Aug 21, 2017 DOWNLOAD TRAINER. Trainer Options. In an effort to maintain the integrity of the files downloaded from our site and to prevent illegal file sharing, this trainer will perform an authenticity check while in use. This check requires an Internet. 2018 6:11:16 AM - Report post will do, thanks for the answer Page 1 of 1. Integrity Plus 6.11.9 Mac OS X 4 MB. Integrity Plus fills the gap between Integrity Verifier free and simplified links and Scrutiny, the toolkit of webmasters. If you manage more than one site, Integrity Plus lets you store settings for each site and switch between them. Generates an XML sitemap and a variety.
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BackgroundAnogenital 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 designTo 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. DiscussionThe 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 registrationThe trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013). The most effective and cost-effective treatment for patients with anogenital warts is unknown. Genital warts are benign lesions which present as lumps or raised plaques in the skin of the anogenital area. Usually painless, but occasionally causing irritation or bleeding, they can be emotionally distressing, and often require prolonged, time consuming and uncomfortable treatment. Relapse after apparently successful treatment occurs frequently. Surgery may be required in persistent cases. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, which are sexually transmitted.There were 122,068 episodes of new or recurrent genital warts treated in sexual health services in England in 2016 , of which 49% were recurrent episodes.
First episode genital warts accounted for 15% of new sexually transmitted infections (STIs) diagnosed, making it the second most common condition after chlamydia. The cost to the NHS of treating anogenital warts in 2016 is estimated at almost £14 million per year, of which about £6 million is for recurrent episodes.Cryotherapy with liquid nitrogen is frequently used to treat anogenital warts, although this treatment requires equipment and facilities usually only available in hospital or specialist community settings, and appropriately trained staff.
Effective treatment may be achieved with a single application, but more often requires repeated clinic attendance. Consequently, most cases of warts are now treated with self-administered topical agents, of which podophyllotoxin is the most common.
Podophyllotoxin has a chemotherapeutic action believed to be based on prevention of tubulin polymerisation required for microtubule assembly and inhibition of nucleoside transport through the cell membrane, leading to inhibition of growth of virally infected cells. It is available as a solution or a cream and has been studied in a number of randomised trials ,. The cream (Warticon®, Glaxo SmithKline) includes the active agent at a lower concentration than the solution (0.15% versus 0.5%) but is generally considered to be easier to apply, better tolerated, and have similar efficacy.
An alternative topical treatment is imiquimod, but this is more expensive, so usually reserved for second-line therapy. Imiquimod is available as a 5% cream (Aldara®, Meda). Some studies have suggested that imiquimod is associated with less recurrence as a result of its mode of action as an immune response modifier ,.
It is a toll-like receptor 7 agonist, and stimulates tissue macrophages to release interferon-alpha and other cytokines which trigger a local cell-mediated response. Imiquimod has no direct antiviral activity. The treatment response may be slower than podophyllotoxin. It is licensed for a treatment duration of up to 16 weeks; most patients will have responded by 8 weeks. The efficacy has been investigated in a number of trials ,.The efficacies of podophyllotoxin and imiquimod as initial therapy for anogenital warts have never been compared in an adequately-powered trial. The only randomised trial comparing the two topical agents was under-powered ( n = 51) and did not report recurrence rates.
There were similar clearance rates (75% vs. 72%, 95% confidence interval 53–98% and 52–86% respectively).
A systematic review of wart treatment undertaken for the European guidelines for the treatment of genital warts , suggested that podophyllotoxin has a similar rate of initial clearance (43–70% at 4 weeks, compared to 55–81% clearance at 16 weeks for imiquimod), but recurrence rates may be lower with imiquimod (6–26% at 6 months for imiquimod, compared to 6–55% at 8–12 weeks for podophyllotoxin). The wide variation between reported studies is also likely related to differences in study design, including the outcome measures and timing.
The review found no evidence of any single therapy being superior overall, largely due to the lack of high-quality comparative studies, with those reported being heterogeneous in design, and with high loss to follow-up. Until this comparison is resolved in randomised studies of sufficient size and robust design it remains impossible to firmly recommend one treatment over the other. UK national guidelines recommend that the choice of first line therapy be based on patient preference and morphology and distribution of lesions, with a clinic treatment algorithm to guide treatment.It is not known whether the clearance or recurrence rate of anogenital warts can be improved by vaccination against HPV 6 and 11, initiated at the same time as topical therapy. HPV vaccines are currently licensed to prevent HPV-associated anogenital warts and cancers; quadrivalent HPV vaccine (qHPV; Gardasil®, Merck Sharp & Dohme) protects against genotypes 6, 11, 16 and 18, and from September 2012 has been the vaccine used in the national vaccination programme in the UK for girls aged 12–13 years. The potential role of the vaccine as therapy or secondary prevention for anogenital warts (or indeed any HPV-associated disease) has yet to be determined. While no randomised controlled trial (RCT) evidence exists, evidence that vaccination against HPV may offer a therapeutic or secondary preventative strategy comes from several sources. Firstly, there are case reports that clearance of anogenital warts may be enhanced by qHPV vaccine ,.
Secondly, patients with anogenital warts or genital intraepithelial neoplasia (cervical CIN, vulval VIN or vaginal VaIN) are at risk of re-infection with the same or different HPV types, or relapse of existing infection ,. Thirdly, limited evidence from placebo-controlled vaccine trials appears to show that women who are HPV seropositive, but DNA-negative for at least one HPV type at trial entry were protected against subsequent disease related to the HPV type to which they were previously exposed. Also, women with genital lesions treated surgically while in the vaccine trial were less likely to develop recurrent or progressive disease if they were in the vaccine arm of the trial. Fourthly, preliminary evidence suggests that the qHPV vaccine may reduce recurrences of respiratory papillomatosis (RRP) in children , and of anal intraepithelial neoplasia (AIN) , both conditions caused by vaccine-type HPVs. Finally, vaccine antibody responses are much stronger than those induced by natural infection , so a strategy of priming or boosting anti-HPV 6/11 responses with qHPV vaccine could influence the persistence of HPV 6/11 infection and therefore the rate of disease recurrence.Studies of the treatment cost and quality of life impact of genital warts, as well as economic analyses of vaccinating against warts have been conducted ,. These studies have documented significant negative impacts on quality of life and substantial health care service costs. The cost of imiquimod remains higher than that of podophyllotoxin.
If the effectiveness of imiquimod proves superior, then an economic analysis would allow an assessment of the maximum cost difference that would warrant its use as first line therapy. All available treatments have significant failure and recurrence rates. By maximising initial response rates and reducing recurrence rates using first-line self-administered treatment, a randomised controlled trial has the capacity to reduce this health and quality of life burden for patients and improve cost effectiveness, now and in the future. Vaccination would add to the cost of treatment of patients with anogenital warts.
If efficacy is demonstrated, then an economic analysis could determine at what level the increased treatment costs would be justified by reduced future healthcare costs and improved quality of life related to persistent or recurrent disease.The proposed trial will assess the comparative efficacy of the two main topical treatments in current use, podophyllotoxin 0.15% cream and imiquimod 5% cream, and will investigate the potential therapeutic benefit of the qHPV vaccine in the management of patients with anogenital warts. The trial will also evaluate the relative costs of the two topical treatments, as well as of the novel use of qHPV vaccination for both treatment and secondary prevention. The adoption of a pragmatic trial design with broad entry criteria for the comparison of the two topical therapies means that the results can be generalised to the large number of health care settings where anogenital warts are treated. The topical therapies assessed and the potential (within the protocol) to use supplementary cryotherapy are closely aligned with current clinical practice. Study settingThe trial is run at selected sexual health clinics in England and Wales (see Additional file: Participating sites); about 80% of cases of genital warts treated in the NHS are treated in sexual health clinics. Study populationThose eligible to participate are adults aged 18 or over presenting to participating sexual health clinics with external anogenital warts which, in the opinion of the investigator, could be appropriately treated with either self-administered imiquimod or podophyllotoxin cream.
Patients with either first episode or repeat episode anogenital warts are eligible.The main exclusion criteria are those who have had treatment for warts in the past 3 months, and those who have previous qHPV vaccine; previous bivalent HPV vaccine is not an exclusion. Other exclusion criteria relate to contraindications to any of the products, including previous intolerance, pregnancy, lactation, and a total wart area in excess of 4 cm 2, which would require treatment under medical supervision. Patients requiring topical steroids applied to the affected area, or on systemic immunosuppressive agents were also excluded.Initially, participants with known HIV infection were excluded but in December 2015 the entry criteria were modified to allow their inclusion. The change in criteria allows the inclusion of the majority of HIV-positive individuals, but still excludes those with more severe immunosuppression, who may be less likely to respond to topical treatment or to HPV vaccine. Current evidence is that those HIV-positive individuals stable on antiretroviral treatment with a CD4 count above 350, and those not on treatment with CD4 count above 500, mount good responses to vaccines, and have similar responses to treatment for some other chronic viral infections, such as hepatitis C ,.
It was concluded that HIV-positive individuals fulfilling these criteria should not be excluded. This would allow an estimated 80% of HIV-positive patients with warts to be eligible. It would also be of benefit to observe if the response to the trial interventions was comparable in those with and without HIV infection, although it is acknowledged that the power to detect any such effect would be limited. As a precaution, HIV status was added as a stratification variable.
Interventions Topical treatment (for up to 16 weeks) ImiquimodParticipants randomised to imiquimod are asked to apply the 5% cream for three days of the week (every other day). The cream should be applied at the participant’s bed time and left on overnight. The cream should be washed off after 6–10 h. PodophyllotoxinParticipants randomised to podophyllotoxin are instructed to apply the 0.15% cream to the lesions twice a day for three consecutive days followed by no treatment for 4 days, in weekly cycles.
The licensed treatment duration is 4 weeks, but it is common practice to extend this period if there is a partial response to therapy. Vaccine treatment qHPV vaccineQuadrivalent HPV vaccine, Gardasil – Sanofi Pasteur MSD, given according to the licenced schedule at 0, 2, and 6 months; vaccine volume 0.5 ml; containing alum adjuvant.
Placebo0.5 ml normal saline injection as control.Participants are randomised to one of 4 groups (Table ):. A.imiquimod cream plus qHPV vaccine;. B.podophyllotoxin cream plus qHPV vaccine;.
C.imiquimod cream plus saline placebo injection. D.podophyllotoxin cream plus saline placebo injection.Allocation to the groups is carried out using minimisation with a random element, with gender, previous occurrence of warts, and trial site as stratification factors. HIV status was added as a stratification factor when the entry criteria were changed.
Participant identifiers and trial arm allocation are computer generated using a secure on-line service, which requires entry of limited participant characteristics.Topical creams are dispensed in unblinded packaging and vaccine treatment is dispensed in blinded packaging using vaccine codes. The vaccinations are administered by trained members of the clinic staff, who are not part of the trial team involved in trial assessments. Screening and baseline assessmentAfter assessing eligibility and obtaining written informed consent, information on the following is collected: the date of first presentation; dates of previous episodes, and treatment of warts; history of sexually transmitted infections and co-morbidities; history of recent sexual contacts; concomitant medication; and quality of life questionnaire.
Baseline assessment includes examination of the anogenital area and documentation of the position and approximate number of warts (in categories: 1–5, 6–10, 11–2020). The maximum diameter of the largest wart is recorded, measured against a size gauge.
A symptom-directed general physical examination is performed if appropriate. A blood sample (for serum) and a swab of the lesions (for HPV DNA) are taken and stored, for future methodological studies. Randomised treatments are prescribed or administered and participants are supplied with information on their use, risks and side-effects. Participants are offered safer sex advice, and access to other sexual and reproductive health services as per routine care.
For women of child bearing potential a pregnancy test is performed. Simple diary cards are provided for the participant to use as a reminder of when the treatment should be applied, record its use, record if, and when, warts have cleared and record symptom scores related to the topical treatment. Follow-up assessmentsRoutine follow up is for 48 weeks in total, with visits at 4, 8, 16, 24 and 48 weeks (see Table ).
Further topical treatment is issued according to the randomisation/reassessment at weeks 4 and 8. Vaccine is administered at weeks 8 and 24. Presence of warts is determined on examination by a member of the trial clinical team at each study visit to confirm clearance/recurrence. Participants are asked to return to the clinic early if they notice a recurrence so that this can be documented (and the date of recurrence recorded) and further treatment offered according to standard of care. If warts recur within the first 16 weeks the participant is prescribed the treatment that they were randomised to at baseline.Cryotherapy should only be administered from 4 weeks (visit 2) onwards if in the opinion of the investigator this is in the best interests of the patient and after assessment of the response to topical treatment to date.
Careful consideration should be given to delaying cryotherapy beyond 4 weeks where a response to topical treatment is observed in the interest of preserving the integrity of the randomised comparison. If a participant is unable to tolerate the allocated treatment, after dose modifications as appropriate, alternative treatment can be administered at the discretion of the investigator. For the purposes of the trial, early use (within 4 weeks of the start of randomised treatment) of alternative treatments and topical treatment switch to the opposite arm before 16 weeks is considered a topical treatment failure. Participants should continue to be followed up and receive vaccinations as per protocol.After week 16, topical treatment can be changed at the discretion of the investigator, including a switch to the other randomised topical treatment. Timing of eventual wart clearance is recorded for the secondary outcome (time to clearance).Participants are provided with a diary card to record treatments applied and the date the warts are last seen and/or recur, and if there are additional visits between week 16 and 48 for clinical care, a record of presence/absence of warts is made.Routine visits include an assessment of treatment response, as reported by the participant, and observed by the clinician, adherence to the treatment regimen, tolerability, health-related quality of life, and the need for additional or extended treatment. Participants are also asked about work days lost due to clinic visits.
Diary cards are collected. An end of trial blood sample is collected at week 48, and a lesion swab, to be stored for later HPV DNA detection is collected in the event of wart recurrence.
Additional visits are arranged in the event of recurrences or other indications for additional treatment or review in line with routine clinical practice, or if significant adverse events occur that require medical assessment. In order to reduce the loss to follow-up rate, a small financial incentive is provided to those participants who attend the week 16 and week 48 visits. Primary outcomeA composite endpoint of wart clearance 16 weeks after starting treatment and remaining wart-free between 16 and 48 weeks. This captures both the initial clearance efficacy as well as the impact on relapse or recurrence.
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