Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study

AmyLeval EvaHerweijer AlexanderPloner SandraEloranta JuliaFridman Simard JoakimDillner CeciliaYoung EvaNetterlid PrSparn LisenArnheim-Dahlstrm Methods Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population. An open cohort of girls and women aged 10 to 44years living in Sweden between 2006 and 2010 (N > 2.2 million) waslinked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination. A total of 124000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20years than girls and women whose parents did not complete high school (relative risk ratio=15.45, 95% confidence interval [CI]=14.65 to 16.30). Among those aged older than 20years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI=73% to 79%) among those who received three doses of the vaccine with their first dose before age 20years. Vaccine effectiveness was highest in girls vaccinated before age 14years (effectiveness=93%, 95% CI=73% to 98%). J Natl Cancer Inst;2013;105:469-474 Background Results Conclusions Prophylactic human papillomavirus (HPV) vaccination programs have been launched around the world with the aim of preventing cervical cancer and other HPV-related cancers. Vaccinated cohorts in Sweden are still too young to assess effectiveness against precancerous lesions or invasive HPV-related cancers. Condyloma acuminata, also referred to as genital warts (GWs), has a shorter incubation time after incident HPV infection and as such is ideal to measure in early evaluations of HPV vaccine effectiveness. The HPV types 6 and 11 cause about 90% of GW. Although GW is often a transient disease, the treatment, psychosocial, and symptom burdens vary considerably between individuals. In the Nordic countries, 10% of women in the population will have had GW by age 45years, with similar numbers indicated among men (1,2). Two vaccines offer protection against high oncogenicrisk types HPV16 and HPV18, but only the quadrivalent HPV (qHPV) vaccine also offers protection against HPV6 and HPV11. The qHPV vaccine was approved and became commercially available in 2006. In Sweden, opportunistic vaccination began in October 2006 and has been partially subsidized for girls aged 13 to 17years since May 2007 (3) (Supplementary Material, available online). As of mid-2011, approximately 130000 Swedish girls and women were vaccinated with at least one dose, 99% of whom were vaccinated with the qHPV vaccine. Clinical trials have shown high vaccine efficacy rates for prevention of HPV infection, GW, and precancerous genital lesions in women aged 16 to 26years (47). Among HPV-naive women, the qHPV vaccine has had nearly 100% protection against GW associated with the four HPV vaccine types and an efficacy of about 83% for all GW (regardless of HPV type) (4,6,7). In intention-totreat analyses, in which young women were vaccinated regardless of their prior HPV exposure but with a maximum of four lifetime sexual partners and no history of abnormal cervical smears, an efficacy against all GW (regardless of HPV type) of 62% was reported (4). Efficacy trials follow strict protocols containing prespecified inclusion and exclusion criteria and may not be fully generalizable to real-life HPV vaccination programs. Seminal ecologic studies from Australia, Sweden, and the United States have shown substantial decreases in cases of GW after the introduction of a vaccination program. These observed decreases provide a rapid assessment of potential vaccine impact (8,9). However, the ecologic design of those studies makes ascertaining the cause of the decline in GW impossible (2,810). Vaccine effectiveness studies are necessary to assess the actual population impact of HPV vaccination on the incidence of HPV-related diseases so as to best inform emerging prevention programs and assess the actual public health impact of the vaccines on intended outcomes in more diverse populations (1012). Few countries have the infrastructure capacity to study vaccine effectiveness rates and population impact on a national level because studying this requires individually identifiable information on vaccination status and eventual disease outcomes. This study was conducted to assess GW incidence rates comparing girls and women vaccinated with the qHPV vaccine with those unvaccinated using individual-level data from the entire Swedish population. Study Population This study was based on a nationwide open cohort of girls and women aged 10 to 44 years living in Sweden between January 1, 2006, and December 31, 2010. To assess effectiveness against incident GW, all individuals with a GW before individual follow-up (n=15656) were excluded from the cohort. Individuals were censored at time of death (n=3377) or their 45th birthday. We did not have access to data on emigration status after December 31, 2002. Therefore, girls and women who emigrated up to this date were excluded (n=152896). Girls and women who received the bivalent HPV vaccine (n=1381) were censored at vaccination. In total, 2209263 girls and women were included in the study. The average follow-up time was 4.4years (SD 1.3years). Ethical approval for this study was granted by the Ethical Review Board of Karolinska Institutet, Solna, Sweden. This study is registered at Clinicaltrials.gov (ID number NCT01553994). Data Sources Data were collected using the Swedish population registers. Every resident has a unique personal identification number, which enables individual record linkage from the Total Population Register with multiple registers (13). Data on vaccination exposure status with either the quadrivalent or bivalent vaccine were retrieved by the Prescribed Drug Register (PDR) and from the Swedish vaccination register (SVEVAC), a national HPV vaccination register that started in 2006 (Supplementary Material, available online). The PDR contains all drug prescriptions dispensed at pharmacies in Sweden since July 1, 2005, including subsidized HPV vaccines for girls aged 13 to 17years. We assumed that almost 100% of the HPV vaccines are registered in the PDR for this group. Data on GW (...truncated)