Human Papillomavirus Negative Women Research Articles

Association between cervical immune markers and cervical high-risk HPV infections.

e17522 Background: Evidence suggests that human papillomavirus (HPV) infection of the cervix, alters local immune markers. The aim of this study was to comprehensively evaluate the types and concentration of cervical cytokines and chemokines in HPV-negative compared to HPV-positive women in sub-Saharan African. Methods: The study population was 275 women enrolled in the African Collaborative Center for Microbiome and Genomics (ACCME) HPV cohort study. The concentration of 27 chemokines, cytokines and growth factors was quantified from cervical samples, using multiplexed bead-based immunoassays. HPV types were characterized using SPF25/LiPA10. Regression models were used to estimate the association between each immune marker and HPV infection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for fold-change in immune marker levels divided into quartiles, using the lowest quantile as a reference category. Results: The mean (±SD) age of the women was 41 (±8) years. Some, 49% (134/275) were HPV negative and 51% (141/275) were HPV positive. Of the HPV positive women, 39% (55/141) had low-risk HPV (lrHPV) types and 93% (131/141) had high-risk HPV (hrHPV) types. Compared to HPV negative women, lrHPV-positive women had significantly higher median concentration of IFN-g, IL-2, IL-4, IL-7, IL-10 and IL-13. While hrHPV-positive women had significantly lower median concentration of GMCSF, interleukin (IL)-1RA and MCP-1; and higher median concentration of interferon-g (IFN-g), IL-b, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15 and MCP-1b, compared to HPV negative women. Women had significantly higher odds of lrHPV infection if they were in the highest quartile for IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70 and IL-13. While women had significantly lower odds of hrHPV infection if they were in the highest quartile for IL-IRA (OR 0.16, 95% CI: 0.07, 0.34) or MCP-1 (OR 0.39, 95% CI: 0.18, 0.83), and significantly higher odds of hrHPV infections if they were in the highest quartile for eotaxin, IFN-g, IL-1b, IL-4, IL-5, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, MIP-1a, MIP-1b or TNFa. Conclusions: Consistent with findings from other populations, higher concentration of pro-inflammatory immune markers in the cervix were associated with higher odds of high-risk HPV infections among African women.

The association of HPV infection and vaginal microbiota of reproductive women in China: A multicenter cohort study protocol

Cervical cancer is a global health concern. Persistent oncogenic human papillomavirus (HPV) infection is a prerequisite for the development of cervical cancer. Emerging research indicates that the vaginal microbiota may play both protective and harmful roles in the acquisition and persistence of HPV and the development of cervical cancer. This multicenter cohort study mainly aims to reveal the association of vaginal microbiota with the outcome of HPV infection in six months in women of reproductive age. We will recruit 50 research centers and enroll a total of about 10,000 female volunteers with a series of strict inclusion and exclusion criteria across China, including HPV positive and HPV negative women. A unified questionnaire will be used to obtain the sociodemographic information, clinical data and lifestyle of all volunteers. Specimens including vaginal secretions swabs and cervical exfoliated cells will be collected at the first visit and follow-up after six months. We will use 16S rRNA sequencing to characterize the vaginal microbiota of volunteers’ vaginal swabs. Twenty-one HPV genotypes and other sexually transmitted pathogens, including Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium and Herpes simplex virus type Ⅱ will be examined using flow-through hybridization and gene chip. The association of HPV infection and vaginal microbiota will be investigated, and the core microbiota attributes to the persistent HPV infection will be analyzed in this study.

Performance of HPV testing, Pap smear and VIA in women attending cervical cancer screening in Kilimanjaro region, Northern Tanzania: a cross-sectional study nested in a cohort

ObjectiveThere is a concern about performance of the screening approaches, where information on the quality of novel and affordable screening approaches that will perform well in remote areas is warranted....

To evaluate the role of placental human papilloma virus (HPV) infection as a risk factor for spontaneous preterm birth: a prospective case control study.

i) To compare the placental human papilloma virus (HPV) deoxynucleic acid (DNA) status of preterm deliveries with full term deliveries and to identify high risk(HR) genotypes (HPV 16 and 18); and ii) To compare the perinatal outcomes of HPV positive with HPV negative pregnant women. A case control study was carried out on 100 antenatal women with singleton live pregnancies admitted in labor ward of a tertiary care teaching hospital from April 2017 to March 2018. The two study groups were i) spontaneous preterm deliveries between 24 and 36+6weeks (n=50) and ii) full term deliveries≥37weeks (n=50). The placental tissue was analysed for HPV DNA and HR HPV genotypes were detected by type specific primers. A comparative analysis of perinatal outcomes between HPV positive and negative women was done. An overall placental tissue HPV prevalence of 12% (12/100) was observed in study cohort which was not significantly different between preterm and full term deliveries (16 vs. 8%, p=0.218). HPV 16 was significantly associated with preterm births (p=0.04). Both HPV affected and non-affected women were comparable in terms of mode of delivery and neonatal outcomes. However, a statistically significant association of preterm neonatal intensive care admissions with HR HPV 16 genotype was observed (p=0.04). Spontaneous preterm births can be attributed to placental HPV infection, specifically HR HPV 16genotype. This association identifies a potentially preventable cause of prematurity and its associated complications, in wake of availability of an effective vaccine.

Association of TNF-α-308G/A and IL-18 Polymorphisms with risk of HPV infection among sexually active women in Burkina Faso.

Human papillomavirus (HPV) infection is the most common sexually transmitted infection worldwide. Persistence infection can lead to the development of cervical cancer potentially due to some genetic factors such as polymorphisms in regulatory and coding regions of cytokine genes. The purpose of this study was to determine whether there is a relationship between TNF-308 G/A or IL18 polymorphisms and high-risk HPV infection among sexually active women from Burkina Faso. Ninety-one HPV infected and two hundred and nine HPV negative women (the latter used as healthy controls) were screened. TNFA-308 G/A and IL18-607 C/A polymorphisms were detected using the TaqMan allelic discrimination. HPV 52 (21.19%), HPV 39 (11.86%) and HPV 33 (11.02%) were the most common HPV genotypes. The TNFA-308A and IL18-607 C alleles were predominant in all women in the study. None of the TNFA and IL18 alleles were associated with HPV infection. The results suggest that there is no relationship between TNF-308 G/A or IL18-607C/A polymorphisms and HPV infection among women in the study.

Different Risk Factors Associated with Persistence or Regression of Squamous Intraepithelial Lesions of Cervix under Rural Conditions in India

Introduction: In many Human Papilloma Virus (HPV) negative women, the Squamous Intraepithelial Lesions (SIL) of cervix often show persistence or progression of the lesion on follow-up which shows involvement of other risk factors of carcinoma cervix. Aim: The aim of the study was to evaluate the different risk factors of cervical cancer in persistent, progressed and regressed cases of SIL to identify the prominent ones among them. Materials and Methods: The study had been of a screening type for early detection of cervical cancer and it was done in the women population of west Lucknow, Uttar Pradesh, India (May, 2013-February, 2020). Cervical smears were collected in 2949 women attending the camps whose cytological examination revealed 498 cases of SIL and follow-up was available in 254 of them done through home visits after 1-4 years. Persistence of SIL was seen in 60 women on follow-up while in the remaining 194, the SIL had regressed to normal. The percentage of different risk factors seen with the persistence or regression of SIL was studied. Results: Among the different risk factors identified, prominent were of young age between 16-30 years with vaginal discharge and their percentage were insignificantly higher with persistence of SIL than in the regression group. Multiparity was also highly associated with both persistence and regression of SIL. The erosion of cervix was significantly associated with SIL persistence while associated inflammation was insignificantly higher in persistent than in the regression group. The percentage of all these factors except erosion of cervix was found higher in HPV- positive than in the HPV negative women. Conclusion: It appears that all the identified risk factors are present both in persistent and regression group but their percentage is higher with persistence of SIL. Hence, presence of any of these factors in these two groups should be viewed with caution to rule out any progression/recurrence of SIL.

HPV infection and the genital cytokine milieu in women at high risk of HIV acquisition

Human papillomavirus (HPV) infection correlates with higher rates of HIV acquisition, but the underlying biological mechanisms are unclear. Here we study associations between HPV and HIV acquisition and relate these to vaginal cytokine profiles in an observational cohort of women at high risk of HIV infection (CAPRISA 004, n = 779) and with 74% HPV prevalence. We report here that HPV infection associates with a 2.5-fold increase in HIV acquisition risk in this population (95% CI: 1.2–5.3). Among 48 vaginal cytokines profiled, cytokines associated with HPV infection overlap substantially with cytokines associated with HIV risk, but are distinct from those observed in HPV negative women. Although our data do not establish a causative link between HPV status and the risk of HIV, we suggest that increasing HPV vaccination coverage may carry an additional benefit of reducing the risk of contracting HIV infection, particularly in regions with high HPV prevalence.

Clinical practice variation and overtreatment risk in women with abnormal cervical cytology in the Netherlands: two-step versus see-and-treat approach

Only a few small studies have compared the 2-step method (biopsy followed by treatment) with a see-and-treat (immediate treatment) approach in women both low-grade or high-grade referral cytology. The clinical practice variation in the Netherlands has not been reviewed before. To determine overtreatment rates in the 2-step versus see-and-treat approach in women referred for colposcopy because of abnormal cytology results, and to evaluate clinical practice variation in the Netherlands. This was a population-based retrospective cohort study including 36,581 women with a histologic result of the cervix identified from the Dutch Pathology Registry (PALGA) between 2016 and 2017. Odds ratios for overtreatment, defined primarily as cervical intraepithelial neoplasia grade 1 or less, were determined for the 2-step and see-and-treat approach in relation to age, high-risk human papillomavirus status, and referral cytology. Of the included women 10,713 women (29.3%) received the 2-step method; 6,851 women (18.7%) underwent see-and-treat; and 19,017 women (52.0%) received conservative management after colposcopy with histologic assessment with cytologic follow-up or another type of treatment. Despite the existence of a national guideline advising see-and-treat only in case of suspected high-grade disease in women who have completed their childbearing, there is a wide practice variation between the 2 strategies in the Netherlands, with 7.0-88.3% of the women receiving see-and-treat per laboratory. The median time between cytology and treatment was 1-2 months (range, 0-12 months) in women receiving see-and-treat and the 2-step method, respectively. A total of 4119 women (23.5%) were overtreated, with older women, high-risk human papillomavirus-negative women, and women with low-grade cytology results being more likely to be overtreated. Women with low-grade cytology results and see-and-treat were associated with a higher overtreatment rate than women receiving the 2-step method (65.0% [1414 of 2174] versus 32.1% [1161 of 3613], respectively; odds ratio, 3.34; 95% confidence interval, 2.92-3.82). However, in women with high-grade cytology results, see-and-treat was inversely associated with overtreatment (11.3% [529 of 4677] versus 14.3% [1015 of 7100], respectively; odds ratio, 0.68; 95% confidence interval, 0.58-0.81). A see-and-treat approach is justified only in women with high-grade cytology results who have completed their childbearing. There is a wide practice variation between the 2 strategies in the Netherlands, and gynecologists should adhere to the guideline to prevent overtreatment.

Prevalence of oral HPV infection in cervical HPV positive women and their sexual partners.

Human papillomavirus (HPV) infection represents the primary cause of anogenital premalignant and malignant disease. Regarding the high prevalence of cervical HPV infection and the increasing incidence of HPV associated oropharyngeal cancer in recent years, a significant viral transmission from the cervical to the oral site, possibly depending on the sexual behavior must be considered. The present study aims to determine the prevalence of oral HPV infection in cervical HPV positive and negative women and their sexual partners. Cervical HPV positive and negative women and their sexual partners took part in the study. Cervical smears, oral smears and mouthwashes were taken from women attending gynecological outpatient clinics in two different institutions. Further, oral smears as well as mouthwashes of their sexual partners were obtained whenever possible. HPV genotyping was performed using the Cobas® polymerase chain reaction and nucleic acid hybridization assay for the detection of 14 high-risk HPV types. In addition, all participants were invited to complete a personal questionnaire. 144 HPV positive and 77 HPV negative women and altogether 157 sexual partners took part in the study. Age, sexual behaviour, medication, smoking and alcohol consumption were distributed equally in both groups. Cervical HPV positive women had a significantly higher number of sexual partners. One woman with a HPV positive cervical smear and one partner of a woman with a HPV positive cervical smear showed an oral HPV infection. No oral HPV infections were detected in the HPV negative control group. The overall incidence of oral HPV infection was 0.5%, the incidence of oral HPV infection in women with a positive cervical smear was 0.7%. The data demonstrate that the overall risk of an oral HPV infection is low. HPV transmission to the oropharynx by autoinoculation or oral-genital contact constitute a rare and unlikely event.

Sexual Dysfunction in Human Papillomavirus Positive Females during Reproductive Age

Objective: Female sexual dysfunction (FSD) has been reported 40% of women of all ages and has important and unique effect on quality of life. We aimed to examine sexual function of patients with positive Human Papillomavirus (HPV) test results and investigate whether HPV has any impact on female sexual functioning since it has become a risk and distress of cancer. Methods: In Turkey, since 2014, women aged 30-65 years are screened for free by Family Health Centers with HPV-DNA test for cervical cancer. Sexually active, with at least basic literacy reproductive aged women who applied to oncology department of gynecology with HPV positive test results were included the study. History of systemic, chronic disease, including psychiatric disease or on psychiatric medication, pelvic organ prolapse, history of pelvic surgery (known to cause female sexual dysfunction), pregnant, body mass index (BMI)>30), and premature menopause women were excluded. Female sexual dysfunction index (FSFI) was used to assess FSD. A score of less than 26 indicated sexual dysfunction. HPV negative healthy women created control group. The groups were matched for age, BMI, parity, socio demographic and educational levels. The demographic, obstetric and gynecologic history of all patients was recorded. Results: A total of 119 women were recruited. Among patients, 54 had HPV positive test results while 65 had negative as controls. There was no significant difference between in mean scores of age, partner’s age, duration of marriage and BMI. The two groups were comparable with respect to number of children, education level and occupational status. The mean score on FSFI was 22.3 ± 6.6 points in HPV positive women and 26.3 ± 4.6 in healthy controls. Except for desire, other domains of FSFI (arousal, lubrication, orgasm, satisfaction, and pain) were statistically significantly lower in HPV positive women compared to controls in our study. Conclusion: Female sexual dysfunction was prevalent among women with HPV infection. These patients are needed to be routinely checked for sexual dysfunction.

Human papillomavirus infection and cervical cancer precursor lesions in women living by Amazon rivers: investigation of relations with markers of oxidative stress.

ABSTRACTObjective To investigate the relation between oxidative stress markers, human papillomavirus infection and cervical cancer precursor lesions.Methods The study comprised women aged 14 to 60 years living in communities located by Amazon rivers in the state of Pará (Itaituba, Limoeiro do Ajuru and Bragança, 126, 68 and 43 women respectively). Papanicolau smears and polymerase chain reaction tests for human papillomavirus DNA detection were performed. Blood samples were collected to test malondialdehyde, total and oxidized glutathione levels.Results Malondialdehyde, total and oxidized glutathione concentrations did not differ significantly (p>0.05) between women with and without low-grade squamous intraepithelial lesions across communities. Malondialdehyde levels (8.02nmols/mL) were almost five times higher in human papillomavirus-positive compared to human papillomavirus-negative women (1.70nmols/mL) living in Itaituba (statistically significant difference; p<0.05). Malondialdehyde levels did not differ significantly (p>0.05) between human papillomavirus-positive and human papillomavirus-negative women living in remaining communities. Significant (p<0.05) differences in total glutathione levels between human papillomavirus-positive and human papillomavirus-negative women (8.20μg/mL and 1.47μg/mL, respectively) were limited to those living in Bragança.Conclusion Malondialdehyde and total glutathione levels were significantly associated with human papillomavirus infection. However, lack of similar associations with squamous lesions suggest oxidative stress alone does not explain correlations with cervical carcinogenesis. Other factors may therefore be involved.

Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection

Changes in cervico-vaginal microbiota with Lactobacillus depletion and increased microbial diversity facilitate human papillomavirus (HPV) infection and might be involved in viral persistence and cancer development. To define the microbial Community State Types (CSTs) associated with high-risk HPV−persistence, we analysed 55 cervico-vaginal samples from HPV positive (HPV+) women out of 1029 screened women and performed pyrosequencing of 16S rDNA. A total of 17 samples from age-matched HPV negative (HPV−) women were used as control. Clearance or Persistence groups were defined by recalling women after one year for HPV screening and genotyping. A CST IV subgroup, with bacterial genera such as Gardnerella, Prevotella, Megasphoera, Atopobium, frequently associated with anaerobic consortium in bacterial vaginosis (BV), was present at baseline sampling in 43% of women in Persistence group, and only in 7.4% of women in Clearance group. Atopobium genus was significantly enriched in Persistence group compared to the other groups. Sialidase-encoding gene from Gardnerella vaginalis, involved in biofilm formation, was significantly more represented in Persistence group compared to the other groups. Based on these data, we consider the CST IV-BV as a risk factor for HPV persistence and we propose Atopobium spp and sialidase gene from G. vaginalis as microbial markers of HPV−persistence.

Research Article Association between polymorphisms in TLR4 gene targeted by microRNA-140 and cervical precancerous lesion in south Chinese women: a case control study

Toll-like receptor 4 (TLR4), one of the key immune system effectors, plays a main role in immune recognition of cervical cancer. Micro-RNAs are involved in regulation of multiple important genes in the progression of cervical cancer. A case-control study of 592 people was conducted from Yun’an County, Yunfu City, Guangdong Province, China. Cervical fall off epithelia were collected to detect human papilloma virus (HPV), followed by Thin Prep cytology test (TCT). Moreover, extraction of DNA from peripheral blood were performed for genotyping from the 296 patients and another 296 age-matched healthy control subjects. Logistic regression was used to determine the risk genotypes for susceptibility to cervical precancerous lesion, and multifactor dimensionality reduction (MDR) was further employed to preliminarily investigate the gene-environment interaction on risk of cervical precancerous lesion. Gene expression of miRNA-140 from serum was done by real-time PCR. We investigated whether target sites of TLR4 gene polytheisms (rs11536896 T>C, rs7873784 G>C) of miR-140 were associated with cervical precancerous lesion risk. The alleles C>A of SNP rs11536896 were significantly different in ASCUS in comparison of case group and control group with HPV infection. The presence of the allele C was associated with a higher risk of developing ASCUS lesion in HPV negative women (OR: 1.75, 95%CI:1.20-2.54, p = 0.003). There was statistically significant difference between the expression of miRNA 140 and the susceptibility to cervical precancerous lesion, in which there is down-regulation of the miRNA-140 in case group (T=6.73i¼ŒP=0.007). Gene-environment interaction analysis by MDR software revealed an association among rs7873784 and hrHPV infection and more types of infected HPV (p < 0.0001, OR: 25.48; 95%Cl: 5.20-124.84). Collectively, these results suggested that rs11536896 and rs787378 from TLR4 gene were associated with risks of cervical precancerous lesion. Thus, this miRNA-140 and SNPsi¼ˆrs11536896rs787378i¼‰ of TLR4 gene could be considered as a potential molecular mechanism and biomarker for detecting and diagnosing cervical cancer in early time

PP046 Screening In Women Vaccinated Against Human Papillomavirus: Governing Innovation

INTRODUCTION:In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age for cervical cancer (CC) screening from 2017. According to the National Prevention Plan 2014–18, HPV-based screening must be implemented for women ≥30 years old, following the Italian Health Technology Assessment (HTA) report recommendations (1). The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention.METHODS:The National Screening Monitoring Centre and the Italian Group for Cervical Screening, following a commitment by the Italian the Ministry of Health (MoH), identified the consensus conference as the most suitable method for addressing this topic. The objective was defining the best screening methods in girls vaccinated against HPV and the knowledge needs for defining evidence-based screening strategies. During the consensus celebration (24 November 2015) a jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews (2).RESULTS:The jury considered changing the screening protocols for girls vaccinated in their 12th year as appropriate. Tailored screening protocols based on vaccination status could be replaced by “one size fits all” protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with the HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5 years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their 15th year or later, the current protocol should be kept.CONCLUSIONS:As further action, in 2016 the Ministry of Health funded a Health Technology Assessment program of the new screening protocol proposed by the consensus conference and a cohort study for determining a safe interval in vaccinated women.

Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference.

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by "one size fits all" protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept.

Safety of extending screening intervals beyond five years in cervical screening programmes with testing for high risk human papillomavirus: 14 year follow-up of population based randomised cohort in the Netherlands

To provide an early risk assessment of extending screening intervals beyond five years for a human papillomavirus (HPV) based cervical screening programme in the Netherlands. 14 year follow-up of a population based randomised cohort from the POBASCAM randomised trial. Organised cervical screening in the Netherlands, based on a programme of three screening rounds (each round done every five years). 43 339 women aged 29-61 years with a negative HPV and/or negative cytology test participating in the POBASCAM trial. Women randomly assigned to HPV and cytology co-testing (intervention) or cytology testing only (control), and managed accordingly. Cumulative incidence of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+). Associations with age were expressed as incidence rate ratios. In HPV positive women, reductions in CIN3+ incidence after negative cytology, HPV type 16/18 genotyping, and/or repeat cytology were estimated. The cumulative incidence of cervical cancer (0.09%) and CIN3+ (0.56%) among HPV negative women in the intervention group after three rounds of screening were similar to the cumulative among women with negative cytology in the control group after two rounds (0.09% and 0.69%, respectively). Cervical cancer and CIN3+ risk ratios were 0.97 (95% confidence interval 0.41 to 2.31, P=0.95) and 0.82 (0.62 to 1.09, P=0.17), respectively. CIN3+ incidence was 72.2% (95% confidence interval 61.6% to 79.9%, P<0.001) lower among HPV negative women aged at least 40 years than among younger women. No significant association between cervical cancer incidence and age could be demonstrated. CIN3+ incidence among HPV positive women with negative cytology, HPV 16/18 genotyping, and/or repeat cytology was 10.4 (95% confidence interval 5.9 to 18.4) times higher than among HPV negative women. Long term incidences of cervical cancer and CIN3+ were low among HPV negative women in this study cohort, and supports an extension of the cervical screening interval beyond five years for women aged 40 years and older. HPV positive women with subsequent negative cytology, HPV16/18 genotyping, and/or repeat cytology have at least a fivefold higher risk of CIN3+ than HPV negative women, indicating that HPV based programmes with long intervals (>five years) should be implemented with risk stratification.Trial registrationPOBASCAM trial number ISRCTN20781131.

Candidate Soluble Immune Mediators in Young Women with High-Risk Human Papillomavirus Infection: High Expression of Chemokines Promoting Angiogenesis and Cell Proliferation.

BackgroundThe causal interpretation of cervical immune response to Human Papillomavirus (HPV) infection is complex and poorly characterized mainly due to the delicate balance that exists between viral infection, increase of inflammatory cytokines and host risk factors. This study aims to explore the significance of cervical immune mediators associated to cell survival, angiogenesis and interaction with immune response, in predicting the risk to develop HPV-related intraepithelial lesions.MethodsA panel of 48 cytokines and growth factors were explored in a selected cohort of 168 immunocompetent women including 88 diagnosed with low (LSIL) or high (HSIL) squamous intraepithelial lesions of the cervix and 80 with normal cervical cytology (NIL). HPV genotyping was performed by Linear Array HPV test and the soluble concentration of 48 immune molecules was analyzed using the Bio-Plex platform.ResultsThe prevalence of single HR-HPV infection was 30% in NIL and 100% in LSIL and HSIL women. The expression of 13 cytokines, including interleukins IL-6, IL-3, IL-12p40, IL-12p70, IL-16, IL-18, LIF, of chemokines CCL7 (MCP-3), CXCL9 (MIG), CXCL12 (SDF-1α) and of the tropic factors VEGF, G-CSF, M-CSF were significantly associated with the presence of infection, with levels being higher in women with precancerous lesions compared to NIL HPV negative women. Only the growth factor GM-CSF was positively associated with the cytological abnormalities.ConclusionsThe ability of HR-HPV to escape from innate immune recognition and to orchestrate the production of specific inflammatory and growth factors, involved in early inflammatory response and in the cell-proliferating phase of intraepithelial damage, was documented in women before the development of cervical lesions.

Tumor necrosis factor (TNF) alpha and interleukin (IL) 18 genes polymorphisms are correlated with susceptibility to HPV infection in patients with and without cervical intraepithelial lesion

Background: The Human Papillomavirus (HPV) predisposes 500 000 women to cervical cancer. Host genetic background may facilitate virus persistence in the uterine cervix. Polymorphisms in regulatory and coding regions of cytokine genes have been associated with susceptibility to some human diseases.Aim: This study aims at investigating whether TNFA -308 G/A and IL18 -137 G/C and -607 C/A polymorphisms are associated with susceptibility to HPV infection/progression to high-grade squamous intraepithelial lesion (HSIL).Subjects and methods: One hundred and twenty-two HPV infected and 132 HPV negative women (the latter used as healthy controls) were analysed. TNFA -308 G/A and IL18 (-137G/C and -607 C/A) polymorphisms were analysed using specific sequence polymorphism PCR (SSP-PCR). Univariate statistical analysis and a logistic regression were performed.Results: The TNFA -308A allele was associated with susceptibility to HPV infection (p = 0.0008), while the IL18 -607A allele conferred protection against HPV infection (p = 0.0043). TNFA -308 G/A and IL18 (-137G/C and -607 C/A) polymorphisms were not associated with development of cervical lesions (p > 0.05). An association was also observed between smoking and susceptibility to the development of HSIL.Conclusion: The findings suggest an association between two TNFA SNPs and susceptibility to HPV infection in women from Northeast Brazil. The results need to be functionally validated and replicated in other populations with different ethnic backgrounds.

A joint model of persistent human papillomavirus infection and cervical cancer risk: Implications for cervical cancer screening.

New cervical cancer screening guidelines in the US and many European countries recommend that women get tested for human papillomavirus (HPV). To inform decisions about screening intervals, we calculate the increase in precancer/cancer risk per year of continued HPV infection. However, both time to onset of precancer/cancer and time to HPV clearance are interval-censored, and onset of precancer/cancer strongly informatively censors HPV clearance. We analyze this bivariate informatively interval-censored data by developing a novel joint model for time to clearance of HPV and time to precancer/cancer using shared random-effects, where the estimated mean duration of each woman's HPV infection is a covariate in the submodel for time to precancer/cancer. The model was fit to data on 9,553 HPV-positive/Pap-negative women undergoing cervical cancer screening at Kaiser Permanente Northern California, data that were pivotal to the development of US screening guidelines. We compare the implications for screening intervals of this joint model to those from population-average marginal models of precancer/cancer risk. In particular, after 2 years the marginal population-average precancer/cancer risk was 5%, suggesting a 2-year interval to control population-average risk at 5%. In contrast, the joint model reveals that almost all women exceeding 5% individual risk in 2 years also exceeded 5% in 1 year, suggesting that a 1-year interval is better to control individual risk at 5%. The example suggests that sophisticated risk models capable of predicting individual risk may have different implications than population-average risk models that are currently used for informing medical guideline development.

Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial

Objectives To assess whether the increased sensitivity of screening for human papillomavirus (HPV) may represent overdiagnosis and to compare the long term duration of protective effect against cervical intraepithelial neoplasia...