Register-based evaluation of HPV vaccination programs

The studies included in this thesis examined the population-level effect of human Papillomavirus (HPV) vaccination on incidence of HPV-related disease outcomes, and participation to cervical screening following vaccination. In study I, a cohort of young Swedish girls ages 10 to 24 was followed for HPV vaccination and condyloma to investigate the effect of vaccination on condyloma by vaccine dose. The results showed greatest protection against condyloma following administration of three HPV vaccine doses. Considerable protection against condyloma was also seen after vaccination with two doses of the quadrivalent HPV (qHPV) vaccine. Risk reductions of 71% and 82% following vaccination with two and three doses, respectively, were seen when vaccination was initiated prior age 17. Greater protection against condyloma was seen in those younger at vaccination initiation. In study II, a birth cohort of women at cervical screening ages (born between 1977 and 1987) was followed for HPV vaccination, invitation to cervical screening, and attendance to screening. The results showed that, compared to unvaccinated women, women HPV vaccinated through opportunistic vaccination were equally likely, if not more likely to attend organized cervical screening following an invitation letter to cervical screening. In study III, a cohort of young Swedish girls and women at ages 23 to 29 was followed for HPV vaccination and cervical lesions, i.e. cervical intraepithelial neoplasia (CIN) stage 2 or worse (CIN2+) and CIN stage 3 or worse (CIN3+), to investigate the effect of vaccination on incidence of cervical lesions after three-dose vaccination. The results showed reductions in risk for CIN2+ and CIN3+ following vaccination in girls and young women that initiated vaccination up until age 29. Greater reductions in risk for cervical lesions were seen in those younger at vaccination initiation. A maximum reduction of 75% and 84% in risk for CIN2+ and CIN3+, respectively, were seen when vaccination was initiated prior to age 17. In study IV, we assessed the incidence of condyloma following the introduction of qHPV in Sweden. During the study period, girls were mainly vaccinated via opportunistic HPV vaccination, and vaccination coverage remained rather low. Declines in condyloma incidence in girls below age 20 were seen following the introduction of qHPV vaccination in Sweden and confirm anticipated effects. In addition, we observed declines in incidence of condyloma among men and in women age 20 and above indicates possible herd protection. In conclusion, the results of these studies contribute to the existing evidence on the population level effect of HPV vaccination and the disease monitoring of HPV related disease in an era where opportunistic HPV vaccination was available. The results of study I have also contributed to the discussions on reduced vaccine dosing schedules. Future monitoring of the disease burden over time, as well as observational studies comparing vaccinated and unvaccinated individuals, are necessary to evaluate whether the organized school-based vaccination program has the anticipated effect in the population

Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis

Background More than 10 years have elapsed since human papillomavirus (HPV) vaccination was implemented. We did a systematic review and meta-analysis of the population-level impact of vaccinating girls and women against human papillomavirus on HPV infections, anogenital wart diagnoses, and cervical intraepithelial neoplasia grade 2+ (CIN2+)to summarise the most recent evidence about the effectiveness of HPV vaccines in real-world settings and to quantify the impact of multiple age-cohort vaccination.Methods In this updated systematic review and meta-analysis, we used the same search strategy as in our previous paper. We searched MEDLINE and Embase for studies published between Feb 1, 2014, and Oct 11, 2018. Studies were eligible if they compared the frequency (prevalence or incidence) of at least one HPV-related endpoint (genital HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre-vaccination and post-vaccination periods among the general population and if they used the same population sources and recruitment methods before and after vaccination. Our primary assessment was the relative risk (RR) comparing the frequency (prevalence or incidence) of HPV-related endpoints between the pre-vaccination and post-vaccination periods. We stratified all analyses by sex, age, and years since introduction of HPV vaccination. We used random-effects models to estimate pooled relative risks.Findings We identified 1702 potentially eligible articles for this systematic review and meta-analysis, and included 65 articles in 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+.After 5\u20138 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% (RR 0\ub717, 95% CI 0\ub711\u20130\ub725) among girls aged 13\u201319 years, and decreased significantly by 66% (RR 0\ub734, 95% CI 0\ub723\u20130\ub749) among women aged 20\u201324 years. The prevalence of HPV 31, 33, and 45 decreased significantly by 54% (RR 0\ub746, 95% CI 0\ub733\u20130\ub766) among girls aged 13\u201319 years. Anogenital wart diagnoses decreased significantly by 67% (RR 0\ub733, 95% CI 0\ub724\u20130\ub746) among girls aged 15\u201319 years, decreased significantly by 54% (RR 0\ub746, 95% CI 0.36\u20130.60) among women aged 20\u201324 years, and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub753\u20130\ub789) among women aged 25\u201329 years. Among boys aged 15\u201319 years anogenital wart diagnoses decreased significantly by 48% (RR 0\ub752, 95% CI 0\ub737\u20130\ub775) and among men aged 20\u201324 years they decreased significantly by 32% (RR 0\ub768, 95% CI 0\ub747\u20130\ub798). After 5\u20139 years of vaccination, CIN2+ decreased significantly by 51% (RR 0\ub749, 95% CI 0\ub742\u20130\ub758) among screened girls aged 15\u201319 years and decreased significantly by 31% (RR 0\ub769, 95% CI 0\ub757\u20130\ub784) among women aged 20\u201324 years.Interpretation This updated systematic review and meta-analysis includes data from 60 million individuals and up to 8 years of post-vaccination follow-up. Our results show compelling evidence of the substantial impact of HPV vaccination programmes on HPV infections and CIN2+ among girls and women, and on anogenital warts diagnoses among girls, women, boys, and men. Additionally, programmes with multi-cohort vaccination and high vaccination coverage had a greater direct impact and herd effects

Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma.

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

High coverage and adherence to dose intervals of the national school-based HPV vaccination program in Sweden during 2012–2019

Background: Close monitoring of vaccination coverage is important for cervical cancer prevention efforts. The study aims to describe the HPV vaccination coverage by dose in girls eligible for HPV vaccination within Sweden’s childhood immunization program and provide an estimate on dose timing compliance. Methods: Vaccination records between 2012 and March 2019 were obtained for girls born in 2000–2006 from the vaccination registers in Sweden. The mid-time population counts for the respective birth cohorts were taken as the denominator. Full-dose coverage and coverage with at least one dose of the vaccine were calculated within the two-dose and three-dose regimen, by region. Dose compliance was calculated within the two-dose regimen. Results: Vaccination coverage with at least one dose of the vaccine was >80% within birth cohorts 2001–2006. Full-dose coverage within a two-dose and three-dose regimen were 73.4% in birth cohorts 2004–2005, and 56.3% in birth cohorts 2000–2001, respectively. Little variation was observed in vaccination coverage between regions. Dose completion was 91.8%, and 72.8% in girls that initiated a two-dose and three-dose regimen, respectively. Among girls receiving a two-dose regimen, 93.0% received the second dose 6–12 months after dose one. Discussion: In conclusion, high levels of HPV vaccination coverage were observed with little variation between regions. Dose timing compliance was particularly high in the two-dose regimen. To fully benefit from the impact of HPV vaccination, it will be important to further push the vaccination coverage and reach the girls that do not or partially engage with HPV vaccination

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

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.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.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).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

Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study.

BackgroundIncidence 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.MethodsAn 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.ResultsA 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%).ConclusionsYoung age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness

Sexually transmitted infections after bereavement – a population-based cohort study

Background: Loss of a loved one has consistently been associated with various health risks. Little is however known about its relation to sexually transmitted infections (STIs). Methods: We conducted a population-based cohort study during 1987–2012 using the Swedish Multi-Generation Register, including 3,002,209 women aged 10-44 years. Bereavement was defined as death of a child, parent, sibling or spouse (N = 979,579, 33 %). STIs were defined as hospital visits with an STI as main or secondary diagnosis. Poisson regression and negative binomial regression were used to estimate incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) of STIs, comparing incidence rates of women who had experienced loss to those who had not. Results: Bereaved women were at significantly higher risk of nearly all STIs studied. The relative risk of any STI was highest during the first year after loss (IRR: 1.45, 95 % CI: 1.27–1.65) and predominantly among women with subsequent onset of psychiatric disorders after bereavement (IRR: 2.61, 95 % CI: 2.00–3.34). Notably, a consistent excess risk, persisting for over five years, was observed for acute salpingitis (IRR: 1.28, 95 % CI: 1.13–1.44), a severe complication of bacterial STIs. Conclusion: These data suggest that women who have experienced bereavement are at increased risk of STIs. Electronic supplementary material The online version of this article (doi:10.1186/s12879-016-1705-x) contains supplementary material, which is available to authorized users

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

Number of individuals, events, and person time by HPV vaccination status in the entire cohort and per education and income level.

<p>^a Women were HPV-vaccinated with at least 1 dose.</p><p>Number of individuals, events, and person time by HPV vaccination status in the entire cohort and per education and income level.</p