Publications by authors named "Karolina Louvanto"

27 Publications

  • Page 1 of 1

HLA-G polymorphism impacts the outcome of oral HPV infections in women.

BMC Infect Dis 2021 May 4;21(1):419. Epub 2021 May 4.

Department of Oral Pathology and Radiology, University of Turku, Turku, Finland.

Backround: Human leukocyte antigen (HLA)-G may have an important role in the natural history of human papillomavirus (HPV) infection. Our aim was to evaluate the role of HLA-G in the outcome of genital and oral HPV infections in women.

Methods: Analyses included 306 women from the Finnish Family HPV-study and were followed-up for six years. Genital and oral samples were tested for 24 different HPV types with multiplex HPV genotyping. HLA-G alleles were determined through direct DNA-sequencing. Unconditional logistic regression was used to determine the associations between HLA-G genotypes and HPV infection outcomes.

Results: Ten HLA-G alleles were identified. Most common HLA-G genotypes were the wild type G*01:01:01/01:01:01 (31.3%) followed by G*01:01:01/01:01:02 (26.8%). G*01:01:01/01:01:01 genotype was associated with increased risk of oral HPV infections by any HPV type or single-type with OR = 1.86 (95% CI 1.14-3.04, P = 0.01) and 2.22 (95% CI 1.14-3.71, P = 0.02), respectively. G*04:01+ allele and the G*01:01:01/01:04:01 genotype both protected from any and single oral HPV infections; OR = 0.46 (95% CI 0.23-0.89, P = 0.02) and 0.53 (95% CI 0.23-0.97, P = 0.03), respectively. G*01:01:02/01:04:01 genotype increased significantly the risk of infertility and its treatments, with respective OR = 5.06 (95% CI 1.22-21.02, P = 0.03) and OR = 9.07 (95% CI 1.22-39.50, P = 0.03). Both HLA-G alleles and genotypes showed several significant associations with the outcomes of oral HPV infections, but none of them had any impact on the outcomes of genital HPV infections in these women.

Conclusions: The host HLA-G genotypes appear to impact the outcomes of oral HPV infections in women but have little if any effect on genital HPV status or infection outcomes.
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http://dx.doi.org/10.1186/s12879-021-06079-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097798PMC
May 2021

Distribution of HPV Genotypes Differs Depending on Behavioural Factors among Young Women.

Microorganisms 2021 Apr 2;9(4). Epub 2021 Apr 2.

Department of Obstetrics and Gynecology, Tampere University Hospital and Tampere University, 33100 Tampere, Finland.

Risk factors for the different human papillomavirus (HPV) genotypes are not well understood, although the risk of cancer is known to vary among them. Our aim was to evaluate the association of diverse behavioral and reproductive factors with genotype-specific HPV prevalence among 879 unvaccinated women aged 18-75 years referred to the colposcopy clinic at Helsinki University Hospital in Finland. Cervical swabs for HPV genotyping were collected in the first visit and assessed for 34 high-risk (hr) and low-risk (lr) HPV genotypes. Participants completed a questionnaire on behavioral, reproductive, and lifestyle factors. Differences in genotype-specific HPV prevalence were analyzed overall and in age groups using binary logistic regression. Smoking was associated with higher prevalence in HPV16 compared with other hrHPV genotypes together with decreasing age, being highest among younger women <30 years old, odds ratio (OR) 3.74 (95% CI 1.42-9.88). The later the sexual debut, the more it seemed to protect from HPV16 infection. The best protection was achieved when the sexual debut took place at >20 years of age, with an OR of 0.43 (95% CI 0.23-0.83). This association was not seen with other hrHPV genotypes. Methods of contraception seemed not to have an effect on hrHPV positivity, regardless of the HPV genotype. The genotype specific hrHPV prevalence differs, depending on behavioral factors, especially among younger women referred to colposcopy.
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http://dx.doi.org/10.3390/microorganisms9040750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066411PMC
April 2021

Oral Human Papillomavirus Infection in Children during the First 6 Years of Life, Finland.

Emerg Infect Dis 2021 Mar 29;27(3):759-766. Epub 2021 Jan 29.

Human papillomavirus (HPV) infections are found in children, but transmission modes and outcomes are incompletely understood. We evaluated oral samples from 331 children in Finland who participated in the Finnish Family HPV Study from birth during 9 follow-up visits (mean time 51.9 months). We tested samples for 24 HPV genotypes. Oral HPV prevalence for children varied from 8.7% (at a 36-month visit) to 22.8% (at birth), and 18 HPV genotypes were identified. HPV16 was the most prevalent type to persist, followed by HPV18, HPV33, and HPV6. Persistent, oral, high-risk HPV infection for children was associated with oral HPV carriage of the mother at birth and seroconversion of the mother to high-risk HPV during follow-up (odds ratio 1.60-1.92, 95% CI 1.02-2.74). Children acquire their first oral HPV infection at an early age. The HPV status of the mother has a major impact on the outcome of oral HPV persistence for her offspring.
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http://dx.doi.org/10.3201/eid2703.202721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920652PMC
March 2021

Determinants of Human Papillomavirus Vaccine Uptake by Adult Women Attending Cervical Cancer Screening in 9 European Countries.

Am J Prev Med 2021 04 24;60(4):478-487. Epub 2020 Dec 24.

Cancer Epidemiology Research Programme, IDIBELL, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain; Faculty of Health Sciences, Universitat Oberta de Catalunya (UOC), Barcelona, Spain.

Introduction: Human papillomavirus-vaccinated cohorts, irrespective of age, will likely reduce their subsequent screening requirements, thus opening opportunities for global cost reduction and program sustainability. The determinants of uptake and completion of a 3-dose human papillomavirus vaccination program by adult women in a European context were estimated.

Study Design: This was an intervention study.

Setting/participants: Study participants were women aged 25-45 years, attending opportunistic or population-based cervical cancer screening in Belgium, Denmark, Finland, France, Germany, Slovenia, Spain, Sweden, and the United Kingdom between April 2016 and May 2018.

Intervention: Study participants completed a questionnaire on awareness and attitudes on adult female human papillomavirus vaccination and were invited to receive free human papillomavirus vaccination.

Main Outcome Measures: Main outcome measures were acceptance, uptake, and completion of vaccination schedule. Determinants of vaccine uptake were explored using multilevel logistic models in 2019.

Results: Among 3,646 participants, 2,748 (range by country=50%-96%) accepted vaccination, and 2,151 (range=30%-93%) received the full vaccination course. The factors associated with higher vaccine acceptance were previous awareness of adult female (OR=1.22, 95% CI=1.00, 1.48) and male (OR=1.59, 95% CI=1.28, 1.97) vaccination. Women in stable relationships (OR=0.56, 95% CI=0.45, 0.69) or with higher educational level (OR=0.76, 95% CI=0.63, 0.93) were more likely to refuse vaccination. Recruitment by postal invitation versus personal invitation from a healthcare professional resulted in lower vaccine acceptance (OR=0.13, 95% CI=0.02, 0.76). Vaccination coverage of >70% of adolescent girls in national public programs was of borderline significance in predicting human papillomavirus vaccine uptake (OR=3.23, 95% CI=0.95, 10.97). The main reasons for vaccine refusal were vaccine safety concerns (range=30%-59%) and the need for more information on human papillomavirus vaccines (range=1%-72%). No safety issues were experienced by vaccinated women.

Conclusions: Acceptance and schedule completion were largely dependent on recruitment method, achieved coverage of national vaccination programs, and personal relationship status. Knowledge of benefits and safety reassurance may be critical to expanding vaccination target ages. Study results suggest that there are no major opinion barriers in adult women to human papillomavirus vaccination, especially when vaccination is offered face to face in healthcare settings.

Trial Registration: EudraCT Number 2014-003177-42.
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http://dx.doi.org/10.1016/j.amepre.2020.08.032DOI Listing
April 2021

Baseline findings and safety of infrequent vs. frequent screening of human papillomavirus vaccinated women.

Int J Cancer 2020 07 16;147(2):440-447. Epub 2019 Dec 16.

Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.

Less frequent cervical cancer screening in human papillomavirus (HPV) vaccinated birth cohorts could produce considerable savings without increasing cervical cancer incidence and loss of life-years. We report here the baseline findings and interim results of safety and accuracy of infrequent screening among HPV16/18 vaccinated females. The entire 1992-1994 birth-cohorts (30,139 females) were invited to a community-randomized HPV16/18-vaccination trial. A total of 9,482 female trial participants received HPV16/18-vaccination in 2007-2009 at age of 13-15. At age 22, 4,273 (45%) of these females consented to attend a randomized trial on frequent (ages 22/25/28; Arm 1: 2,073 females) vs. infrequent screening (age 28; Arm 2: 2,200 females) in 2014-2017. Females (1,329), who had got HPV16/18 vaccination at age 18 comprised the safety Arm 3. Baseline prevalence and incidence of HPV16/18 and other high-risk HPV types were: 0.5% (53/1,000 follow-up years, 10 ) and 25% (2,530/10 ) in the frequently screened Arm 1; 0.2% (23/10 ) and 24% (2,413/10 ) in the infrequently screened Arm 2; and 3.1% (304/10 ) and 23% (2,284/10 ) in the safety Arm 3. Corresponding prevalence of HSIL/ASC-H and of any abnormal cytological findings were: 0.3 and 4.2% (Arm 1), 0.4 and 5.3% (Arm 2) and 0.3 and 4.7% (Arm 3). Equally rare HSIL/CIN3 findings in the infrequently screened safety Arm A3 (0.4%) and in the frequently screened Arm 1 (0.4%) indicate no safety concerns on infrequent screening despite the up to 10 times higher HPV16/18 baseline prevalence and incidence in the former.
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http://dx.doi.org/10.1002/ijc.32802DOI Listing
July 2020

Viral load of human papillomavirus types 16/18/31/33/45 as a predictor of cervical intraepithelial neoplasia and cancer by age.

Gynecol Oncol 2019 11 8;155(2):245-253. Epub 2019 Oct 8.

Division of Cancer Epidemiology, Faculty of Medicine, McGill University, Montréal, Canada.

Objective: We assessed whether human papillomavirus (HPV) viral load is an independent predictor of underlying cervical disease and its diagnostic accuracy by age.

Methods: The Biomarkers of Cervical Cancer Risk study was a case-control study from 2001 to 2010 in Montréal, Canada. Cases were histologically-confirmed cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), or cervical cancer cases. Controls were women presenting for routine screening with normal cytology results. We quantified HPV16/18/31/33/45 viral load from exfoliated cervical cells using a real-time PCR assay. Diagnostic accuracy of viral load was assessed using the area under the receiver operating characteristic curve (AUC). We restricted the analysis to the 632 cases and controls who were HPV16/18/31/33/45 positive.

Results: Geometric mean HPV16/18/31/33/45 viral load increased with severity of lesion grade, ranging from 0.7, 3.1, 4.8, 7.2, and 12.4 copies/cell in normal, CIN1, CIN2, CIN3&AIS, and cervical cancer respectively. The adjusted odds ratio of CIN1+ and CIN2+ increased respectively by 1.3 (95%CI 1.1-1.4) and 1.2 (95%CI 1.1-1.3) per log-transformed viral copy/cell increase of HPV16/18/31/33/45. This association was mainly driven by HPV16, 18, and 31 viral loads. The AUC of HPV16/18/31/33/45 viral load for discriminating between normal and CIN1+ women was 0.70 (95%CI 0.64-0.76) in HPV-positive women, and was 0.76 (95%CI 0.66-0.86) for women ≥30 years and 0.66 (95%CI 0.58-0.74) for women under 30 years.

Conclusions: HPV viral load has lower diagnostic accuracy than has been reported for other HPV screening triage tests. However, it may be useful for triaging HPV tests in settings without cytology results such as HPV self-sampling.
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http://dx.doi.org/10.1016/j.ygyno.2019.09.010DOI Listing
November 2019

Methylation in Predicting Progression of Untreated High-grade Cervical Intraepithelial Neoplasia.

Clin Infect Dis 2020 06;70(12):2582-2590

Center for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom.

Background: There is no prognostic test to ascertain whether cervical intraepithelial neoplasias (CINs) regress or progress. The majority of CINs regress in young women, and treatments increase the risk of adverse pregnancy outcomes. We investigated the ability of a DNA methylation panel (the S5 classifier) to discriminate between outcomes among young women with untreated CIN grade 2 (CIN2).

Methods: Baseline pyrosequencing methylation and human papillomavirus (HPV) genotyping assays were performed on cervical cells from 149 women with CIN2 in a 2-year cohort study of active surveillance.

Results: Twenty-five lesions progressed to CIN grade 3 or worse, 88 regressed to less than CIN grade 1, and 36 persisted as CIN1/2. When cytology, HPV16/18 and HPV16/18/31/33 genotyping, and the S5 classifier were compared to outcomes, the S5 classifier was the strongest biomarker associated with regression vs progression. The S5 classifier alone or in combination with HPV16/18/31/33 genotyping also showed significantly increased sensitivity vs cytology when comparing regression vs persistence/progression. With both the S5 classifier and cytology set at a specificity of 38.6% (95% confidence interval [CI], 28.4-49.6), the sensitivity of the S5 classifier was significantly higher (83.6%; 95% CI, 71.9-91.8) than of cytology (62.3%; 95% CI, 49.0-74.4; P = 0.005). The highest area under the curve was 0.735 (95% CI, 0.621-0.849) in comparing regression vs progression with a combination of the S5 classifier and cytology, whereas HPV genotyping did not provide additional information.

Conclusions: The S5 classifier shows high potential as a prognostic biomarker to identify progressive CIN2.
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http://dx.doi.org/10.1093/cid/ciz677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286376PMC
June 2020

Age-specific HPV type distribution in high-grade cervical disease in screened and unvaccinated women.

Gynecol Oncol 2019 08 5;154(2):354-359. Epub 2019 Jun 5.

Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 2, 00290 Helsinki, Finland. Electronic address:

Background And Aim: Age-specific type-distribution of high-risk human papillomavirus (hrHPV) in cervical precancerous lesions is subject to change in the HPV vaccination era. Knowing the pre-vaccination type-distribution helps to anticipate changes induced by mass vaccination and optimize screening.

Methods: We recruited 1279 women referred to colposcopy for abnormal cytology into a population-based study on HPV type distribution in diagnostic cervical samples (ISRCTN10933736). The HPV genotyping findings were grouped as: HPV16/18+, other hrHPV+ (HPV31/33/35/39/45/51/52/56/58/59/66/68), non-vaccine targeted hrHPV+ (HPV35/39/51/56/59/66/68), low-risk HPV, and HPV negative. We estimated the HPV group-specific prevalence rates according to diagnostic histopathological findings in the age groups of <30 (n = 339), 30-44.9 (n = 614), and ≥45 (n = 326).

Results: Altogether 503 cases with high grade squamous intraepithelial lesion or worse (HSIL+) were diagnosed. More than half, 285 (56.7%) of HSIL+ cases were associated with HPV16/18: 64.3% (101/157) in women <30 years (reference group), 58.4% (157/269) in women 30-44.9 years (risk ratio (RR) 0.91, 95% confidence interval (95% CI) 0.78-1.06), and 35.1% (27/77) in women ≥45 years of age (RR 0.55, 95% CI 0.39-0.75). Conversely, other hrHPV's were associated with 191 (38.0%) of HSIL+: 31.9% (50/157) in women <30, 36.8% (99/269) in women 30-44.9 years, 54.6% (42/77) and in women ≥45 (RR 1.71, 95% CI 1.26-2.33). The proportion of non-vaccine targeted hrHPV and HPV negative HSIL+ increased with advancing age.

Conclusions: Pre-vaccination HPV type distribution in HSIL+ was distinctly polarised by age with HPV16/18 attributed disease being markedly more prevalent in women aged <30. In the older women the other hrHPV types, however, dominated suggesting a need for more age-dependent screening strategies.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.024DOI Listing
August 2019

Human Papillomavirus Viral Load and Transmission in Young, Recently Formed Heterosexual Couples.

J Infect Dis 2019 08;220(7):1152-1161

Gerald Bronfman Department of Oncology, Division of Cancer Epidemiology, McGill University, Montreal, Quebec, Canada.

Background: We studied the association between human papillomavirus (HPV) viral load (VL) and HPV concordance.

Methods: The HITCH cohort study included young, heterosexual, recently formed, sexually active couples. Questionnaires and genital samples were collected at 0 and 4 months. Samples were tested for HPV DNA by polymerase chain reaction (PCR; Linear Array). VLs of HPV6/11/16/18/31/42/51 were quantified using type-specific real-time PCR. Correlations between VL and type-specific HPV prevalence and incidence were evaluated using multilevel, mixed-effects linear/logistic regression models.

Results: We included 492 couples. VLs were higher in penile than vaginal samples. VL at subsequent visits correlated significantly within men (r, 0.373), within women (r, 0.193), and within couples (r range: 0.303-0.328). Men with high VL had more type-specific persistent HPV infections (odds ratio [OR], 4.6 [95% confidence interval {CI}, 2.0-10.5]). High VL in men was associated with prevalent (OR, 5.3 [95% CI, 2.5-11.2]) and incident (OR, 6.7 [95% CI, 1.5-30.7]) type-specific HPV infections in their partner. Women's VL was associated with type-specific HPV prevalence in their partner at the same (OR, 5.9) and subsequent (OR, 4.7) visit.

Conclusions: Persistent HPV infections have limited VL fluctuations. VL between sex partners are correlated and seem predictive of transmission episodes.
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http://dx.doi.org/10.1093/infdis/jiz238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736425PMC
August 2019

Predictive Value of HPV Testing in Self-collected and Clinician-Collected Samples Compared with Cytology in Detecting High-grade Cervical Lesions.

Cancer Epidemiol Biomarkers Prev 2019 07 23;28(7):1134-1140. Epub 2019 Apr 23.

Division of Cancer Epidemiology, McGill University, Montreal, Canada.

Background: Self-sampling has become an attractive proposition now that human papillomavirus (HPV) primary testing is being incorporated into cervical cancer screening programs worldwide. We compared predictive values of HPV testing based on self- and physician-collected samples, and cytology, in detecting high-grade cervical intraepithelial neoplasia (CIN).

Methods: The Cervical And Self-Sample In Screening (CASSIS) study enrolled 1,217 women ages 16-70 years prior to scheduled colposcopies. Vaginal specimens were self-collected using the validated HerSwab device. Cervical specimens were collected by gynecologists. Specimens were tested for presence of high-risk HPV (hrHPV) by the Cobas 4800 HPV test. We estimated positive predictive values (PPV) and negative predictive values (NPV) and 95% confidence intervals (CI) for a subset of women ( = 700) who underwent cervical biopsy and cytology at the actual CASSIS visit.

Results: hrHPV was detected in 329 women (47%) with HerSwab and in 327 (46.7%) with physician sampling. Respective values for HPV16/18 were 119 (17%) and 121 (17.3%). On histology, 134 women had CIN1, 49 had CIN2, 48 had CIN3, 5 had CIN2/CIN3, and 3 had cancers. PPVs for CIN2 of any hrHPV were 28% (95% CI, 23.2-33.1) and 29.7% (95% CI, 24.8-34.9) for HerSwab and physician samples, respectively. Corresponding values for HPV16/18 were 43.7% (95% CI, 34.6-53.1) and 43.8% (95% CI, 34.8-53.1). PPV of cytology (ASC-US+) was 26.6% (95% CI, 21.6-32.0). Corresponding NPVs (same order as PPVs) were 96.4% (95% CI, 93.9-98.1), 97.8% (95% CI, 95.6-99), 90.9% (95% CI, 88.2-93.1), 91% (95% CI, 88.4-93.2), and 94.7% (95% CI, 91.8-96.8).

Conclusions: Our results confirm that HPV self-sampling has comparable performance with a physician-collected sample in detecting cervical lesions.

Impact: HPV self-sampling has the potential to increase coverage in cervical cancer screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1338DOI Listing
July 2019

From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity.

Acta Cytol 2019 15;63(2):148-158. Epub 2019 Feb 15.

Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

Persistent high-risk human papillomavirus (HPV) infection has been associated with increased risk for cervical precancerous lesions and cancer. The host's genetic variability is known to play a role in the development of cervical cancer. The human leukocyte antigen (HLA) genes are highly polymorphic and have shown to be important risk determinants of HPV infection persistence and disease progression. HLA class I and II cell surface molecules regulate the host's immune system by presenting HPV-derived peptides to T-cells. The activation of T-cell response may vary depending on the HLA allele polymorphism. The engagement of the T-cell receptor with the HPV peptide-HLA complex to create an active costimulatory signal is essential for the activation of the T-cell response. Functional peptide presentation by both HLA class I and II molecules is needed to activate efficient helper and effector T-cell responses in HPV infection recognition and clearance. Some of these HLA risk alleles could also be used as preventive tools in the detection of HPV-induced cervical lesions and cancer. These HLA alleles, together with HPV vaccines, could potentially offer possible solutions for reducing HPV-induced cervical cancer as well as other HPV-related cancers.
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http://dx.doi.org/10.1159/000494985DOI Listing
May 2019

Hand-to-genital and genital-to-genital transmission of human papillomaviruses between male and female sexual partners (HITCH): a prospective cohort study.

Lancet Infect Dis 2019 03 10;19(3):317-326. Epub 2019 Feb 10.

Division of Cancer Epidemiology, Department of Oncology, McGill University, Montreal, QC, Canada; Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, QC, Canada.

Background: Hand-to-genital contact is hypothesised to be a transmission mode of human papillomavirus (HPV) of the Alphapapillomavirus genus. We compared the relative importance of hand-to-genital and genital-to-genital HPV transmission between sexual partners.

Methods: In this prospective cohort study, we recruited and followed up female university students aged 18-24 years and their male sexual partners in Montreal, QC, Canada (2005-11). Participants were eligible if they had initiated sexual activity within the past 6 months. Women were examined at clinic visits at baseline and every 4-6 months for up to 24 months. Men had a baseline visit and a single follow-up visit approximately 4 months later. Partners provided hand and genital swab samples, which we tested for DNA of 36 HPV types using PCR. We assessed predictors of incident type-specific HPV detections using Cox proportional hazards models.

Findings: Participants were recruited between June 5, 2006, and April 4, 2013. 264 women and 291 men had valid hand samples. The hazard ratio (HR) of incident detection of HPV in genital samples from women was 5·0 (95% CI 1·5-16·4) when her partner was positive for the same HPV type on his hand versus negative, but adjustment for his genital HPV status reduced the HR to 0·5 (0·1-1·8). Similarly, the HR of incident detection of HPV on men's genitals was 17·4 (95% CI 7·9-38·5) when his partner was positive for the same HPV type on her hand versus negative, but adjustment for her genital HPV status reduced the HR to 2·3 (0·9-6·2). Conversely, the HR of type-specific incident detection of HPV in genital samples associated with partner genital HPV positivity was 19·3 (95% CI 11·8-31·8) for women and 28·4 (15·4-52·1) for men after adjustment for their hand HPV status.

Interpretation: Clinicians can reassure their patients that HPV transmission is unlikely to occur through hand-to-genital contact. The majority of genital HPV infections are likely to be caused by genital-to-genital sexual transmission.

Funding: Canadian Institutes for Health Research, National Institutes of Health, Fonds de la Recherche en Santé du Québec, and Merck & Co.
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http://dx.doi.org/10.1016/S1473-3099(18)30655-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404546PMC
March 2019

Validation of a new HPV self-sampling device for cervical cancer screening: The Cervical and Self-Sample In Screening (CASSIS) study.

Gynecol Oncol 2018 06 17;149(3):491-497. Epub 2018 Apr 17.

Division of Cancer Epidemiology, McGill University, Montreal, Canada. Electronic address:

Objective: We compared the self-sampling performance of the newly designed HerSwab™ device with a physician-collected cervical sample and another self-sample using the cobas® PCR Female swab for the detection of cervical intraepithelial neoplasia (CIN) and cancer.

Methods: Women referred for colposcopy at McGill University affiliated hospital clinics collected two consecutive self-samples, one with HerSwab™ and one with cobas® swab, after receiving instructions. The order of sampling was randomized. The colposcopist then collected a cervical sample and conducted a colposcopic examination. Samples were tested for human papillomavirus (HPV) DNA. Sensitivity and specificity to detect CIN2+ and respective 95% confidence intervals (CI) were calculated to compare sampling approaches. The HPV testing agreement between samples was measured using the Kappa statistic.

Results: Of 1217 women enrolled, 1076 had complete results for HPV and cytology; 148 (13.8%) had CIN1, 147 (13.7%) had CIN2/3, and 5 (0.5%) had cancer. There was very good agreement between methods for HPV detection (HerSwab™ versus physician: kappa=0.84; cobas® swabs versus physician: kappa=0.81; HerSwab™ versus cobas® swabs: kappa=0.87). The sensitivity of HPV detection for CIN2+ was 87.6% (95%CI: 79.8-93.2) with self-sampling using HerSwab™, 88.6% (95%CI: 80.9-94.0) with self-sampling using the cobas® swab, and 92.4% (95%CI: 85.5-96.7) with physician sampling. Corresponding estimates of specificity were 58.1% (95%CI: 54.1-62.1), 55.0% (95%CI: 50.9-59.0) and 58.7% (95%CI: 54.6-62.6). Cytology (ASC-US or more severe) done on the physician-collected specimen was 80.2% (95%CI: 70.8-87.6) sensitive and 61.4% (95%CI: 57.2-65.5) specific for CIN2+.

Conclusions: The HerSwab™ had good agreement with physician sampling in detecting HPV, and adequate performance in detecting high-grade lesions among women referred to colposcopy for abnormal cytology.
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http://dx.doi.org/10.1016/j.ygyno.2018.04.004DOI Listing
June 2018

HLA-G and vertical mother-to-child transmission of human papillomavirus infection.

Hum Immunol 2018 Jun 12;79(6):471-476. Epub 2018 Mar 12.

Department of Oral Pathology and Radiology, University of Turku, Lemminkäisenkatu 2, 20520 Turku, Finland; Department of Pathology, Turku University Hospital, Kiinanmyllynkatu 10, 20520 Turku, Finland. Electronic address:

Role of host factors in transmission of human papillomavirus (HPV)-infection from mother to her offspring is not known. Our aim was to study whether human leukocyte antigen (HLA)-G allele concordance among the mother-child pairs could facilitate vertical transmission of HPV, because HLA-G may contribute to immune tolerance in pregnancy. Altogether, 310 mother-child pairs were included from the Finnish Family HPV study. Overall, nine different HLA-G alleles were identified. The HLA-G genotype concordance of G01:01:01/01:04:01 increased the risk of high risk (HR)-HPV genotype positivity in cord blood and infant's oral mucosa. The mother-child concordance of G01:01:02/01:01:02 increased the risk of oral HPV positivity with HR-HPV genotypes both in the mother and offspring; OR 2.45 (95%CI 1.24-4.85). Discordant HLA-G allele for G01:04:01 and for G01:06 was significantly associated with infant's oral low risk (LR)-HPV at birth, OR 3.07 (95%CI 1.01-9.36) and OR 5.19 (95%CI 1.22-22.03), respectively. HLA-G had no association with HPV genotype-specific concordance between the mother and child at birth nor influence on perinatal HPV status of the child. Taken together, our results show that HLA-G molecules have a role in predicting the newborn's likelihood for oral HPV infection at birth.
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http://dx.doi.org/10.1016/j.humimm.2018.03.002DOI Listing
June 2018

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis.

BMJ 2018 02 27;360:k499. Epub 2018 Feb 27.

Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To estimate the regression, persistence, and progression of untreated cervical intraepithelial neoplasia grade 2 (CIN2) lesions managed conservatively as well as compliance with follow-up protocols.

Design: Systematic review and meta-analysis.

Data Sources: Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from 1 January 1973 to 20 August 2016.

Eligibility Criteria: Studies reporting on outcomes of histologically confirmed CIN2 in non-pregnant women, managed conservatively for three or more months.

Data Synthesis: Two reviewers extracted data and assessed risk of bias. Random effects model was used to calculate pooled proportions for each outcome, and heterogeneity was assessed using I statistics.

Main Outcome Measures: Rates of regression, persistence, or progression of CIN2 and default rates at different follow-up time points (3, 6, 12, 24, 36, and 60 months).

Results: 36 studies that included 3160 women were identified (seven randomised trials, 16 prospective cohorts, and 13 retrospective cohorts; 50% of the studies were at low risk of bias). At 24 months, the pooled rates were 50% (11 studies, 819/1470 women, 95% confidence interval 43% to 57%; I=77%) for regression, 32% (eight studies, 334/1257 women, 23% to 42%; I=82%) for persistence, and 18% (nine studies, 282/1445 women, 11% to 27%; I=90%) for progression. In a subgroup analysis including 1069 women aged less than 30 years, the rates were 60% (four studies, 638/1069 women, 57% to 63%; I=0%), 23% (two studies, 226/938 women, 20% to 26%; I=97%), and 11% (three studies, 163/1033 women, 5% to 19%; I=67%), respectively. The rate of non-compliance (at six to 24 months of follow-up) in prospective studies was around 10%.

Conclusions: Most CIN2 lesions, particularly in young women (<30 years), regress spontaneously. Active surveillance, rather than immediate intervention, is therefore justified, especially among young women who are likely to adhere to monitoring.

Systematic Review Registration: PROSPERO 2014: CRD42014014406.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826010PMC
http://dx.doi.org/10.1136/bmj.k499DOI Listing
February 2018

Breast Milk Is a Potential Vehicle for Human Papillomavirus Transmission to Oral Mucosa of the Spouse.

Pediatr Infect Dis J 2017 07;36(7):627-630

From the *Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland; †Department of Oral Pathology and Radiology, University of Turku, Turku, Finland; ‡Department of Obstetrics and Gynecology, Turku University Hospital, University of Turku, Turku, Finland; §Department of Clinical Research, Biohit Oyj, Helsinki, Finland; and ¶Department of Pathology, Turku University Hospital, Turku, Finland.

Background: Human papillomavirus (HPV) DNA has been detected in breast milk, but its origin has remained obscure. The aim of the study was to analyze the prevalence and persistence of HPV in breast milk in the Finnish Family HPV cohort study. The association of breast milk HPV positivity with the family members' oral HPV status was evaluated.

Methods: We included 308 families to the study where the mother was breast feeding her offspring. Mothers collected the milk samples manually at day 3, and at months 2, 6 and 12. Cervical and/or oral samples were collected from all family members. HPV testing was performed using nested polymerase chain reaction and Luminex-based Multimetrix kit.

Results: Breast milk HPV DNA was found in 10.1% (31/308), 20.1% (39/194) and 28.8% (17/59) of samples at day 3, months 2 and 6, respectively. The following HPV genotypes were detected: 6, 16, 18, 33, 45, 53, 56, 59, 66 and 82. Breast milk HPV persisted among 5.5% (9/164) of the lactating mothers. No significant associations were detected between the persistent breast milk HPV and the offspring's oral incident HPV infection. Breast milk HPV positivity showed a strong association with the fathers' oral HPV positivity at baseline, as well as at 6- and 12-month follow-up visits, with odds ratio (OR) = 3.24 [95% confidence interval (CI): 1.04-10.12], OR = 6.34 (95% CI: 1.84-21.89) and OR = 14.25 (95% CI: 1.16-174.80), respectively.

Conclusions: HPV in breast milk is prevalent among the lactating mothers and HPV can also persist in breast milk. The breast milk is a potential vehicle for HPV transmission to oral mucosa of the spouse but not of the offspring.
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http://dx.doi.org/10.1097/INF.0000000000001546DOI Listing
July 2017

Randomised trial on treatment of vaginal intraepithelial neoplasia-Imiquimod, laser vaporisation and expectant management.

Int J Cancer 2016 Nov 28;139(10):2353-8. Epub 2016 Jul 28.

Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital.

Vaginal intraepithelial neoplasia (VAIN) is associated with human papillomavirus (HPV) infection. The most common treatment modality is laser vaporisation, but recurrences are common. Imiquimod is an immune response modulator which is used for the treatment of external condylomas and other HPV-related genital neoplasias. The aim of the study was to evaluate the efficacy and tolerability of vaginally administered imiquimod in comparison with laser vaporisation and expectant management of high-grade VAIN. This proof of principle pilot study was a prospective 16-week randomised trial. We enrolled 30 patients with histologically confirmed VAIN 2 or 3 into three study arms: vaginally administered imiquimod, laser vaporisation and expectant management. Follow-up colposcopy visits included high-risk human papillomavirus (hrHPV) testing, cytology and punch biopsies. At baseline 77% (n = 20/26) of the patients were hrHPV positive. HPV clearance was significantly higher in the imiquimod arm (63%, n = 5/8) than in the laser arm (11%, n = 1/9) (p = 0.05) or in the expectant management arm (17%, n = 1/6) (p = 0.138). At baseline 25 patients (83%) had VAIN 2 and five (17%) had VAIN 3. None of the lesions progressed during the follow-up. Histological regression (≤VAIN 1) was observed in 80% (n = 8/10) of patients in the imiquimod arm, 100% (n = 10/10) of the laser arm (p = 0.474) and 67% (n = 6/9) of the expectant management arm (p = 0.628). Vaginal imiquimod appears to be as effective as laser treatment in high-grade VAIN.
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http://dx.doi.org/10.1002/ijc.30275DOI Listing
November 2016

Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16.

Int J Cancer 2015 Mar 19;136(6):E638-45. Epub 2014 Sep 19.

Department of Oncology, Division of Cancer Epidemiology, McGill University, Montreal, QC, Canada.

Methylation of human papillomavirus (HPV) and host genes may predict cervical cancer risk. We examined the methylation status of selected sites in HPV16 and human genes in DNA extracted from exfoliated cervical cell samples of 244 women harboring HPV16-positive cancer or cervical intraepithelial neoplasia (CIN) or negative for intraepithelial lesions or malignancy (NILM). We quantified the methylation of CpG sites in the HPV16 L1 gene (CpG 6367 and 6389) and in the human genes EPB41L3 (CpG 438, 427, 425) and LMX1 (CpG 260, 262, 266, 274) following bisulfite treatment and pyrosequencing. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic utility of methylation level for the different sites and for a joint predictor score. Methylation in all sites significantly increased with lesion severity (p < 0.0001). Area under the curve (AUC) was highest among the CIN2/3 vs. cancer ranging from 0.786 to 0.853 among the different sites. Site-specific methylation levels strongly discriminated CIN2/3 from NILM/CIN1 and cancer from CIN2/3 (range of odds ratios [OR]: 3.69-12.76, range of lower 95% confidence bounds: 1.03-4.01). When methylation levels were mutually adjusted for each other EPB41L3 was the only independent predictor of CIN2/3 vs. NILM/CIN1 contrasts (OR = 9.94, 95%CI: 2.46-40.27). High methylation levels of viral and host genes are common among precancerous and cancer lesions and can serve as independent risk biomarkers. Methylation of host genes LMX1 and EPB41L3 and of the viral HPV16 L1 sites has the potential to distinguish among precancerous lesions and to distinguish the latter from invasive disease.
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http://dx.doi.org/10.1002/ijc.29196DOI Listing
March 2015

HPV testing with cytology triage for cervical cancer screening in routine practice.

Am J Obstet Gynecol 2014 May 25;210(5):474.e1-7. Epub 2013 Dec 25.

Department of Pathology, McGill University and Jewish General Hospital, Montreal, QC, Canada; Department of Obstetrics and Gynecology, McGill University and Jewish General Hospital, Montreal, QC, Canada. Electronic address:

Objective: The purpose of this study was to evaluate the feasibility and effectiveness of Viral Testing Alone with Pap (Papanicolaou) Triage for Screening Cervical Cancer in Routine Practice (VASCAR) in a publicly funded university-affiliated hospital in Montreal, Canada.

Study Design: Women who are 30-65 years old are screened with the Hybrid Capture-2 assay. Women with negative results are retested at 3-year intervals; women with positive results are triaged with conventional cytologic methods. Women with Papanicolaou positive test results (≥atypical squamous cells of undetermined significance) are referred to colposcopy; women with Papanicolaou negative test results are retested with Hybrid Capture-2 assay and a Papanicolaou test in 1 year. Results were compared with a historic era (annual cytology with ≥atypical squamous cells of undetermined significance threshold for colposcopy referral) in the 3 years before VASCAR.

Results: VASCAR included 23,739 eligible women, among whom 1646 women (6.9%) tested positive for the human papillomavirus (HPV). Because of the need for subsequent sampling for cytologic testing, follow-up evaluation for cytologic triage was relatively poor; only 46% and 24% of HPV-positive women were Papanicolaou-triaged and underwent biopsy, respectively. Protocol violations occurred mainly in the early phases of implementation (12%). Detection of high-grade cervical intraepithelial neoplasia increased nearly 3-fold (rate ratio, 2.78; 95% confidence interval [CI], 2.1-3.7) during VASCAR, mostly because of a doubling in the rate of high-grade cervical intraepithelial neoplasia (34.0%; 95% CI, 21.2-48.8) compared with the historic cytology-only era (16.3%; 95% CI, 13.2-19.8). VASCAR reduced the median time to colposcopy from a positive screen from 11 months (95% CI, 10.48-11.50) to 3 months (95% CI, 2.64-3.80).

Conclusion: VASCAR is feasible; however, it requires cosampling for HPV and cytology and for continuous education of healthcare providers of the HPV-Papanicolaou triage protocol. Efficacy in disease detection and reduction in time to colposcopy referrals compared with the historic cytology era is encouraging but should be considered preliminary because of the small number of patients who were tested.
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http://dx.doi.org/10.1016/j.ajog.2013.12.033DOI Listing
May 2014

Polymorphism in the promoter region of the Toll-like receptor 9 gene and cervical human papillomavirus infection.

J Gen Virol 2013 Aug 15;94(Pt 8):1858-1864. Epub 2013 May 15.

HPV Institute, School of Medicine, Santa Casa de São Paulo, and Dept Radiology and Basic Oncology, School of Medicine, University of São Paulo, São Paulo, Brazil.

Polymorphism in the Toll-like receptor (TLR) 9 gene has been shown to have a significant role in some diseases; however, little is known about its possible role in the natural history of human papillomavirus (HPV) infections. We investigated the association between a single-nucleotide polymorphism (SNP) (rs5743836) in the promoter region of TLR9 (T1237C) and type-specific HPV infections. Specimens were derived from a cohort of 2462 women enrolled in the Ludwig-McGill Cohort Study. We randomly selected 500 women who had a cervical HPV infection detected at least once during the study as cases. We defined two control groups: (i) a random sample of 300 women who always tested HPV negative, and (ii) a sample of 234 women who were always HPV negative but had a minimum of ten visits during the study. TLR9 genotyping was performed using bidirectional PCR amplification of specific alleles. Irrespective of group, the WT homozygous TLR9 genotype (TT) was the most common form, followed by the heterozygous (TC) and the mutant homozygous (CC) forms. There were no consistent associations between polymorphism and infection risk, either overall or by type or species. Likewise, there were no consistently significant associations between polymorphism and HPV clearance or persistence. We concluded that this polymorphism in the promoter region of TLR9 gene does not seem to have a mediating role in the natural history of the HPV infection.
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http://dx.doi.org/10.1099/vir.0.052811-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749521PMC
August 2013

Genotype-specific incidence and clearance of human papillomavirus in oral mucosa of women: a six-year follow-up study.

PLoS One 2013 3;8(1):e53413. Epub 2013 Jan 3.

Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine and Medicity Research Laboratory, University of Turku, Turku, Finland.

Background: There are no previous longitudinal studies on genotype-specific natural history of human papillomavirus (HPV) infections in oral mucosa of women.

Methods: In the Finnish Family HPV Study, 329 pregnant women were enrolled and followed up. HPV-genotyping of oral scrapings was performed with nested PCR and Multimetrix® test (Progen, Heidelberg, Germany). Incidence and clearance times and rates for each HPV-genotype identified in oral mucosa were determined. Predictors for incident and cleared HPV infections for species 7/9 genotypes were analyzed using Poisson regression model.

Results: Altogether, 115 baseline HPV-negative women acquired incident oral HPV infection, and 79 women cleared their infection. HPV16 and multiple HPVs most frequently caused incident infections (65% and 12%) in 13.3 and 17.1 months respectively, followed by HPV58, HPV18 and HPV6 (close to 5% each) in 11-24 months. HPV58, HPV18 and HPV66 were the most common to clear. HPV6 and HPV11 had the shortest clearance times, 4.6 months and 2.5 months, and the highest clearance rates, 225.5/1000 wmr and 400/1000 wmr, respectively. The protective factors for incident oral HPV-species 7/9 infections were 1) new pregnancy during follow-up and 2) having the same sexual partner during FU. Increased clearance was related with older age and a history of atopic reactions, whereas previous sexually transmitted disease and new pregnancy were associated with decreased clearance.

Conclusions: HPV16 was the most frequent genotype to cause an incident oral HPV-infection. Low risk HPV genotypes cleared from oral mucosa more quickly than high risk HPV genotypes. Pregnancy affected the outcome of oral HPV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0053413PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536668PMC
August 2013

Prevalence, genotype distribution and persistence of human papillomavirus in oral mucosa of women: a six-year follow-up study.

PLoS One 2012 30;7(8):e42171. Epub 2012 Aug 30.

Department of Oral Pathology, Institute of Dentistry, and Medicity Research Laboratory, Faculty of Medicine, University of Turku, Turku, Finland.

Background: Human papillomavirus (HPV) infections have been linked to a subset of oral and oropharyngeal cancers. However, little is known on the natural history of oral HPV infections. We designed the prospective Finnish HPV Family Study to assess the dynamics of HPV infections in parents and their infants. This study reports HPV genotype distribution and virus persistence in oral mucosa of the mothers.

Materials And Methods: Totally, 324 pregnant women were enrolled at the 3(rd) trimester of pregnancy and followed-up for 6 years. Oral scrapings taken with a brush were collected and HPV-genotyping was performed with nested PCR and Multimetrix® test (Progen, Heidelberg, Germany). The predictors of persistent oral HPV species 7/9 infections were analyzed using generalized estimating equation models.

Results: The point prevalence of oral HPV varied from 15% to 24% during the 6-year follow-up. Altogether, 18 HPV genotypes were identified either as single or multiple-type oral infections. HPV16 was the most prevalent type at 9.7%-18.4%, followed by HPV18, HPV6, and multiple infections. Altogether, 74 women had persistent oral HPV infection determined as at least two consecutive samples positive with the same HPV genotype. HPV16 and HPV6 were the two most frequent types to persist (76% and 9%) for a mean of 18.6 and 20.2 months, respectively, followed by multiple infections (8%) for 18.3 months. An increased risk for persistent oral HPV infection with species 7/9 was associated with being seropositive for low-risk (LR)-HPV-types at baseline, whereas the use of oral contraceptives and a second pregnancy during follow-up were protective. Clinical oral lesions were detected in 17% of these women, one-third of whom had persistent oral HPV-infections.

Conclusion: HPV16 and HPV6 were the most common genotypes in oral HPV-infections and were also most likely to persist. Use of oral contraceptives and a second pregnancy protected against oral HPV persistence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042171PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431392PMC
February 2013

High-risk human papillomavirus associated with incident cervical intraepithelial neoplasia developing in mothers in the Finnish Family HPV Study cohort.

Scand J Infect Dis 2012 Feb 6;44(2):115-25. Epub 2011 Nov 6.

Department of Obstetrics and Gynaecology, Turku University Hospital, Turku, Finland.

Background: Cofactors of high-risk (HR) human papillomavirus (HPV) in the progression of cervical intraepithelial neoplasia (CIN) are incompletely characterized. In this study these cofactors were investigated in a longitudinal setting.

Methods: A cohort of 329 women (mean age 25.5 y) were enrolled in the Finnish Family HPV Study, and followed-up for 6 y with serial cervical samples for HPV genotyping, virus integration status, and HPV serology. Hospital records were reviewed until March 2010 and linked with HPV detection data. All incident CIN lesions were subjected to HPV genotyping. HPV covariates were studied in an age- and HPV-matched nested case-control (1:4) setting.

Results: Twelve of the 329 women developed an incident CIN: 2 CIN1, 3 CIN2, and 7 CIN3. HPV16 was detected most frequently (7/12), followed by HPV58 (2/12), HPV18, HPV31, and HPV42. HPV integration was present in 4/12 cases. Long-lasting persistence of HPV31 and HPV16 preceded incident CIN2 and CIN3. In multivariate conditional logistic regression, the risk for incident CIN increased up to 4-fold with increasing number of deliveries (p = 0.024) and decreased with history of genital warts (p = 0.036).

Conclusion: Baseline HR-HPV infections and their persistence precede incident CIN by several years. The 2 independent covariates of HR-HPV were (1) number of deliveries (increasing the risk), and (2) history of genital warts (protective effect).
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http://dx.doi.org/10.3109/00365548.2011.619999DOI Listing
February 2012

Incident cervical infections with high- and low-risk human papillomavirus (HPV) infections among mothers in the prospective Finnish Family HPV Study.

BMC Infect Dis 2011 Jun 22;11:179. Epub 2011 Jun 22.

Medicity Research Laboratory and Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Lemminkäisenkatu 2, 20520 Turku, Finland.

Background: The knowledge on type specificity and factors that increase or decrease the risk of incident HPV-infections is important to better understand the dynamics of HPV-infections.

Methods: A series of 329 pregnant women were enrolled in Finnish Family HPV Study at 3rd trimester of pregnancy and followed-up for 6 years, during which 203 baseline HPV-negative women acquired incident HPV infection. Incidence times and incidence rates (IR) were calculated for 24 low-and high-risk HPV-types detected by Multiplex-HPV-genotyping at each visit. Poison regression was used to estimate predictors of incident HPV infections of species 7 and 9 HPV-genotypes.

Results: HPV16 was the most frequent (47.8%) incident genotype followed by multiple-type infections (25.1%), and single infection with HPV18, 70, 6 and 45. Actuarial mean times to incident event were longest for HPV31 (34.5 months) and HPV45 (32.8 months), while crude mean times were longest for HPV56 (42.4 months) and HPV16 (23.1 months). Actuarial IR was highest for HPV16 and multiple-type infections. Independent protective factors against incident infections were 1) > 2 life-time sexual partners (p = 0.014), 2) later initiation of oral contraceptives (age > 20 years) (p = 0.017) and 3) pregnancy at FU visit (p = 0.0001).

Conclusions: Among newly delivered mothers, higher number of life-time sexual partners, initiation of OC use after age 20 and becoming pregnant during FU decreased the risk for incident species 7/9 HPV infections.
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http://dx.doi.org/10.1186/1471-2334-11-179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143927PMC
June 2011

Human papillomavirus and predictors of cervical intraepithelial neoplasia among young mothers in a prospective follow-up study.

Acta Obstet Gynecol Scand 2011 Feb 7;90(2):167-73. Epub 2010 Dec 7.

Medicity Research Laboratory and Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Finland.

Objective: To study the incidence times and rates for cervical intraepithelial neoplasia (CIN) and its predictors.

Material And Methods: This is a prospective follow-up study at Turku University Hospital, Finland. The Finnish Family human papillomavirus (HPV) study comprised 329 pregnant women followed up for 3 years. In an extension of the follow-up period, 171 women participated in an additional 3 years follow-up. Cervical scrapings for HPV testing and cervical smears were collected at each follow-up visit (2, 12, 24 and 36 months and 6 years). Following two abnormal cervical smears, colposcopy with biopsies was done. The main outcome measures were actuarial and crude incidence times, incidence rates and predictors of incident CIN.

Results: During the follow-up period, 10 women (3.2%) developed biopsy-confirmed CIN, and four presented with incident atypical squamous cells suggesting high-grade squamous intraepithelial lesion cytology. The CIN/squamous intraepithelial lesion developed in 74.5 and 66.3 months, with crude incidence rates of 13.4/1,000 and 15.1/1,000 women months at risk, respectively. In multivariate Poisson regression, independent predictors of incident CIN were as follows: high-risk HPV positive at baseline (incidence rate ratio = 5.54; 95% confidence interval 1.02-30.14, p= 0.048); type-specific high-risk HPV persistence during follow-up (incidence rate ratio = 5.84; 95% confidence interval 2.28-17.93, p= 0.0001); cervical smear cytologically diagnosed for atypical squamous cells of undetermined significance or worse at any follow-up visit (incidence rate ratio = 4.56; 95% confidence interval 2.37-8.78, p= 0.0001); and new sexual partner during follow-up (incidence rate ratio = 9.45; 95% confidence interval 1.90-46.97, p= 0.006).

Conclusion: The results indicate that combined use of cervical smear and HPV testing, with prompt referral to colposcopy, enables accurate detection of incident CIN well before progression to invasive cancer. In addition to baseline and persistent high-risk HPV, abnormal cervical smear and new sexual partner are key predictors of incident CIN.
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http://dx.doi.org/10.1111/j.1600-0412.2010.01029.xDOI Listing
February 2011

Genotype-specific persistence of genital human papillomavirus (HPV) infections in women followed for 6 years in the Finnish Family HPV Study.

J Infect Dis 2010 Aug;202(3):436-44

Medicity Research Laboratory and Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.

Background: Persistent human papillomavirus (HPV) infection is the most important risk factor for cervical cancer, and understanding genotype-specific HPV persistence is essential for elucidating the natural history of HPV infections.

Methods: In the Finnish Family HPV Study, 329 pregnant women (mean age, 25.5 years) were recruited during the third trimester of pregnancy and were followed up for 6 years. Multiplex HPV genotyping for 27 low- and high-risk HPV types was used to define genotype-specific prevalence at each visit. Generalized estimating equation models were constructed to estimate predictors of type-specific persistence (positive results at 2 consecutive visits) of species 7 and 9 HPV genotypes.

Results: HPV16 was the most common type, followed by HPV types 18, 31, 35, 45, 58, 70, and 6. Prevalence of multiple infections ranged from 21% to 45%. Persistence was most prolonged for HPV types 35, 58, and 52, with durations of 38.7, 32.1, and 24.2 months, respectively, and was equal for multiple-type infections and HPV16, with durations of 21 and 24 months, respectively. Independent predictors of type-specific persistence of species 7 and 9 HPV genotypes were age (odds ratio, 1.13 [95% confidence interval, 1.02-1.25]; P=.017), oral sex (odds ratio, 0.37 [95% confidence interval, 0.17-0.81]; P=.013), and young age (<13 years) at initiation of smoking (odds ratio, 0.51 [95% confidence interval, 0.27-0.98]; P=.046).

Conclusion: HPV16 was the most frequent persisting HPV genotype followed by multiple infections. Early initiation of smoking, practicing oral sex and older age increase the risk for persistence of species 7 and 9 HPV genotypes.
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http://dx.doi.org/10.1086/653826DOI Listing
August 2010

Genotype-specific clearance of genital human papillomavirus (HPV) infections among mothers in the Finnish family HPV study.

J Clin Microbiol 2010 Aug 16;48(8):2665-71. Epub 2010 Jun 16.

Department of Oral Pathology, Institute of Dentistry and Medicity Research Laboratory, Faculty of Medicine, Lemminkäisenkatu 2, 20520 Turku, Finland.

The majority of cervical human papillomavirus (HPV) infections in young women are transient, but whether the clearance differs among different HPV genotypes and the different factors predicting genotype-specific clearance are partly unknown. In the Finnish Family HPV Study, 131 of 252 women (mean age, 25.5 years) cleared their infection during the prospective follow-up of 6 years (median, 62.4 months; range, 1.6 to 94.5 months). Cervical scrapings collected at each visit were tested for 24 low-risk and high-risk (HR) HPV types with multiplex HPV genotyping. Poison regression (panel data) was used to estimate predictors for the clearance of species 7 and 9 HPV genotypes. Of all HPV genotypes detected in these women, multiple-type and HPV type 16 (HPV16) infections showed clearance least frequently (46.1% and 50.5%, respectively). The actuarial and crude mean times to first clearance were variable among different genotypes. The actuarial clearance rate (events/person-time at risk) was highest for HPV16 and multiple-type infections, while HPV66 and -82 had the highest crude clearance rate. Independent predictors increasing type-specific clearance of species 7/9 HPV genotypes were older age (incidence rate ratio [IRR] = 1.1; 95% confidence interval [95% CI], 1.03 to 1.18; P = 0.002) and baseline oral HR HPV DNA-negative status (IRR = 2.94; 95% CI, 1.03 to 8.36; P = 0.042), while a higher number of sexual partners during the follow-up decreased the probability of clearance (IIR = 0.35; 95% CI, 0.15 to 0.83; P = 0.018). To conclude, HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance.
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http://dx.doi.org/10.1128/JCM.00783-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916623PMC
August 2010