Trial Information

Gardasil® Population-Based Condyloma Effectiveness Study In Swedish Women Including Condyloma Incidence Estimations For Swedish Men And Women

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.