Effectiveness Study of Gardasil on Condyloma
Condition: Condyloma; Genital Warts
MeSH terms: Condylomata Acuminata
Study type: Observational

Summary: 
      Overview and rationale: Through Swedish health care registers it is possible vaccine
      effectiveness. The overall aim is to develop tools for fast and reliable evaluation of
      vaccines focusing on effectiveness. In this study the investigators will assess the
      population impact on condyloma prescribed drugs after HPV-vaccination and to estimate the
      economic burden of hospitalizations due to condyloma. Genital warts (condyloma) are one of
      the most common sexually transmitted diseases in Sweden, estimated 20 000 identified cases
      per year, and are primarily treated with Podofyllotoxin and Immiquimod. One of the approved
      HPV vaccines also protects against condyloma. In clinical trials, this vaccine is safe and
      highly efficacious (90-100%) against persistent infection with HPV 6 and 11 and genital warts
      in women and men. However, these results are from clinical trials and do not answer the
      question weather the vaccine works when delivered, as it would be in the real world. By
      linkage between the Svevac, the patient register and the Drug prescription register the
      investigators can estimate the effectiveness of the HPV vaccine in preventing cases of
      condyloma in a defined population.

      Method and execution: This is a retrospective collection of data from Swedish health care
      registries where the study population will consist of persons who are HPV-vaccinated as well
      as a non-HPV-vaccinated control group (identified through the population-based register,
      matched on sex, age and living area). The primary statistical analysis will be a calculation
      of prescriptions of condyloma treatments after vaccination compared to the non-vaccinated
      control group.
    

Detailed description: 
      GARDASIL® POPULATION-BASED CONDYLOMA EFFECTIVENESS STUDY IN SWEDISH WOMEN BACKGROUND Human
      papilloma virus (HPV) has been established as a necessary but not sufficient cause of
      cervical cancer. Over 100 HPV types have been identified, of which 40 infect the genital
      tract. HPV16, followed by HPV18, are the most frequent in cervical cancer and contribute to
      70% of all invasive cervical cancers. All together, around 15 high-risk (or oncogenic) HPV
      types have been identified. Cervical cancer is the second most common cancer among women
      globally, with an estimated half a million new cases and a quarter of a million deaths each
      year.

      Two of the 40 genital HPV types, 6 and 11, are so called low risk types causing genital warts
      (condyloma). Genital warts are one of the most common sexually transmitted infections and the
      clinical burden has been increasing the past decades. The warts are benign but often cause
      mental or emotional stress in those experiencing them.

      There are two available vaccines against HPV. Both of these vaccines have shown 95% efficacy
      against HPV16 and 18-related precancerous lesions in clinical trials but the follow-up time
      is so far limited to 5.5 years. One of the vaccines, Gardasil®, also offers protection
      against HPV 6 and 11. In clinical trials, this vaccine is safe and highly efficacious
      (90-100%) against persistent infection with HPV 6 and 11 and genital warts in women and men.
      Recently the first study on the effect of Gardasil® on national population level was
      published. The study showed a substantial decline of condyloma in Australian women after
      introduction of GARDASIL®. However, there were some limitations to this study. It was not
      based on entirely true population-based data, they could not adjust for residency status and
      they could not link cases to vaccination status.

      The aim of this study is to investigate whether Gardasil® is effective against condyloma in
      vaccinated women compared to non-vaccinated women by using registry-based data. The study is
      also going to investigate whether Gardasil® has an effect on cases with previous history of
      condyloma, which is possible with our data. Further, we will try to estimate the economic
      burden of hospital visits due to genital warts and investigate whether Gardasil® has an
      affect on these hospital visits. It is estimated that out of 20 000 visits to health care,
      for condyloma, one third requires surgery due to recurrence, and of those one third will
      require surgery again. The study will take advantage of the unique Swedish population-based
      health care databases, which allows linking and follow-up at the individual level.

      OBJECTIVES

        -  To assess the population impact on Podofyllotoxin/Aldara prescription and hospital
           visits on condyloma in Sweden after vaccination with GARDASIL®.

        -  To assess if vaccination with GARDASIL® has an effect on recurrence of genital warts.

        -  To estimate the economic burden of hospital visits due to genital warts.

      MATERIALS AND METHODS Study design The study is a historically prospective analysis of
      population-based nationwide cohorts comprising participants with individual-level
      longitudinal information on HPV vaccination status and prescription of Podofyllotoxin/Aldara.
      Vaccination status will be obtained from national vaccination registers, and drug
      prescription register (Sweden) and information about Podofyllotoxin/Aldara from the drug
      prescription register. Information about hospital visits due to genital warts will be
      obtained from the national in- and out patient registry. The study is observational and as
      such vaccination will be according to local regulations, policies and practices.

      Registers used HPV vaccination status will be obtained from the Swedish vaccination register
      (SVEVAC) and the Swedish drug prescription register. The Swedish vaccination register
      (SVEVAC) currently registers, through a user-friendly web-based large-scale system, all HPV
      vaccinations in Sweden nationally, since the start of HPV vaccination in 2006. SVEVAC holds
      information on personal ID-number, sex, age, date of vaccination, time of vaccination, type
      of vaccine, vaccine lot number, and health unit (county and municipality). Registration with
      personal ID-number is voluntary, but subject must actively state if they don't want to be
      registered. Written information to the subject and inquiry on consent for all aspects of the
      registration and register based follow-up will be administered in an efficient way (subject
      to approval from Ethics Committee). Present experience with HPV vaccination is that 95% of
      vaccinated subjects accept this registration. In Sweden opportunistic HPV vaccination has
      been available since May 2006 and is recommended to young adults. The vaccine has been
      subsidised for girls age 13-17 since May 2007 through the Swedish drug reimbursement system.
      A prescription from a medical doctor is then required. All drug prescriptions are since 2005
      registered in a national drug prescription register. To compare all HPV vaccinated subjects
      the drug prescription register will be scrutinized to complete information on HPV
      vaccination. The drug register holds information on prescription date, number of doses,
      ID-number, sex, type of vaccination. Today approximately 100 000 Swedish females have been
      vaccinated with the HPV vaccine, as well as 800 males. The majority of vaccinations were with
      Gardasil® (98%).

      From the drug prescription register we will obtain information on Podofyllotoxina and Aldara
      prescriptions, date of prescription and dose. In the majority of cases prescriptions are for
      self-treatment at home.

      All in-patient health care in Sweden is registered with personal ID-number at a national
      level since 1987. The so-called Patient register is kept by the Swedish National Board of
      Health and Welfare (NBHW). From 2001, out-patient care at hospitals has been included in this
      register. Information on adverse events will be obtained from this register. The
      International Classification of Diseases 10th revision (ICD-10) has been used to code
      diagnoses since 1997.

      Many specialist clinics are based at hospitals and using patient register it will be possible
      to catch visits to those clinics as well as day surgery.

      Study population and study size This is a population-based study and will comprise
      girls/women vaccinated with GARDASIL® in Sweden between May 2005 and October 2010. The study
      will also include all women who were prescribed Podofylloxin/Aldara between January 2005 and
      December 2010 and also women who have a recorded hospital visit due to genital warts from
      2005 to December 2009. The study cohort will include girls/women born between 1989 and 1996.
      In this way we will include the oldest and youngest girls/women who may benefit from
      subsidised vaccination within the study period.

      As of October 2010, 98% of the vaccinations registered were Gardasil®. 108 670 women have
      been vaccinated with at least one dose, 92 296 with two doses and 66 150 with three doses.
      Approximately 87% of the vaccinated girls/women are between 13 to 17 years of age and 10% are
      between 18-25 years of age. In a report from the NBHW (2007) the estimated number of cases
      with condyloma is about 20 000 every year, taking both prescription of Podofyllotoxin/Aldara
      and hospital visits into account. Approximately half of those are women.

      To link information on vaccination status, and health care data from population based
      registers data the Swedish personal ID number will be used.

      Study outcome To study the effect of Gardasil on condyloma incidence we will compare
      incidence of genital warts in vaccinated versus non-vaccinated women. The majority of cases
      will be identified through the Drug prescription register and about 20% will be found in
      patient register. To find cases through the Drug prescription register ACT codes will be used
      for Podofyllotoxin and Aldara (see below) and ICD-10 codes for the In- and Out patient
      registers.

      The described register will also be used to investigate whether vaccination with Gardasil has
      changed the burden of recurrent warts by identifying women who had genital warts before
      vaccination and after and compare with those not vaccinated. The burden of hospital visits
      will also be investigated by comparing vaccinated and non-vaccinated women.

      ACT codes used in the Drug prescription register ACT-code used for Gardasil®: J07BM01
      ACT-code for Podofyllotoxin: D06BB04 ACT-code used for Aldara: D06BB10 ICD-10 codes Hospital
      visit due to genital warts will be found in the in- and out patient register. The ICD-10 code
      used to indentify patients are: A63 and D26.

      Statistical methods This is a cohort study and the data will be analyzed using statistical
      methods for survival analysis. In particular, to study the population impact on genital wart
      incidence in Sweden after vaccination with GARDASIL® we will model the association between
      exposure (vaccination status) and outcome (genital warts determined via either prescription
      of Podophyllotoxin/Aldara or hospital visit due to genital warts) using Cox and/or Poisson
      regression. Incidence rate ratios (IRR) and 95 % confidence intervals will be used to
      quantify the effect of the vaccine on the risk for genital warts. All girls will be followed
      up from May 2006 and attained age will be used as the underlying time scale in the model.
      Because full effectiveness of the vaccine is assumed to be achieved after 3 doses the
      exposure will be included in the statistical model as a time-varying exposure classified from
      no vaccination (unexposed), partially completed vaccination (1 to 2 doses) and fully
      vaccinated (exposed). The analysis will account for possible confounding factors such as
      sexual risk taking behaviors, using genital wart history as marker, socioeconomic status of
      the parents and type of prescribed treatment (Podophyllotoxin orAldara).

      To assess risk of recurrence of condyloma, IRR adjusted for prior genital wart history,
      determined in the same way as for outcome, will be used.

      To estimate temporal trends in the economic burden of hospital visits due to genital warts we
      will identify and report descriptive data on all recorded hospital visits due to genital
      warts in the Swedish Patient registries as a function of calendar year (2005-2009) as well as
      mode of treatment (Podophyllotoxin/Aldara /surgery).

      Limitations We cannot exclude that we will not be able to catch all cases that seek medical
      care. Some cases that visit primary health care may be treated during the visit and this will
      not be recorded anywhere. However, most of these cases do receive a prescription for
      self-treatment.

      Because the majority of vaccinees are between 13-17 years of age they may not have had
      genital warts before vaccination and therefore recurrence of warts may be difficult to catch
      in our study population.

      Ethical approval The study will be conducted after approval of the Ethics Committee of
      Karolinska Institutet.
    

Observational model: Cohort
Time perspective: Retrospective
Sampling method: Probability Sample
Study population: 
        Historically prospective study of population-based nationwide cohorts.