Evaluation of an isothermal amplification HPV detection assay for primary cervical cancer screening.

OBJECTIVE: The aim of this research was to evaluate independently the performance of a new isothermal amplification assay for cervical cancer screening compared to two previously validated PCR-based assays and histologic endpoints. METHODS: This is a sub-study from the Chinese multi-center screening trial (CHIMUST). The self-collected and clinician-collected specimens stored in PreservCyt at - 4 °C from 6042 women with complete data were tested with the AmpFire assay. These specimens had been previously tested with Cobas and SeqHPV assays. In the primary study all patients with an abnormal test were referred to colposcopy where all had directed and/or random biopsies plus ECC. No additional patients were called back based on the AmpFire results. RESULTS: 6042/6619 women had complete data (mean age 44.1). There were 57 cases of CIN 2, 35 cases of CIN 3 and 2 cancers. The sensitivity for CIN2+ and CIN3+ were similar among the three assays (both direct and self-collected). For the specificities in all categories (CIN2+/CIN3+ and self and direct collection), isothermal amplification assay was either equal to or more specific than Cobas but consistently less specific than SeqHPV. CONCLUSION: The AmpFire HPV assay showed similar sensitivity to Cobas and SeqHPV for CIN2+ and CIN3+ on both self and clinician-collections (P>0.05), with good specificity. The speed, low cost, and simplicity of this assay will make it particularly suited for low and middle resource settings. Its accuracy with self-collection makes it applicable for mass screening programs.

Chronic migraine-cephalgia related to trigeminal artery: a case report of innovative regenerative approach.

Persistent trigeminal artery (PTA) originates from the posterior bend or lateral wall of the intra-cavernous carotid artery and is the most common occurring type of remnant primitive fetal arteries. In literature, there is limited number of reports on migraine-cephalgia (MC) associated with coexisting PTA. The primitive anastomose arteries that fully belong to the intracranial arterial vascular system are not supposed to perform any supportive functional activity; usually they are subjected to normal biological decay caused by the aging process and metabolic dysfunctions. The hypothesis suggests that these primitive fetal arteries such as PTA may not undergo a fast and structural deterioration but they might be active contributors to a series of mechanisms that can cause a variety of idiopathic complaints. Consequently this would bring a different therapeutic approach other than their surgical removal, which is the accepted option today as a solution for these problems. In this case report, a chronic unilateral MC due to coexisting PTA adjacent to trigeminal nerve is presented. The caliber and location of the PTA was confirmed by a CT-Angiography. The MC treatment was achieved by administration of bio-identical testosterone, human placenta extract (HPE), b-nicotinamide adenine dinucleotide (NADH) and low dose amlopidine.

Bone decay and beyond: how can we approach it better.

Osseo-degeneration is a disorder related to several factors, that may lead to the disruption of several skeletal regions providing support, such as the femur head, the vertebrae and the alveolar bone. The functional condition can be restored by means of grafting procedures, using different materials: calcium powder, xenografts, ceramics and metals. Such procedures aim at reforming an adequate bone volume and strength, that is necessary to support loading forces. Bone regeneration requires that the basic biological principles of osteogenesis, osteoinduction, osteoconduction and biocompatibility are followed. The success of regenerative procedures may depend on the inner structural, mechanical and metabolic condition of the host's bone on which implants should be inserted, on the surgical technique, and on the biomaterial used. Among these, the aging process of the patient appears to be relevant. It can be associated with metabolic disease leading to systemic functional decay, which involves a gradual steady decline of hormonal, immune function and osteo-metabolic activity. The latter can affect the positive outcomes of bone reconstruction and implant therapy. This review will analyze the biological and physiological factors involved in the bone tissue break-down, such as the influences from gut microbiome unbalance and the consequent metabolic, endocrine, immune dysfunctions, the surgery procedures and the quality of the grafting material used. The decline of bone architecture and strength should be corrected by using an appropriate clinical regenerative approach, based on a bio-endocrine, metabolic and immunologic know-how. The final characteristics of the regenerated bone must be able to support the loading forces transmitted by the implants, independent of the body location, and should be individualized according to the different condition of each patient.

A systematic review on persistent trigeminal artery, in searching for a therapeutic solution to idiopathic and unresponsive trigeminal nerve inflammations and migraines.

The rarely diagnosed persistent trigeminal artery (PTA) originates from the posterior bend or lateral wall of the intracavernous carotid artery and is the most common occurring type of remnant primitive fetal arteries. Even if PTA is uncommon, information and awareness about it could be of great help for clinicians dealing with cranial vascular imaging and operating this region. In addition, it could give a supporting response to the presence of a wide range of idiopathic and unresponsive disturbs that sometimes are erroneously interpreted and treated. There are very few published scientific reports of coexisting PTA and unilateral trigeminal neuralgia and migraine-cephalgia (MC). In this review we describe few reported and unreported cases regarding the manifestation of unresponsive trigeminal neuralgia and migraine due to the presence of PTA. Patients usually present with a clinical symptomatology with unstable blood hypertension, pain of typical trigeminal neuralgia and MC that cover unilaterally the occipital area over the second and third divisions of the nerve. The outbreaks may often become more severe during physical exertion, stress and hypertension. Angio-MRI may reveal the PTA with an occasional occurrence of parietal cavernoma. We also describe a case of chronic left MC case associated with an adjacent PTA close to the trigeminal nerve position. The size and location of the PTA was confirmed by a CT-Angiography. The MC was safely treated by bio-identical testosterone, human placenta extract (HPE), b-nicotinamide adenine dinucleotide (NADH) and low dose amlopidine. It is hypothesized that these types of primitive anastomose arteries that fully belong to the intracranial arterial vascular system do not perform any supportive functional activity. Nevertheless, they undergo the normal biological decay caused by the aging process and metabolic dysfunctions. Therefore, such primitive fetal arteries as PTA might be subjected not only to a faster structural deterioration but they would actively contribute to a series of mechanisms causing a variety of idiopathic intracranial vascular and structural symptoms. Consequently, this would change the primary therapeutic approach to solve this problem, today represented by surgical removal. Anatomic implications related to treatment procedure are also discussed.

A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results.

The effective management of women with human papillomavirus (HPV)-positive, cytology-negative results is critical to the introduction of HPV testing into cervical screening. HPV typing has been recommended for colposcopy triage, but it is not clear which combinations of high-risk HPV types provide clinically useful information. This study included 18,810 women with Hybrid Capture 2 (HC2)-positive, cytology-negative results and who were age ≥30 years from Kaiser Permanente Northern California. The median follow-up was 475 days (interquartile range [IQR], 0 to 1,077 days; maximum, 2,217 days). The baseline specimens from 482 cases of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) and 3,517 random HC2-positive noncases were genotyped using 2 PCR-based methods. Using the case-control sampling fractions, the 3-year cumulative risks of CIN3+ were calculated for each individual high-risk HPV type. The 3-year cumulative risk of CIN3+ among all women with HC2-positive, cytology-negative results was 4.6%. HPV16 status conferred the greatest type-specific risk stratification; women with HC2-positive/HPV16-positive results had a 10.6% risk of CIN3+, while women with HC-2 positive/HPV16-negative results had a much lower risk of 2.4%. The next most informative HPV types and their risks in HPV-positive women were HPV33 (5.9%) and HPV18 (5.9%). With regard to the etiologic fraction, 20 of 71 cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma in the cohort were positive for HPV18. HPV16 genotyping provides risk stratification useful for guiding clinical management; the risk among HPV16-positive women clearly exceeds the U.S. consensus risk threshold for immediate colposcopy referral. HPV18 is of particular interest because of its association with difficult-to-detect glandular lesions. There is a less clear clinical value of distinguishing the other high-risk HPV types.

The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy.

OBJECTIVE: It has been suggested that colposcopy can miss a significant percentage of high-grade cervical intraepithelial neoplasia (CIN2+). Improved disease ascertainment was evaluated by taking multiple lesion-directed biopsies. METHODS: In a cross-sectional multicenter study in the Netherlands and Spain, 610 women referred to colposcopy following abnormal cervical cytology results were included. Multiple directed biopsies were collected from lesions and ranked according to impression. A non-directed biopsy of normal-appearing tissue was added if fewer than four biopsies were collected. We evaluated the additional CIN2+ yield for one and two directed biopsies. Colposcopic images were reviewed for quality control. RESULTS: In women with at least two lesion-directed biopsies the yield for CIN2+ increased from 51.7% (95%CI; 45.7-57.7) for one directed biopsy to 60.4% (95%CI; 54.4-66.2, p<0.001) for two biopsies. The highest CIN2+ yield was observed in women who were HPV16-positive, had high-grade squamous intraepithelial lesion (HSIL) cytology, and high-grade colposcopy impression. The yield increased from 83.1% (95%CI; 71.5-90.5) with one directed biopsy to 93.2% (95%CI; 83.8-97.3) with two directed biopsies. Only 4.5% additional CIN2+ were detected in biopsies not targeting abnormal areas on the cervix. CONCLUSIONS: A second lesion-directed biopsy is associated with a significant increase in CIN2+ detection. Performing a second lesion-directed biopsy and using a low threshold for abnormality of any acetowhitening should become the standard clinical practice of colposcopy.

The impact of human papillomavirus genotype on colposcopic appearance: a cross-sectional analysis.

OBJECTIVE: To study colposcopic performance in diagnosing high-grade cervical intraepithelial neoplasia or cervical cancer (CIN2+ and CIN3+) using colposcopic characteristics and high-risk human papillomavirus (hrHPV) genotyping. DESIGN: Cross-sectional multicentre study. SETTING: Two colposcopy clinics in The Netherlands and Spain. POPULATION: Six hundred and ten women aged 17 years and older referred for colposcopy because of abnormal cytology. METHODS: A cervical smear was obtained. Colposcopists identified the worst lesion, graded their impression and scored the colposcopic characteristics of the lesions. Up to four biopsies were collected, including one biopsy from visually normal tissue. MAIN OUTCOME MEASURES: CIN2+ and CIN3+, positive for HPV16 or other high-risk HPV types (non-16 hrHPV-positive). RESULTS: The mean age in HPV16-positive CIN2+ women was 35.1 years compared with 39.1 years in women with other hrHPV types (P = 0.002). Sensitivity for colposcopy to detect CIN2+ was 87.9% (95%CI 83.2-91.5), using colposcopic cut-off of 'any abnormality'. The remaining CIN2+ were found by a biopsy from visually normal tissue or endocervical curettage (ECC). Detection of CIN2+ by lesion-targeted biopsies was not different between HPV16-positive women [119/135; 88.1% (95%CI 81.2-92.9)] and non-16 hrHPV-positive women [100/115; 87.0% (95%CI 79.1-92.3); P = 0.776]. In multivariate analysis, 'acetowhitening' [odds ratio (OR) 1.91, 95%CI 1.56-3.17], 'time of appearance' (OR 1.95, 95%CI 1.21-3.15) and 'lesion >25% of visible cervix' (OR 2.25, 95%CI 1.44-3.51) were associated with CIN2+. CONCLUSIONS: In this population following European screening practice, HPV16-related CIN2+ lesions were detected at younger age and showed similar colposcopic impression as non-16 hrHPV high-grade lesions. There was no relationship between any of the colposcopic characteristics and HPV16 status.

Plasma cytokine levels and human papillomavirus infection at the cervix in rural Nigerian women.

INTRODUCTION: We conducted a study to test the hypothesis that systemic dysregulation of Th1/Th2 cytokine levels was associated with detection of carcinogenic or overall human papillomavirus (HPV) at the cervix among 964 women residing in a rural village in Nigeria. METHODS: Levels in plasma were measured for 19 cytokines, including Th1-like cytokines IL-2, IL-12 (p40), TNF-a, IFN-g; Th2-like cytokines IL-4, IL-5, IL-6, IL-10, IL-13; innate/inflammation cytokines IL-1a, IL-1b, IL-8, eotaxin, MCP-1, MIP-1a, and IL-7; and cell development cytokines G-CSF, VEGF, and IL-17. Analysis was restricted to 5 cytokines, TNF-α (Th1), IL-8 (Th2), eotaxin and MCP-1 (innate/inflammation), and G-CSF (cell development), whose levels were detected in 80% or more of the samples measured as well as had a coefficient of variation of <30%. RESULTS: Strong correlations were noted between levels of eotaxin and TNF-α (r=0.75), IL-8 and MCP-1 (r=0.60), eotaxin and G-CSF (r=0.44), and G-CSF and IFN-γ (r=0.43). Detection of carcinogenic or non-carcinogenic HPV DNA was unrelated to cytokine levels, except for levels of eotaxin and TNF-α, which were inversely correlated, albeit weakly, with detection of any carcinogenic HPV (P=0.048 and P=0.067, respectively). In analyses stratified by age group, levels of eotaxin were inversely correlated with detection of any HPV DNA (P=0.026) and carcinogenic HPV (P=0.042) in older, but not younger, women. CONCLUSIONS: Our results do not support the hypothesis of association between systemic cytokine dysregulation and detection of HPV at the cervix in Nigerian women, but subgroup analyses raise questions about inverse associations between eotaxin and TNF-α in older women.

Evaluation of linear array human papillomavirus genotyping using automatic optical imaging software.

Variations in biological behavior suggest that each carcinogenic human papillomavirus (HPV) type should be considered individually in etiologic studies. HPV genotyping assays might have clinical applications if they are approved for use by the FDA. A widely used genotyping assay is the Roche Linear Array HPV genotyping test (LA). We used LA to genotype the HPV isolates from cervical specimens from women with the full spectrum of cervical disease: cervical cancer, cervical intraepithelial neoplasia (CIN), and HPV infections. To explore the feasibility and value of the automated reading of the LA results, we custom-designed novel, optical imaging software that provides optical density measurements of LA bands. We compared unmagnified visual examination with the automated measurements. The two measurements were highly associated. By either method, the threshold between a negative and a positive result was fairly sharp, with a clear bimodal distribution. Visually, most positive results were judged to be strong or medium, with fewer equivocal results categorized as weak (9.5% of positive samples), very weak (6.5% of positive samples), or extremely weak (7.7% of positive samples). The automated measurements of the intensities were significantly associated with the strength of the visual categories (P < 0.001). At the extremes of the automated signal intensities (< or = 20 units or > or = 120 units), the bands were almost always categorized visually as negative and positive, respectively. In the equivocal zone (20 to 119 units), specimens were more increasingly likely to be judged to be visually positive as the number of other, definite infections on the same strip increased (P for trend < 0.001). Multiple, concurrent infections comprise > or = 25% of HPV infections; thus, any systematic visual tendency that influences their evaluation when the result is equivocal should be minimized. Therefore, automated reading is probably worth development if easy-to-calibrate hardware and software can be optimized.

Performance of cytology and human papillomavirus testing in relation to the menstrual cycle.

Cervical smears prepared around the time of menses have been linked to unsatisfactory specimens and false negative results; however, it is unclear whether liquid-based cytology is similarly affected and data relating date of last menstrual period (LMP) to human papillomavirus (HPV) DNA testing are conflicting. Accordingly, we evaluated liquid-based cytology and HPV test results using Hybrid Capture 2 and PCR by LMP (days 0-10; 11-21; 22-28). We studied 5060 participants in ALTS, the Atypical Squamous Cells of Undetermined Significance (ASCUS) Low Grade Squamous Intraepithelial Lesion (LSIL) Triage Study. On average, women had 3.4 examinations (median 4, range 1-5) during a 2-year period of observation permitting an examination of intra-individual variation in cytology and HPV by LMP. Although uncommon, unsatisfactory cytology specimens were most likely on days 0-10. For satisfactory specimens, the frequency with which cytologic categories were reported varied by time since LMP, although differences were modest and did not affect the chance of abnormal cytology or its severity among women diagnosed with CIN2+. The frequency of positive HC2 tests did not vary with date of LMP. Among HPV infected women, independent of eventual diagnosis and the number of viral genotypes present, mid-cycle specimens yielded the highest frequency of LSIL cytologic interpretations and the highest HPV load; however, the magnitude of these effects were small. Intraindividual correlations of cytology or HPV by LMP were generally weak. We conclude that mid-cycle specimens yield slightly higher HPV DNA loads and slightly increased LSIL interpretations, but the clinical impact is marginal. Standardizing collection times would slightly improve interpretation of trends in HPV load. Finally, these data are consistent with the view that the biological properties of the HPV-infected cervix vary with the date of the LMP.

Human leukocyte antigen class I and II haplotypes and risk of cervical cancer.

Human leukocyte antigen (HLA) variations may affect immune response to human papillomavirus infection and subsequent cervical neoplasia risk. We investigated the frequency and relationship between HLA-A-B and HLA-A-B-DR haplotypes among women with cervical cancer/high-grade lesions (n=365) and cytologically normal population controls (n=681) within three cervical neoplasia studies in the US and Costa Rica. Notable differences in haplotype frequencies were observed; the HLA-A*01-B*08 haplotype occurred in >5% of US Caucasians but in <1% of Costa Ricans. The most prevalent HLA-A*24-B*40-DR*04 haplotype in Costa Rica (5%) was found in <1% of US Caucasians. No HLA haplotype was significantly associated with cervical neoplasia, suggesting that individual allele associations reported to date (e.g. HLA-DR*13) are not likely explained by underlying haplotypes.

Determinants of human papillomavirus 16 serological conversion and persistence in a population-based cohort of 10 000 women in Costa Rica.

Determinants of human papillomavirus (HPV)-16 serological conversion and persistence were assessed in a population-based cohort of 10 049 women in Guanacaste, Costa Rica. Serologic responses to HPV-16 were measured in 7986 women by VLP-based enzyme-linked immunosorbent assay at both study enrollment (1993/94) and at 5-7 years of follow-up. Seropositive women were defined as >/=5 standard deviations above the mean optical density obtained for studied virgins at enrollment (n=573). Seroconnversion (n=409), persistence (n=675), and clearance (n=541) were defined based on enrollment and follow-up serology measurements. Age-specific distributions revealed that HPV-16 seroconversion was highest among 18- to 24-year-old women, steadily declining with age; HPV-16 seropersistence was lowest in women 65+ years. In age-adjusted multivariate logistic regression models, a 10-fold risk increase for HPV-16 seroconversion was associated with HPV-16 DNA detection at enrollment and follow-up; two-fold risk of seroconversion to HPV-16 was associated with increased numbers of lifetime and recent sexual partners and smoking status. Determinants of HPV-16 seropersistence included a 1.5-fold risk increase associated with having one sexual partner during follow-up, former oral contraceptive use, and a 3-fold risk increase associated with HPV-16 DNA detection at both enrollment and follow-up. Higher HPV-16 viral load at enrollment was associated with seroconversion, and higher antibody titres at enrollment were associated with seropersistence.

A case-control study of endogenous hormones and cervical cancer.

Both parity and oral contraceptive use are associated with elevated circulating levels of sex hormones, at least transiently, and with increased risk of cervical cancer in human papillomavirus (HPV)-infected women. We directly evaluated whether elevations in the physiologic levels of these hormones predispose to the development of cervical neoplasia. We identified 67 premenopausal and 43 postmenopausal women with cervical intraepithelial neoplasia 2, 3, or cervical cancer (>/=CIN2) diagnosed during enrollment of a population-based cohort of 10 077 women. Four controls, two chosen randomly and two chosen from women testing positive for cancer-associated HPV, were matched to each case on menopausal status, age, days since last menses (pre), or years since menopause (post). Sex hormone-binding globulin, oestradiol, oestrone, oestrone-sulphate, dehydroepiandrosterone sulphate, and progesterone were measured in enrollment plasma. There was no consistent association between the sex hormones and risk of >/=CIN2. Excluding cases with invasive disease had a minimal impact on results. Though this case-control study was based on a well-defined population, it was limited by reliance on a single measure of hormone levels taken at the time of diagnosis. Nonetheless, our results do not support the hypothesis that plasma levels of sex hormones have an important bearing on the risk of cervical neoplasia in HPV-infected women.

A population based study of herpes simplex virus 2 seroprevalence in rural Costa Rica.

OBJECTIVES: To determine seroprevalence and determinants of herpes simplex virus 2 (HSV-2) seropositivity, in a random sample of a population based cohort of 10 049 women of Guanacaste, Costa Rica, using a highly sensitive and specific serological assay. METHODS: Seroprevalence was determined by a type specific HSV-2 ELISA assay in an age stratified random sample of 1100 women. Univariate and multivariate logistic regression was used to calculate odds ratios and 95% confidence intervals for risk factors of seropositivity. RESULTS: Overall age adjusted HSV-2 seroprevalence was 38.5% (95% CI, 37.5 to 39.5), and it was strongly associated with increasing age (p(Trend<0.0001)), both among monogamous women and women with multiple sexual partners. A greater number of lifetime sexual partners increased the risk of seropositivity, with a 28.2% (95% CI, 24.4 to 32.2) seroprevalence among monogamous women and 75% (95% CI, 65.6 to 83.0) seroprevalence for those with four or more partners (OR = 7.6 95% CI, 4.7 to 12.4 p(Trend<0.0001)). Barrier contraceptive use was negatively associated with HSV-2 seropositivity (OR 0.54, 95% CI, 0.31 to 0.94). Women with antibodies against HPV 16, 18, or 31 were 1.6 times more likely to be HSV-2 seropositive (OR 1.6, 95% CI, 1.2 to 2.1). CONCLUSIONS: HSV-2 infection is highly endemic in Guanacaste, even among lifetime monogamous women, suggesting a role of male behaviour in the transmission of the infection. Until vaccination against HSV-2 is available, education to prevent high risk sexual behaviour and the use of condoms appear as preventive measures against HSV-2.

Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10000 women in Costa Rica.

Human papillomavirus (HPV) seroprevalence and determinants of seropositivity were assessed in a 10049-woman population-based cohort in Guanacaste, Costa Rica. Serologic responses based on VLP-based ELISA were obtained from the plasma collected at study enrollment in 1993/1994 for HPV-16 (n=9949), HPV-18 (n=9928), HPV-31 (n=9932), and HPV-45 (n=3019). Seropositivity was defined as five standard deviations above the mean optical density obtained for studied virgins (n=573). HPV-16, -18, -31, and -45 seroprevalence was 15, 15, 16, and 11%, respectively. Of women DNA-positive for HPV-16, -18, -31, or -45, seropositivity was 45, 34, 51, and 28%, respectively. Peak HPV seroprevalence occurred a decade after DNA prevalence; lifetime number of sexual partners was the key determinant of seropositivity independent of DNA status and age. DNA- and sero-positive women showed the highest risk for concurrent CIN3/cancer, followed by DNA-positive, sero-negative women.

Cervicography for triage of women with mildly abnormal cervical cytology results.

OBJECTIVE: To estimate the sensitivity and specificity of cervicography in detecting cervical cancer precursor lesions in women participating in the National Cancer Institute's multicenter atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion triage study (ALTS). STUDY DESIGN: Cervigrams were obtained from 3134 women with a referral Papanicolaou smear diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. Cervigram and cervical histology results were compared by using cervical intraepithelial neoplasia (CIN) 2 and CIN 3 disease end points. RESULTS: Of 3134 women, 444 had histologic findings of more than or equal to CIN 2 and 222 had CIN 3. Cervicography interpretation by using a threshold of greater than or equal to atypical had a sensitivity, specificity, and positive and negative predictive values of 79.3%, 61.0%, 13.4%, and 97.5%, respectively, for detecting greater than or equal to CIN 3. Cervicography was more sensitive (80.8% vs 57.1%), but less specific (55.7% vs 81.8%), for detecting CIN 3 in women younger than 35 years compared with women 35 years or older, respectively. CONCLUSIONS: Cervicography functioned moderately well at detecting CIN 2 or CIN 3 in women with atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion Papanicolau smear results. Cervigram sensitivity was better for younger women.

Human leukocyte antigen class I and II alleles and risk of cervical neoplasia: results from a population-based study in Costa Rica.

To examine human leukocyte antigen (HLA) involvement in the development of all grades of cervical neoplasia, a nested case-control study of 10,077 women in Guanacaste, Costa Rica, was conducted. Participants had invasive cervical cancer, high-grade squamous intraepithelial lesions (HSILs; n=166), or low-grade squamous intraepithelial lesions (LSILs); were positive for human papillomavirus (HPV) with no evidence of cervical neoplasia (n=320); or were HPV negative with no evidence of cervical neoplasia but with a history of high-risk sexual behavior (n=173). Compared with women who were HPV negative, women with HLA-DRB1*1301 were associated with decreased risk for cancer/HSILs (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.2-0.7) and for LSILs/HPV (OR, 0.6; 95% CI, 0.3-0.9). Women with both HLA-B*07 and HLA-DQB1*0302 had an 8.2-fold increased risk for cancer/HSILs (95% CI, 1.8-37.2) and a 5.3-fold increased risk for LSILs/HPV (95% CI, 1.2-23.7). These results support the hypothesis that multiple risk alleles are needed in order to increase risk for cervical neoplasia, but a single protective allele may be sufficient for protection.

An association of cervical inflammation with high-grade cervical neoplasia in women infected with oncogenic human papillomavirus (HPV).

Previous reports of genital conditions, such as nonspecific genital infection/sore or vaginal discharge associated with cervical cancer (L. A. Brinton et al., J. Natl. Cancer Inst. (Bethesda), 79: 23-30, 1987; C. J. Jones et al., Cancer Res., 50: 3657-3662, 1990), suggest a possible link between either genital tract inflammation or changes in bacteria flora consistent with bacterial vaginosis (BV) and cervical cancer. To test whether changes in vaginal bacterial flora or the degree of cervical inflammation are associated with women having a human papillomavirus (HPV) infection or with women infected with oncogenic HPV having high-grade cervical lesions (high-grade squamous intraepithelial lesions or cancer), we conducted a case-control study of women <50 years old enrolled in the Costa Rican natural history study of HPV and cervical neoplasia. To test whether BV and inflammation were associated with HPV DNA positivity, Analysis 1 was restricted to women with no or mild (low-grade or equivocal) cytological abnormalities, and the degree of inflammation and Nugent score (a measure of BV) were compared between women infected (n = 220) and not infected (n = 130) with HPV. To test whether BV and inflammation were associated with high-grade lesions, Analysis 2 was restricted to women infected with oncogenic HPV, and the degree of inflammation and Nugent score were compared between women with (n = 95) and without (n = 158) high-grade cervical lesions. In Analysis 1, BV and cervical inflammation were not associated with HPV infection. In Analysis 2, BV was not associated with high-grade lesions. However, we found a marginally significant positive trend of increasing cervical inflammation associated with high-grade lesions in oncogenic HPV-infected women, (P(trend) = 0.05). Overt cervicitis was associated with a 1.9-fold increase in risk of high-grade lesions (95% confidence interval, 0.90-4.1). The results of this study suggest that cervical inflammation may be associated with high-grade lesions and may be a cofactor for high-grade cervical lesions in women infected with oncogenic HPV.