Eva Herweijer

Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study

Background 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. Methods An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked 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. Results A total of 124 000 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 20 years 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 20 years, 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 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%). Conclusions Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.

Incidence of Genital Warts in Sweden Before and After Quadrivalent Human Papillomavirus Vaccine Availability

BACKGROUND More than 90% of genital warts (GW) cases are caused by human papillomavirus (HPV) types 6 and 11. The introduction of HPV vaccines necessitates the estimation of the population-based incidence of GW immediately before and after vaccination uptake. METHODS Incidence proportions were calculated using the entire population aged 10–44 years living in Sweden during 2006–2010. The Prescribed Drug Register and the National Patient Register were used to define GW episodes. Time trends were estimated using Poisson regression. RESULTS In 2010, age-stratified incidence proportions of GW were highest for 20-year-old women (956 cases/100 000), while the incidence proportion among males was greatest at the slightly older age of 24 years (1137 cases/100 000). Crude rates were marginally higher among males than among females during 2006–2007 and appeared to later diverge. Between 2008 and 2010, the overall incidence appeared to increase among males, and the incidence among females declined. Females aged 17 and 18 years had a >25% decline in GW rates between 2006 and 2010, with significant decreases through the age of 25 years. CONCLUSIONS This study provides a reasonable estimation of the incidence of GW in the Swedish population by use of register data, with results comparable to those from previous smaller studies. There was a downward trend of GW incidence among younger females between 2006 and 2010.

Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma

IMPORTANCE Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine. OBJECTIVE To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting. DESIGN, SETTING, AND PARTICIPANTS An open cohort of all females aged 10 to 24 years living in Sweden (n = 1,045,165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers. MAIN OUTCOMES AND MEASURES Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting. RESULTS A total of 20,383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100,000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100,000 person-years. CONCLUSIONS AND RELEVANCE Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.

Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: A population-based study.

Human papillomavirus (HPV) types 16/18, included in HPV vaccines, contribute to the majority of cervical cancer, and a substantial proportion of cervical intraepithelial neoplasia (CIN) grades 2/3 or worse (CIN2+/CIN3+) including adenocarcinoma in situ or worse. The aim of this study was to quantify the effect of quadrivalent HPV (qHPV) vaccination on incidence of CIN2+ and CIN3+. A nationwide cohort of girls and young women resident in Sweden 2006–2013 and aged 13–29 (n = 1,333,691) was followed for vaccination and histologically confirmed high‐grade cervical lesions. Data were collected using the Swedish nationwide healthcare registers. Poisson regression was used to calculate incidence rate ratios (IRRs) and vaccine effectiveness [(1‐IRR)x100%] comparing fully vaccinated with unvaccinated individuals. IRRs were adjusted for attained age and parental education, and stratified on vaccination initiation age. Effectiveness against CIN2+ was 75% (IRR = 0.25, 95%CI = 0.18–0.35) for those initiating vaccination before age 17, and 46% (IRR = 0.54, 95%CI = 0.46–0.64) and 22% (IRR = 0.78, 95%CI = 0.65–0.93) for those initiating vaccination at ages 17–19, and at ages 20–29, respectively. Vaccine effectiveness against CIN3+ was similar to vaccine effectiveness against CIN2+. Results were robust for both women participating to the organized screening program and for women at prescreening ages. We show high effectiveness of qHPV vaccination on CIN2+ and CIN3+ lesions, with greater effectiveness observed in girls younger at vaccination initiation. Continued monitoring of impact of HPV vaccination in the population is needed in order to evaluate both long‐term vaccine effectiveness and to evaluate whether the vaccination program achieves anticipated effects in prevention of invasive cervical cancer.

The Participation of HPV-Vaccinated Women in a National Cervical Screening Program: Population-Based Cohort Study

Background Concerns have been raised that HPV-vaccination might affect women’s cervical screening behavior. We therefore investigated the association between opportunistic HPV-vaccination and attendance after invitation to cervical screening. Methods A cohort of all women resident in Sweden, born 1977-1987 (N=629,703), and invited to cervical screening, was followed October 2006 - December 2012. Invitations to screening were identified via the National Quality Register for Cervical Cancer Prevention, as was the primary outcome of a registered smear. Vaccination status was obtained from two nationwide health data registers. Hazard ratios (HR) were estimated using Cox regression adjusted for age, education level and income (HRadj). Women were individually followed for up to 6 years, of which the first and second screening rounds were analyzed separately. Results Screening attendance after three years of follow-up was 86% in vaccinated women (N=4,897) and 75% in unvaccinated women (N=625,804). The crude HR of screening attendance in vaccinated vs. unvaccinated women was 1.31 (95% CI 1.27-1.35) in the first screening round. Adjustment for education and income reduced but did not erase this difference (HRadj=1.09, 95% CI 1.05-1.13). In the second screening round, attendance was likewise higher in HPV-vaccinated women (crude HR=1.26, 95% CI 1.21-1.32; HRadj=1.15, 95% CI 1.10-1.20). Conclusions HPV-vaccination is so far associated with equal or higher attendance to cervical screening in Sweden in a cohort of opportunistically vaccinated young women. Most but not all of the difference in attendance was explained by socioeconomic differences between vaccinated and unvaccinated women. HPV vaccine effectiveness studies should consider screening attendance of HPV-vaccinated women when assessing incidence of screen-detected cervical lesions.

Current cervical cancer prevention strategies including cervical screening and prophylactic human papillomavirus vaccination: a review.

Purpose of review As screening methods evolve and human papillomavirus (HPV) vaccination efforts gain traction, knowledge of the current evidence on effectiveness of prevention methods is critical to support further development of programs. Recent findings Screening has dramatically reduced cervical cancer incidence and mortality; however, further progress could be made with implementing new screening techniques, such as HPV DNA testing. Continued focus has been given to methods such as visual inspection with acetic acid/Lugols iodine (VIA/VILI) and self-testing, which may provide an alternative in settings and populations wherein infrastructural challenges and logistical barriers pose challenges to achieving high screening coverage. Postlicensure studies of HPV vaccine show continued effectiveness against genital warts, the first outcome possible to measure. Of note, age-at-vaccination seems to play a pivotal role in effectiveness. Studies examining safety of the HPV vaccines could not confirm any increased risk associated with vaccination. Summary Existing cervical screening techniques are effective; however, programs should consider implementing HPV DNA testing where applicable and further process developments for alternative methods may result in improved results. The HPV vaccine is safe and effective and should be given before sexual debut to achieve maximum protection.

Incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study.

To assess whether quadrivalent human papillomavirus (qHPV) vaccination is associated with increased incidence of new‐onset autoimmune disease in girls and women with pre‐existing autoimmune disease.

Timing of two versus three doses of quadrivalent HPV vaccine and associated effectiveness against condyloma in Sweden: a nationwide cohort study

Objective To assess incidence of condyloma after two doses of quadrivalent human papillomavirus (qHPV) vaccine, by time since first vaccine dose, in girls and women initiating vaccination before age 20 years. Design Register-based nationwide open cohort study. Setting Sweden. Participants Girls and women initiating qHPV vaccination before age 20 years between 2006 and 2012. The study cohort included 264 498 girls, of whom 72 042 had received two doses of qHPV vaccine and 185 456 had received all three doses. Main outcome measure Incidence rate ratios (IRRs) of condyloma estimated by time between first and second doses of qHPV in months (m) and age at vaccination, adjusted for attained age. Results For girls first vaccinated with two doses before the age of 17 years, the IRR of condyloma for 0–3 months between the first and second doses was 1.96 (95% CI 1.43 to 2.68) as compared with the standard three-dose schedule. The IRRs were 1.27 (95% CI 0.63 to 2.58) and 4.36 (95% CI 2.05 to 9.28) after receipt of two doses with 4–7 months and 8+ months between doses, respectively. For women first vaccinated after the age of 17 years, vaccination with two doses of qHPV vaccine and 0–3 months between doses was associated with an IRR of 2.12 (95% CI 1.62 to 2.77). For an interval of 4–7 months between doses, the IRR did not statistically significantly differ to the standard three-dose schedule (IRR=0.81, 95% CI 0.36 to 1.84). For women with 8+ months between dose 1 and dose 2 the IRR was 3.16 (95% CI 1.40 to 7.14). Conclusion A two-dose schedule for qHPV vaccine with 4–7 months between the first and second doses may be as effective against condyloma in girls and women initiating vaccination under 20 years as a three-dose schedule. Results from this nationwide study support immunogenicity data from clinical trials.Objective To assess incidence of condyloma after two doses of quadrivalent human papillomavirus (qHPV) vaccine, by time since first vaccine dose, in girls and women initiating vaccination before age 20 years. Design Register-based nationwide open cohort study. Setting Sweden. Participants Girls and women initiating qHPV vaccination before age 20 years between 2006 and 2012. The study cohort included 264 498 girls, of whom 72 042 had received two doses of qHPV vaccine and 185 456 had received all three doses. Main outcome measure Incidence rate ratios (IRRs) of condyloma estimated by time between first and second doses of qHPV in months (m) and age at vaccination, adjusted for attained age. Results For girls first vaccinated with two doses before the age of 17 years, the IRR of condyloma for 0–3 months between the first and second doses was 1.96 (95% CI 1.43 to 2.68) as compared with the standard three-dose schedule. The IRRs were 1.27 (95% CI 0.63 to 2.58) and 4.36 (95% CI 2.05 to 9.28) after receipt of two doses with 4–7 months and 8+ months between doses, respectively. For women first vaccinated after the age of 17 years, vaccination with two doses of qHPV vaccine and 0–3 months between doses was associated with an IRR of 2.12 (95% CI 1.62 to 2.77). For an interval of 4–7 months between doses, the IRR did not statistically significantly differ to the standard three-dose schedule (IRR=0.81, 95% CI 0.36 to 1.84). For women with 8+ months between dose 1 and dose 2 the IRR was 3.16 (95% CI 1.40 to 7.14). Conclusion A two-dose schedule for qHPV vaccine with 4–7 months between the first and second doses may be as effective against condyloma in girls and women initiating vaccination under 20 years as a three-dose schedule. Results from this nationwide study support immunogenicity data from clinical trials.

HIV drug therapy duration; a Swedish real world nationwide cohort study on InfCareHIV 2009-2014.

Background As HIV infection needs a lifelong treatment, studying drug therapy duration and factors influencing treatment durability is crucial. The Swedish database InfCareHIV includes high quality data from more than 99% of all patients diagnosed with HIV infection in Sweden and provides a unique opportunity to examine outcomes in a nationwide real world cohort. Methods Adult patients who started a new therapy defined as a new 3rd agent (all antiretrovirals that are not N[t]RTIs) 2009–2014 with more than 100 observations in treatment-naive or treatment-experienced patients were included. Dolutegravir was excluded due to short follow up period. Multivariate Cox proportional hazards models were used to estimate hazard ratios for treatment discontinuation. Results In treatment-naïve 2541 patients started 2583 episodes of treatments with a 3rd agent. Efavirenz was most commonly used (n = 1096) followed by darunavir (n = 504), atazanavir (n = 386), lopinavir (n = 292), rilpivirine (n = 156) and raltegravir (n = 149). In comparison with efavirenz, patients on rilpivirine were least likely to discontinue treatment (adjusted HR 0.33; 95% CI 0.20–0.54, p<0.001), while patients on lopinavir were most likely to discontinue treatment (adjusted HR 2.80; 95% CI 2.30–3.40, p<0.001). Also raltegravir was associated with early treatment discontinuation (adjusted HR 1.47; 95% CI 1.12–1.92, p = 0.005). The adjusted HR for atazanavir and darunavir were not significantly different from efavirenz. In treatment-experienced 2991 patients started 4552 episodes of treatments with a 3rd agent. Darunavir was most commonly used (n = 1285), followed by atazanavir (n = 806), efavirenz (n = 694), raltegravir (n = 622), rilpivirine (n = 592), lopinavir (n = 291) and etravirine (n = 262). Compared to darunavir all other drugs except for rilpivirine (HR 0.66; 95% CI 0.52–0.83, p<0.001) had higher risk for discontinuation in the multivariate adjusted analyses; atazanavir (HR 1.71; 95% CI 1.48–1.97, p<0.001), efavirenz (HR 1.86; 95% CI 1.59–2.17, p<0.001), raltegravir (HR 1.35; 95% CI 1.15–1.58, p<0.001), lopinavir (HR 3.58; 95% CI 3.02–4.25, p<0.001) and etravirine (HR 1.61; 95% CI 1.31–1.98, p<0.001).Besides the 3rd agent chosen also certain baseline characteristics of patients were independently associated with differences in treatment duration. In naive patients, presence of an AIDS-defining diagnosis and the use of other backbone than TDF/FTC or ABC/3TC increased the risk for early treatment discontinuation. In treatment-experienced patients, detectable plasma viral load at the time of switch or being highly treatment experienced increased the risk for early treatment discontinuation. Conclusions Treatment durability is dependent on several factors among others patient characteristics and ART guidelines. The choice of 3rd agent has a strong impact and significant differences between different drugs on treatment duration exist.

Substantially reduced incidence of genital warts in women and men six years after HPV vaccine availability in Sweden

BACKGROUND Between 2007 and 2011, opportunistic HPV-vaccination was available in Sweden and partially subsidized to girls aged 13-17, reaching a ∼30% overall coverage. METHODS All Swedish women/men aged 15-44 were followed between 2006 and 2012 for condyloma. Average annual percent changes (AAPCs) in incidence were estimated. RESULTS Substantial decreases were seen in women aged 15-24 from 2008-onwards (AACP-range: -8.5% to -18.5%); similar effects were seen for men aged 15-29 (AACP-range: -7.0% to -16.6%) from 2010-onwards. DISCUSSION Despite low population vaccination coverage in women and no coverage in men, similar condyloma incidence reductions were observed among men and women, with delays of >1 years in men.