will be blinded to the authors and their institutions, the source of funding, and the acknowledgments of each article to reduce the likelihood of bias in the assessment. One reviewer (HC) will conduct a double data entry.
Assessment of risk of bias in included studies
Two reviewers (HC and HL) will independently assess the risk of bias for each study and report it in the 'Risk of bias table' according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). The 'Risk of bias' table consists of four domains: sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessors; and inclusion of all randomly assigned participants. The trials are scored as 'yes' for a low risk of bias, 'no' for a high risk of bias, and 'unclear' for an unclear or unknown risk of bias as follows.
• Generation of allocation sequence:
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Yes ‐ adequate sequence generation was reported using one of the following approaches: random‐number tables, computer‐generated random numbers, coin toss, or card shuffle;
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Unclear ‐ did not mention;
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No ‐ other method of allocation that appeared to be biased.
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•Allocation concealment:
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Yes ‐ adequate measures to conceal allocation, such as central randomization; serially numbered, opaque sealed envelopes; or another description that contained convincing elements of concealment;
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Unclear ‐ unclearly concealed trials in which the author did not report an allocation concealment approach;
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No ‐ inadequately concealed allocation with an approach that does not fall into one of the categories in 'adequate'.
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• Blinding:
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Blinding of patients (yes, no, or unclear);
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Blinding of caregivers (yes, no, or unclear);
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Blinding of outcome assessors (yes, no, or unclear).
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• Inclusion of all randomly assigned participants:
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Yes ‐ included all randomly assigned participants;
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Unclear ‐ did not mention;
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No ‐ did not include all randomly assigned participants.
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We will use the GRADE approach to evaluate the quality of evidence for outcomes. We will downgrade or upgrade the quality level of the studies depending on the presence of the following factors (Higgins 2008).
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Downgrade quality level for:
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limitations in study design and implementation (for example, whether the authors stated that the treated lesion was really a wart);
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indirectness of evidence;
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unexplained heterogeneity or inconsistency of results;
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imprecision of results;
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high probability of publication bias.
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Upgrade quality level when:
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there is a large magnitude of effect;
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when all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when the results show no effect;
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there is a dose‐response gradient.
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Disagreements among reviewers will be resolved by discussion or by consulting the Cochrane Sexually Transmitted Diseases Group. The reviewers will be blinded to the authors and their institutions, the source of funding, the acknowledgments, and the results of each article to reduce the likelihood of bias in the assessment.
Measures of treatment effect
We will compare outcome measures for binary data using risk ratios. For continuous data, we will use the mean difference. If continuous data have been reported using geometric means, we will combine the findings on a log scale and report the results on the original scale. We will report medians and ranges in tables only.
Unit of analysis issues
For cluster‐randomized trials, particular sources of bias will be considered. Depending on the information available, the effective sample size or inflated standard error method will be used to conduct a meta‐analysis. Sensitivity analyses will be performed to investigate the robustness of the conclusions.
For crossover trials, their suitability and particular sources of bias will be assessed. Paired analysis will be conducted.
For studies with more than two treatment groups, the relevant intervention groups will be determined. To avoid a unit‐of‐analysis error, groups will be combined to create a single pair‐wise comparison.
Dealing with missing data
We will try to contact the trial authors to retrieve any missing data. If the missing data are unavailable, we will impute them by assuming that the treatment produced a poor outcome. We will then perform sensitivity analyses to examine the potential impact of the missing data and discuss these results in the 'Discussion' section.
Assessment of heterogeneity
We will measure heterogeneity visually or using the I² statistic. If there is considerable heterogeneity, we will not perform a meta‐analysis.
Assessment of reporting biases
Potential bias will be tested using a funnel plot or another corrective analytical method, depending on the number of clinical trials included in the review.
Data synthesis
Where it is appropriate to pool data and heterogeneity is detected, we will use a random‐effects model to conduct a meta‐analysis.
Subgroup analysis and investigation of heterogeneity
We intend to explore the following potential sources of heterogeneity using subgroup analyses.
1. Route of interferon administration.
2. Dosage of interferon.
3. Regimen of interferon.
4. Type of interferon.
5. Method of preparing interferon.
6. Sex of the patient.
7. Lesion site.
8. Severity of the disease (for example, number of lesions).
The outcome measures will be discussed in relation to the above subgroups.
Sensitivity analysis
If necessary, trials with lower methodological quality will be excluded to examine their effect on the results. The effect of assuming poor outcomes for missing values will also be examined in a sensitivity analysis.
