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Human Papillomavirus Infection: Protocol for a Randomised Murray et al. BMC Medical Research Methodology (2018) 18:125 https://doi.org/10.1186/s12874-018-0581-z STUDY PROTOCOL Open Access Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial) Macey L. Murray1, Jade Meadows1, Caroline J. Doré1, Andrew J. Copas2, Lewis J. Haddow2, Charles Lacey3, Mark Jit4,5, Kate Soldan5, Kate Bennett1, Michelle Tetlow1, Mayura Nathan6 and Richard Gilson2* Abstract Background: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. Methods and design: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three- dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. Discussion: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. Trial registration: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013). Keywords: Podophyllotoxin, Imiquimod, Quadrivalent HPV vaccine, Human papillomavirus, Anogenital warts * Correspondence: [email protected] 2UCL Centre for Clinical Research in Infection and Sexual Health, The Mortimer Market Centre, Institute for Global Health, University College London, London WC1E 6JB, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Murray et al. BMC Medical Research Methodology (2018) 18:125 Page 2 of 9 Background most patients will have responded by 8 weeks. The The most effective and cost-effective treatment for pa- efficacy has been investigated in a number of trials tients with anogenital warts is unknown. Genital warts [11, 14–21]. are benign lesions which present as lumps or raised pla- The efficacies of podophyllotoxin and imiquimod as ques in the skin of the anogenital area. Usually painless, initial therapy for anogenital warts have never been but occasionally causing irritation or bleeding, they can compared in an adequately-powered trial [22]. The only be emotionally distressing, and often require prolonged, randomised trial comparing the two topical agents was time consuming and uncomfortable treatment. Relapse under-powered (n = 51) and did not report recurrence after apparently successful treatment occurs frequently. rates [11]. There were similar clearance rates (75% vs. Surgery may be required in persistent cases. About 90% 72%, 95% confidence interval 53–98% and 52–86% re- of genital warts are caused by human papillomavirus spectively). A systematic review of wart treatment (HPV) types 6 or 11, which are sexually transmitted. undertaken for the European guidelines for the treat- There were 122,068 episodes of new or recurrent ment of genital warts [22], suggested that podophyllo- genital warts treated in sexual health services in toxin has a similar rate of initial clearance (43–70% at England in 2016 [1], of which 49% were recurrent 4 weeks, compared to 55–81% clearance at 16 weeks for episodes. First episode genital warts accounted for imiquimod), but recurrence rates may be lower with imi- 15% of new sexually transmitted infections (STIs) di- quimod (6–26% at 6 months for imiquimod, compared agnosed, making it the second most common condi- to 6–55% at 8–12 weeks for podophyllotoxin). The wide tion after chlamydia. The cost to the NHS of treating variation between reported studies is also likely related anogenital warts in 2016 is estimated at almost £14 to differences in study design, including the outcome million per year, of which about £6 million is for re- measures and timing. The review found no evidence of current episodes [2]. any single therapy being superior overall, largely due to Cryotherapy with liquid nitrogen is frequently used to the lack of high-quality comparative studies, with those treat anogenital warts, although this treatment requires reported being heterogeneous in design, and with high equipment and facilities usually only available in hos- loss to follow-up. Until this comparison is resolved in pital or specialist community settings, and appropri- randomised studies of sufficient size and robust design it ately trained staff. Effective treatment may be achieved remains impossible to firmly recommend one treatment with a single application, but more often requires re- over the other. UK national guidelines recommend that peated clinic attendance. Consequently, most cases of the choice of first line therapy be based on patient pref- warts are now treated with self-administered topical erence and morphology and distribution of lesions, with agents, of which podophyllotoxin is the most common a clinic treatment algorithm to guide treatment [23]. [3]. Podophyllotoxin has a chemotherapeutic action be- It is not known whether the clearance or recurrence lieved to be based on prevention of tubulin polymerisa- rate of anogenital warts can be improved by vaccination tion required for microtubule assembly and inhibition against HPV 6 and 11, initiated at the same time as top- of nucleoside transport through the cell membrane, ical therapy. HPV vaccines are currently licensed to pre- leading to inhibition of growth of virally infected cells. vent HPV-associated anogenital warts and cancers; It is available as a solution or a cream and has been quadrivalent HPV vaccine (qHPV; Gardasil®, Merck studied in a number of randomised trials [3–11]. The Sharp & Dohme) protects against genotypes 6, 11, 16 cream (Warticon®, Glaxo SmithKline) includes the ac- and 18, and from September 2012 has been the vaccine tive agent at a lower concentration than the solution used in the national vaccination programme in the UK (0.15% versus 0.5%) but is generally considered to be for girls aged 12–13 years. The potential role of the vac- easier to apply, better tolerated, and have similar effi- cine as therapy or secondary prevention for anogenital cacy. An alternative topical treatment is imiquimod, warts (or indeed any HPV-associated disease) has yet to but this is more expensive, so usually reserved for be determined. While no randomised controlled trial second-line therapy. Imiquimod is available as a 5% (RCT) evidence exists, evidence that vaccination against cream (Aldara®, Meda). Some studies have suggested HPV may offer a therapeutic or secondary preventative that imiquimod is associated with less recurrence as a strategy comes from several sources. Firstly, there are result of its mode of action as an immune response case reports that clearance of anogenital warts may be modifier [12, 13]. It is a toll-like receptor 7 agonist, and enhanced by qHPV vaccine [24, 25]. Secondly, patients stimulates tissue macrophages to release interferon-alpha with anogenital warts or genital intraepithelial neoplasia and other cytokines which trigger a local cell-mediated re- (cervical [CIN], vulval [VIN] or vaginal [VaIN]) are at sponse. Imiquimod has no direct antiviral activity. The risk of re-infection with the same or different HPV treatment response may be slower than podophyllotoxin. types, or relapse of existing infection [26, 27]. Thirdly, It is licensed for a treatment duration of up to 16 weeks; limited evidence from placebo-controlled vaccine trials Murray et al. BMC Medical Research Methodology (2018) 18:125 Page 3 of 9 appears to show that women who are HPV seropositive, will investigate the potential therapeutic benefit of the but DNA-negative for at least one HPV type at trial qHPV vaccine in the management of patients with ano- entry were protected against subsequent disease related genital warts. The trial will also evaluate the
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