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1.  Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case–control study nested within the Manchester cohort 
British Journal of Cancer  2000;83(11):1565-1572.
To distinguish risk factors for acquisition of cervical human papillomavirus (HPV) infection from the determinants of neoplasia among infected individuals we have conducted a three-arm case-control study nested within a large population-based cohort of women (the Manchester cohort) screened for HPV at entry using L1 consensus primer PCR. The study includes 181 HPV-positive controls who did not develop high-grade cervical intraepithelial neoplasia (CIN3) during follow-up, 203 HPV-negative controls, and 199 HPV-positive cases with histologically confirmed CIN3. Detailed information on sexual, reproductive and gynaecological history, oral contraceptive use and smoking was obtained at face-to-face interview. There was a striking division between risk factors for infection and those predictive of disease. Comparing the HPV-positive against the HPV-negative controls, the only risk factors for infection were number of sexual partners (OR for six or more = 3.89; 95% Cl = 1.99–7.62), a relatively recent new sexual relationship (OR for a new partner within the previous 2 years = 4.17; 95% Cl = 2.13–8.33), and a history of previous miscarriage (OR = 2.59; 95% Cl = 1.28–5.21). The determinants of CIN3 among infected women were, in contrast, early age at first intercourse (OR for 16 years old or less = 3.23; 95% Cl = 1.33–7.69), a long time since starting a new sexual relationship (OR for 6 years or more = 4.94; 95% Cl = 2.51–9.71), and cigarette smoking, with strong evidence for a dose– response (OR for current smoking habit 20+ per day = 2.57; 95% Cl = 1.49–4.45). Oral contraceptive use was not significantly associated with either HPV infection or CIN3. © 2000 Cancer Research Campaign
PMCID: PMC2363425  PMID: 11076670
cervical neoplasia; CIN3; HPV; sexual behaviour; smoking
2.  Prevalence and determinants of human papillomavirus infection and cervical lesions in HIV-positive women in Kenya 
British Journal of Cancer  2012;107(9):1624-1630.
We assessed the association of human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) with various characteristics, CD4 count and use of combination antiretroviral therapy (cART) among HIV-positive women.
Cross-sectional study of 498 HIV-positive women who underwent HPV PCR-based testing, cytology, and systematic cervical biopsy.
In all, 68.7% of women were HPV-positive, 52.6% had high-risk (hr) HPV, and 40.2% multiple type infections. High-risk human papillomavirus-positivity did not vary significantly by age but it was negatively associated with education level. The most frequent types in 113 CIN2/3 were HPV16 (26.5%), HPV35 (19.5%), and HPV58 (12.4%). CD4 count was negatively associated with prevalence of hrHPV (P<0.001) and CIN2/3 among non-users of cART (P=0.013). Combination antiretroviral therapies users (⩾2 year) had lower hrHPV prevalence (prevalence ratio (PR) vs non-users=0.77, 95% confidence interval (CI): 0.61–0.96) and multiple infections (PR=0.68, 95% CI: 0.53–0.88), but not fewer CIN2/3. The positive predictive value of hrHPV-positivity for CIN2/3 increased from 28.9% at age <35 years to 53.3% in ⩾45 years.
The burden of hrHPV and CIN2/3 was high and it was related to immunosuppression level. Combination antiretroviral therapies ( ⩾2 year) use had a favourable effect on hrHPV prevalence but cART in our population may have been started too late to prevent CIN2/3.
PMCID: PMC3493776  PMID: 23033006
HIV; cervical neoplasia; human papillomavirus; combination antiretroviral therapy; Africa
3.  Prevalence of high risk human papillomavirus types among Nicaraguan women with histological proved pre‐neoplastic and neoplastic lesions of the cervix 
Sexually Transmitted Infections  2006;82(4):334-336.
To determine the prevalence of high risk human papillomavirus (HPV) types in Nicaraguan women with histological proved pre‐neoplastic and neoplastic cervical lesions, and to assess its potential impact on preventive strategies.
206 women with histopathological confirmed cervical lesions (CIN I or worse) were screened for HPV DNA on a liquid based cytology sample, using an HPV short fragment polymerase chain reaction based assay. HPV positive samples were genotyped with a reverse hybridisation line probe assay (Lipa). HPV negative samples were re‐analysed using type specific real time polymerase chain reaction.
Of all lesions CIN II or worse, 12% tested negative. Prevalence of high risk HPV increased from 48.1% in cervical intraepithelial neoplasia I (CIN I) to 94.7% in invasive squamous cervical carcinoma (SCC). The most prevalent high risk HPV types were, in order of prevalence rate, HPV 16, 58, 31 and 52. HPV 16 and/or HPV 31 were present in 63.2% of SCC cases.
Targeting HPV 16 and 31 with prophylactic vaccines could possibly have an important impact on the incidence of invasive cervical carcinoma in Nicaragua. Further research is needed to define the oncogenic potential of other high prevalent HPV genotypes. Meanwhile, primary prevention and cervical cancer screening programmes should be optimised.
PMCID: PMC2564726  PMID: 16877588
cervical cancer; women's health; human papillomavirus
4.  Risk of Cervical Pre-Cancer and Cancer Among HIV-Infected Women With Normal Cervical Cytology and No Evidence of Oncogenic HPV Infection 
U.S. cervical cancer screening guidelines for HIV-uninfected women 30 years of age and older have recently been revised, increasing the suggested interval between Pap tests from three years to five years among those with normal cervical cytology (the Pap test) who test negative for oncogenic human papillomavirus (HPV). Whether a three-year or five-year screening interval might be used in HIV-infected women who are cytologically normal and oncogenic HPV-negative is unknown.
To determine the risk of cervical pre-cancer or cancer defined cytologically (high-grade squamous intraepithelial lesions or greater [HSIL+]) or histologically (cervical intraepithelial neoplasia 2 or greater [CIN-2+]), as two separate endpoints, in HIV-infected women and HIV-uninfected women who at baseline had a normal Pap test and were negative for oncogenic HPV.
Design, Setting and Participants
Participants included 420 HIV-infected women and 279 HIV-uninfected women with normal cervical cytology at their enrollment in a multi-institutional cohort, between October 1, 2001 and September 30, 2002, with follow-up through April 30, 2011. Clinical sites were in the Bronx, Brooklyn, Chicago, Los Angeles, San Francisco, and Washington, DC. Semi-annual visits included Pap testing and, if indicated, cervical biopsy. Cervicovaginal lavage specimens from enrollment were tested for HPV DNA using PCR. The primary analysis was truncated at five years of follow-up.
Main Outcome Measure
The five-year cumulative incidence of cervical pre-cancer and cancer.
No oncogenic HPV was detected in 369 (88%; 95% CI, 84%-91%) of the HIV-infected women and 255 (91%; 95% CI, 88%-94%) of the HIV-uninfected women with normal cervical cytology at enrollment. Among these oncogenic HPV-negative women two cases of HSIL+ were observed; an HIV-uninfected woman and an HIV-infected woman with a CD4 cell count of 500/μL or greater. Histologic data were obtained from four of the six sites. There were six cases of CIN-2+ in N=145 HIV-uninfected women (cumulative incidence = 5% [95% CI, 1%-8%]) and nine cases in N=219 HIV-infected women (cumulative incidence = 5% [95% CI, 2%-8%]). This included one case of CIN-2+ in N=44 oncogenic HPV-negative HIV-infected women with CD4 cell counts less than 350/μL (cumulative incidence = 2% [95% CI, 0%-7%]), one case in N=47 women with CD4 cell counts of 350 to 499/μL (cumulative incidence = 2% [95% CI, 0%-7%]), and seven cases in N=128 women with CD4 cell counts of 500/μL or greater (cumulative incidence = 6% [95% CI, 2%-10%]). One HIV-infected and one HIV-uninfected woman had CIN-3, but none had cancer.
The five-year cumulative incidence of HSIL+ and CIN-2+ was similar in HIV-infected women and HIV-uninfected women who were cytologically normal and oncogenic HPV-negative at enrollment.
PMCID: PMC3556987  PMID: 22820789
5.  The Clinical Meaning of a Cervical Intraepithelial Neoplasia Grade 1 Biopsy 
Obstetrics and gynecology  2011;118(6):1222-1229.
To determine whether the diagnosis of cervical intraepithelial neoplasia grade 1 (CIN1) increases the risk of cervical intraepithelial neoplasia grade 3 (CIN3) above what is observed for human papillomavirus (HPV) infection.
Using data from the atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) triage study (ALTS), we compared the 2-year cumulative risk of CIN3 for women with an enrollment diagnosis of CIN1 (n = 594) (median age = 23 years) compared with those with negative histology or no biopsy taken at colposcopy (“no CIN1,” n = 570) (median age = 24 years). Baseline cervical specimens were tested for carcinogenic HPV by a clinical HPV test and HPV genotypes by polymerase chain reaction. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) as a measure of association of enrollment status, including CIN1 compared with no CIN1 diagnosis, with 2-year worst outcomes of CIN3.
The two-year risks of CIN3 were 10.3% (95%CI: 7.9%–13.0%) for women with CIN1, 7.3% (95%CI: 4.6%–10.9%) for negative histology, and 6.4% (95%CI: 3.8%–9.9%) for women referred to colposcopy and no biopsies were taken (p = 0.1). The 2-year risk of CIN3 for women positive for HPV16, HPV18, or other carcinogenic HPV genotypes was 19.1%, 13.9%, and 5.7%, respectively, and did not differ significantly by the baseline cytology interpretation (ASCUS or LSIL). Taking HPV genotypes into account, having a CIN1 (compared with no CIN1) was not a risk factor for developing CIN3 (OR = 0.99, 95%CI: 0.54–1.8).
A CIN1 diagnosis does not represent a significant risk factor for CIN3 above the risk attributed to its molecular cause, genotype-specific HPV infection.
PMCID: PMC3229199  PMID: 22105250
6.  Viral Load in the Natural History of Human Papillomavirus Type 16 Infection: A Nested Case–control Study 
The Journal of Infectious Diseases  2011;203(10):1425-1433.
Background. Viral load may influence the course of human papillomavirus type 16 (HPV-16) infection.
Methods. This case-control study was nested within the 2-year Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study, in which women were followed semiannually for HPV and cervical intraepithelial neoplasia (CIN). Case patients (n = 62) were women diagnosed with CIN3 following HPV-16–positive detection at a follow-up visit. HPV-16–positive controls (n = 152) without CIN2 or CIN3 were matched to cases based on the follow-up visit in which viral load was measured. Real-time polymerase chain reaction was used for HPV-16 DNA quantification.
Results. The risk of CIN3 increased with increasing HPV-16 DNA load at the follow-up visit (odds ratio, 1.63; 95% confidence interval, 1.33–1.99 per 1 log10 unit increase); the association was not affected by whether HPV-16 was present at enrollment. When HPV-16 was present at both enrollment and follow-up, viral load remained high among cases (P = .77) but decreased substantially among controls (P = .004). Among women with HPV-16 found initially during follow-up, viral load in the first HPV-16–positive sample was associated with short-term persistence; load was higher in those with infection, compared with those without infection, 1 visit after the initial positivity (P = .001).
Conclusions. Viral load of newly detected infections and changes in viral load predict persistence and progression of HPV-16 infections.
PMCID: PMC3080901  PMID: 21415020
7.  Risk Factors for Persistent Cervical Intraepithelial Neoplasia Grades 1 and 2 Managed by Watchful Waiting 
This study examines risk factors for persistent cervical intraepithelial neoplasia (CIN) and whether human papillomavirus (HPV) testing predicts persistent lesions.
Materials and Methods
Women with histologically diagnosed CIN 1 or CIN 2 (n = 206) were followed every 3 months without treatment. HPV genotyping, plasma levels of ascorbic acid, and red blood cell folate were obtained. Cervical biopsy at 12 months determined the presence of CIN. Relative risk (RR) was estimated by log-linked binomial regression models.
At 12 months, 70% of CIN 1 versus 54% of CIN 2 lesions spontaneously regressed (p< 0.001). Levels of folate or ascorbic acid were not associated with persistent CIN at 12 months. Compared to HPV negative women, those with multiple HPV types (RRs ranged from 1.68 to 2.17 at each follow-up visit) or high-risk types (RRs range = 1.74 to 2.09) were at increased risk for persistent CIN; women with HPV 16/18 had the highest risk (RRs range = 1.91 to 2.21). Persistent infection with a high-risk type was also associated with persistent CIN (RRs range = 1.50 – 2.35). Typing for high-risk HPVs at 6 months only had a sensitivity of 46% in predicting persistence of any lesions at 12 months.
Spontaneous regression of CIN 1 and CIN 2 occurs frequently within 12 months. HPV infection is the major risk factor for persistent CIN. However, HPV testing cannot reliably predict persistence of any lesion.
PMCID: PMC3652877  PMID: 21811178
cervical intraepithelial neoplasia; human papillomavirus
8.  Human Papillomavirus (HPV) Genotypes in Women with Cervical Precancer and Cancer at Kaiser Permanente Northern California† 
The human papillomavirus (HPV) Persistence and Progression Cohort is a natural history study of carcinogenic HPV positive women. Here, we present the HPV genotypes found in first ∼500 cases of cervical intraepithelial neoplasia grade 3 (CIN3) or more severe disease (CIN3+) diagnosed at the study baseline.
Women aged 30 and older were screened for cervical cancer using Pap smears and tested for carcinogenic HPV using Hybrid Capture 2 (HC2; Qiagen). We randomly selected women who tested HPV positive and were diagnosed with CIN3+ (n = 448) or without CIN3+ (
Among HC2-positive women, HPV16 (48.9%), HPV31 (9.2%), and HPV18 (8.5%) were the most common HPV genotypes in CIN3+. There was a decrease at older ages in the fraction of CIN3 (ptrend = 0.006), adenocarcinoma in situ (AIS) (ptrend = 0.08), and CIN3/AIS (ptrend = 0.002) associated with HPV16. Compared to the other carcinogenic HPV genotypes in aggregate, HPV18 was strongly associated with CIN3+ in women with a normal Pap (odds ratio ([OR] = 5.7, 95%CI = 1.2-26) but not in women with abnormal Pap (OR = 1.3, 95%CI = 0.74-2.3).
HPV16 is associated with cervical precancer diagnosed in younger women (vs. older women). HPV18 infections were linked to precancerous lesions that were missed by cytology.
The progression timeline of HPV16 differs from other carcinogenic HPV genotypes, which may impact the use of HPV16 detection in the management of HPV-positive women.
PMCID: PMC3117227  PMID: 21415357
Pap; cervical intraepithelial neoplasia (CIN); cervical cancer; human papillomavirus (HPV); atypical squamous cells of undetermined significance (ASC-US); hybrid capture 2 (HC2)
Cancer research  2009;69(8):3262-3266.
Epidemiologic studies have reported the under-representation of cervical precancerous lesions caused by human papillomavirus (HPV) types 18 and 45 (HPV18/45) compared to the proportion of cervical cancers attributed to these HPV types. We investigated the timing of diagnosis of histologic cervical intraepithelial neoplasia grade 3 or worse (CIN3+) using data from the ASCUS-LSIL Triage Study (ALTS). Of the 2,725 women who underwent enrollment colposcopy 412 of 472 (87.3%) diagnosed with histologic CIN3+ over the 2-year duration of ALTS could be assigned to a HPV type or group of types and were included in this analysis. Eighty-four percent of HPV16-positive CIN3+ were diagnosed at enrollment, compared with 57% of HPV18/45-positive CIN3+, and 58% of CIN3 positive for other carcinogenic HPV types at enrollment. In contrast, only 8% of HPV16-positive CIN3+ were diagnosed at exit, while 31% were HPV18/45-positive and 22% were positive for other carcinogenic types at study exit (p<0.001).. These results indicate the under-representation of HPV18/45 in pre-cancers while HPV16-associated CIN3+ is diagnosed much earlier. Whether the under-representation of 18/45 may be due to occult pathology needs further investigation.
PMCID: PMC3155840  PMID: 19351830
HPV genotypes; precancerous cervical lesions; timing of diagnosis
British Journal of Cancer  1996;73(6):831-836.
The aim of this paper was to provide epidemiological evidence to support the notion that cervical intraepithelial neoplasia (CIN) without human papillomavirus (HPV) is a true entity. If a diagnosis of HPV-negative cervical neoplasia is erroneous, one would not expect there to be any differences in risk factors between HPV-positive and HPV-negative patients. Patients at a gynaecological outpatient clinic of a university hospital [a total of 265 consecutive women with dyskaryotic cervical smears who were subsequently diagnosed with CIN I (n=37), CIN II (n=48) or CIN III (n=180)] completed a structured questionnaire regarding smoking habits and sexual history. Analysis of an endocervical swab for Chlamydia trachomatis, analysis of a cervical scrape for HPV, and morphological examination of cervical biopsy specimens were also performed. HPV was found in 205 (77.4%) out of the 265 women. Univariate analysis showed that current age (P=0.02), current smoking behaviour (P=0.002) and the number of sexual partners (P=0.02) were significantly associated with the presence of HPV. Age at first sexual intercourse, a past history of venereal disease or genital warts, and current infection with Chlamydia trachomatis were not associated with the presence of HPV. Using multivariate logistic regression analysis, the number of sexual partners and current smoking behaviour showed an independent significant association with HPV. HPV-negative and HPV-positive CIN patients differ with respect to the risk factors for HPV. These findings suggest that HPV-negative CIN is a separate true entity.
PMCID: PMC2074377  PMID: 8611390
British Journal of Cancer  2005;92(9):1800-1802.
We prospectively evaluated the 5-year predictive values of adding high-risk human papillomavirus (hrHPV) testing to cytology for the detection of ⩾cervical intraepithelial neoplasia (CIN)3 lesions in a population-based cohort of 2810 women. At baseline, nine (0.3%) women had prevalent lesions ⩾CIN3, all being hrHPV positive. After 5 years of follow-up, four (6.5%) of the 62 hrHPV-positive women with normal cytology developed lesions ⩾CIN3, vs only one (0.05%) of the 2175 hrHPV-negative women with normal cytology. High-risk human papillomavirus testing or combined screening revealed a much higher sensitivity, at the cost of a small decrease in specificity, and a higher negative predictive value for the detection of lesions ⩾CIN3 till the next screening round (5 years) than cytology alone.
PMCID: PMC2362030  PMID: 15827553
human papillomavirus; cervical cancer; screening; long-term
Factors associated with progression from cervical intraepithelial neoplasias (CIN) grade 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among carcinogenic HPV types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression, and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16-positive women (n=225) and 33.6 years for HPV16-negative women (n=104), respectively. The average lesion size did not differ by HPV16 status (p=0.83). Among HPV16-positive women with CIN3, lesions were significantly larger in women 30 years and older (p=0.03). Colposcopic impression was worse in women with HPV16 infections (p=0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16-positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, while HPV16-related CIN2 is more likely to persist. Lesion size seems to be the most important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification, but may pose challenges to finding small lesions in colposcopy.
PMCID: PMC3409928  PMID: 22488167
HPV16; CIN3; biopsy; colposcopy; screening
Contraception  2009;79(5):10.1016/j.contraception.2008.11.009.
Depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN) and combined oral contraceptives (COCs) have been shown to have a negative effect on bone mineral density (BMD) in adolescents. The aim of this study was to investigate BMD in 15-to 19-year-old new users of DMPA, NET-EN and COCs.
Study Design
This 5-year longitudinal study followed-up new users of DMPA (n=115), NET-EN (n=115), and COCs (n=116), and 144 nonuser controls. BMD was measured at the distal radius using dual x-ray absorptiometry.
BMD increased in all groups (annual percent increase: nonusers, 1.49%; DMPA, 1.39%; NET-EN, 1.03%; COCs, 0.84%) during follow-up (p<0.001). There was evidence for lower BMD increases per annum in NET-EN (p=.050) and COC (p=.010) users compared to nonusers but no difference between DMPA and nonusers (p=.76). In 14 NET-EN discontinuers, an overall reduction of 0.61% per year BMD was followed upon cessation by an increase of 0.69% per year (p=.066).
This study suggests that BMD increases in adolescents may be less in NET-EN and COC users; however, recovery of BMD in NET-EN users was found in the small sample of adolescents followed post-discontinuation.
PMCID: PMC3833049  PMID: 19341845
Sexually transmitted diseases  2012;39(8):591-597.
Clinical studies demonstrate increased prevalence of human papillomavirus (HPV)-associated disease in HIV-infected individuals and an increased risk of HIV acquisition in HPV-infected individuals. The mechanisms underlying this synergy are not defined. We hypothesize that women with cervical intraepithelial neoplasia (CIN) will exhibit changes in soluble mucosal immunity that may promote HPV persistence and facilitate HIV infection.
The concentrations of immune mediators and endogenous anti-Escherichia coli activity in genital tract secretions collected by cervicovaginal lavage were compared in HIV-negative women with high-risk HPV-positive (HRHPV+) CIN-3 (n = 37), HRHPV+ CIN-1 (n = 12), or PAP-negative control subjects (n = 57).
Compared with control subjects, women with CIN-3 or CIN-1 displayed significantly higher levels of proinflammatory cytokines including interleukin (IL)-1α, IL-1β, and IL-8 (P < 0.002) and significantly lower levels of anti-inflammatory mediators and antimicrobial peptides, including IL-1 receptor antagonist, secretory leukocyte protease inhibitor (P < 0.01), and human β defensins 2 and 3 (P < 0.02). There was no significant difference in endogenous anti-E. coli activity after controlling for age and sample storage time.
HRHPV+ CIN is characterized by changes in soluble mucosal immunity that could contribute to HPV persistence. The observed mucosal inflammation suggests a mechanism that may also contribute to the epidemiologic link between persistent HPV and HIV.
PMCID: PMC3981065  PMID: 22801340
Contraception  2010;81(1):30-34.
Weight gain is commonly reported as a side effect of hormonal contraception and can lead to method discontinuation or reluctance to initiate the method. The purpose of this study was to investigate weight change in adolescent aged 15-19 years who were new users of depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), combined oral contraceptives (COCs), and non-users of hormonal contraception.
Study design
This longitudinal study recruited initiators of DMPA (n=115), NET-EN (n=115), COCs (n=116), and non-users of contraception (n=144). Participants were followed-up for 4-5 years and height, weight and contraceptive use was recorded at each visit.
Women using DMPA or NET-EN throughout or switching between the two, had gained an average of 6.2 kg compared to average increases of 2.3 kg in the COC group, 2.8 kg in non-users and 2.8 kg among discontinued users of any method (p=0.02). There was no evidence of a difference in weight gain between women classified as non-obese or classified as overweight/obese in any of the four study groups at baseline.
There is fairly strong evidence that hormonal injectable users gain more weight than COC users, discontinuers and non-users of contraception.
PMCID: PMC3764463  PMID: 20004270
DMPA; NET-EN; COCs; weight; adolescents
Objective: HIV-positive women are known to be at high-risk of human papillomavirus (HPV) infection and its associated cervical pathology. Here, we describe the prevalence and distribution of HPV genotypes among HIV-positive and -negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).
Methods: We report data on 1,371 HIV-positive women and 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies in Cape Town, South Africa, conducted among women who had no history of cervical cancer screening recruited from the general population. All women were tested for HIV. Cervical samples were tested for high-risk HPV DNA (Hybrid Capture 2) with positive samples tested to determine the specific genotype (Line Blot). CIN status was determined based on colposcopy and biopsy.
Results: The HPV prevalence was higher among HIV-positive women (52.4%) than among HIV-negative women (20.8%) overall and in all age groups. Younger women, aged 17–19 years, had the highest HPV prevalence regardless of HIV status. HIV-positive women were more likely to have CIN 2 or 3 than HIV-negative women. HPV 16, 35, and 58 were the most common high-risk HPV types with no major differences in the type distribution by HIV status. HPV 18 was more common in older HIV-positive women (40–65 years) with no or low grade disease, but less common in younger women (17–29 years) with CIN 2 or 3 compared to HIV-negative counterparts (p < 0.03). Infections with multiple high-risk HPV types were more common in HIV-positive than HIV-negative women, controlling for age and cervical disease status.
Conclusion: HIV-positive women were more likely to have high-risk HPV than HIV-negative women; but, among those with HPV, the distribution of HPV types was similar by HIV status. Screening strategies incorporating HPV genotyping and vaccination should be effective in preventing cervical cancer in both HIV-positive and -negative women living in sub-Saharan Africa.
PMCID: PMC3953716  PMID: 24672770
HIV-infections; HPV; genotype; HPV vaccine; cervical cancer screening
Virology Journal  2012;9:117.
Immunosuppressive therapy protects the transplanted organ but predisposes the recipient to chronic infections and malignancies. Transplant patients are at risk of cervical intraepithelial neoplasia (CIN) and cervical cancer resulting from an impaired immune response in the case of primary infection or of reactivation of a latent infection with human papillomavirus of high oncogenic potential (HR-HPV).
The aim of this study was to assess the prevalence of HR-HPV cervical infections and CIN in 60 female kidney graft recipients of reproductive age in comparison to that in healthy controls. Cervical swabs were analyzed for the presence of HR-HPV DNA. HR-HPV-positive women remained under strict observation and were re-examined after 24 months for the presence of transforming HR-HPV infection by testing for HR-HPV E6/E7 mRNA. All the HR-HPV-positive patients were scheduled for further diagnostic tests including exfoliative cytology, colposcopy and cervical biopsy.
The prevalence of HR-HPV did not differ significantly between the study group and the healthy controls (18% vs 25%, p = 0.37). There was no correlation between HR-HPV presence and the immunosuppresive regimen, underlying disease, graft function or time interval from transplantation. A higher prevalence of HR-HPV was observed in females who had had ≥2 sexual partners in the past. Among HR-HPV-positive patients, two cases of CIN2+ were diagnosed in each group. In the course of follow-up, transforming HR-HPV infections were detected in two kidney recipients and in one healthy female. Histologic examination confirmed another two cases of CIN2+ developing in the cervical canal.
Female kidney graft recipients of reproductive age are as exposed to HR-HPV infection as are healthy individuals. Tests detecting the presence of HR-HPV E6/E7 mRNA offer a novel diagnostic opportunity in those patients, especially in those cases where lesions have developed in the cervical canal.
PMCID: PMC3489881  PMID: 22709394
Renal transplantation; HPV mRNA; HR-HPV; Immunosuppressive therapy; Cervical intraepithelial neoplasia
Results of cervical cytology screening showing atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesions (LSIL) indicate risk for high-grade cervical intraepithelial neoplasia (CIN 2 or 3). In a community-based randomized trial we compared the test performance of human papillomavirus (HPV) DNA testing with that of 6-month repeat Papanicolaou (Pap) test in detecting histologically confirmed CIN 2 or 3.
We randomly assigned 212 women aged 16-50 years with ASCUS or LSIL on cervical cytology screening to undergo either immediate HPV DNA testing or a repeat Pap test in 6 months. Cervical swabs for the HPV DNA testing and the Pap smears were obtained by their familiy physicians. We tested the swabs for oncogenic HPV using the Hybrid Capture II assay (Digene Corp., Beltsville, Md.). Community-based pathologists examined the Pap smears. All women were referred for colposcopy by their family physicians. Two gynecological pathologists assessed the histology findings. We calculated test performance in women who completed the trial using CIN 2 or 3 as the reference standard.
A total of 159 women completed the study. Compared with HPV DNA testing, which detected 87.5% (7/8) of the cases of CIN 2 or 3, repeat Pap smear showing high-grade intraepithelial neoplasia (HSIL) detected 11.1% (1/9) of cases (p = 0.004), and repeat Pap smear showing ASCUS, LSIL or HSIL detected 55.6% (5/9) (p = 0.16). Corresponding specificities were 50.6%, 95.2% (p = 0.002) and 55.6% (p = 0.61). Loss to follow-up was 17.1% in the HPV test group and 32.7% in the repeat Pap group (p = 0.009). Given the 7 cases of CIN 2 or 3 detected by HPV testing and the 5 cases detected by the repeat Pap smear, the incremental cost of HPV testing was calculated to be $3003 per additional case of CIN identified.
HPV DNA testing was more costly but was associated with significantly less loss to follow-up. It may detect more cases of CIN 2 or 3 in women with low-grade cytologic abnormalities.
PMCID: PMC80165  PMID: 11022584
Journal of Clinical Microbiology  2009;47(8):2458-2464.
In the present study we investigated the cross-sectional positivity for DNA and E6/E7 mRNA from high-risk human papillomavirus (HPV) types in 643 women with high-grade cervical neoplasia (135 cases of cervical intraepithelial neoplasia grade 2 [CIN2], 495 cases of CIN3/adenocarcinoma in situ [ACIS], and 13 cases of invasive carcinoma) and in 736 women with normal cytology by using the Amplicor and PreTect HPV-Proofer assays. In addition, genotyping was performed using Linear Array for women with normal cytology and a positive HPV test and in all women with histologically confirmed CIN2+. In women with normal cytology, 8.3% (61/736) were Amplicor positive and 3.3% (24/736) were PreTect HPV-Proofer positive (P < 0.001). Concordant results between the Amplicor and PreTect HPV-Proofer tests were present in 90.3% (665/736). In women with CIN2+ lesions 96.4% (620/643) were positive by Amplicor, 98.4% (633/643) by linear array, and 64.1% (412/643) by PreTect HPV-Proofer. Concordant results for the three HPV assays were present in 63.8%. The genotype profile detected by linear array and PreTect HPV-Proofer showed substantial agreement for HPV types 16, 18, 33, and 45. HPV type 16 and/or 18 was detected in 58.8% (378/643) of the women with high-grade neoplasia. Detection of E6/E7 mRNA by PreTect HPV-Proofer increased with severity of the cervical lesion. Detection of HPV DNA, however, was not associated with histology grade. In conclusion, the detection of HPV varied according to the assay used, and the concordance between the tests was poor. Our results indicate that mRNA testing may be a biomarker for progression of cervical neoplasia, but the optimal genotype mix remains to be determined.
PMCID: PMC2725639  PMID: 19535524
Journal of Clinical Microbiology  2012;50(4):1240-1244.
The triage of women with high-risk (HR) human papillomavirus (HPV)-positive smears for atypical squamous cells of undetermined significance (ASC-US) to colposcopy is now an integrated option in clinical guidelines. The performance of cobas 4800 HPV and that of Hybrid Capture 2 (HC2) for HR HPV DNA detection in cervical samples in PreservCyt were compared in 396 women referred to colposcopy for ASC-US. Of these, 316 did not have cervical intraepithelial neoplasia (CIN), 47 had CIN1, 29 had CIN2 or CIN3 (CIN2+), and 4 had CIN of unknown grade. HR HPV was detected in 129 (32.6%) and 149 (37.6%) samples with HC2 and cobas 4800 HPV, respectively (P = 0.15). The clinical sensitivities and specificities for detecting CIN2+ were 89.7% (95% confidence interval [CI], 72.8 to 97.2%) and 66.7% (95% CI, 61.7 to 71.3%) with cobas 4800 HPV and 93.1% (95% CI, 77.0 to 99.2%) and 72.2% (95% CI 67.4 to 76.5%) with HC2. The performance of cobas 4800 HPV was similar to that of HC2 for identifying women with ASC-US who would benefit the most from colposcopy.
PMCID: PMC3318562  PMID: 22301023
Cervical cancer is a major source of illness and death among women worldwide and genital infection with oncogenic human papillomavirus (HPV) its principal cause. There is evidence of the influence of the male factor in the development of cervical neoplasia. Nevertheless, the pathogenic processes of HPV in men are still poorly understood. It has been observed that different HPV types can be found among couples. The objective of the present study was to investigate HPV infections in female patients (n = 60 females/group) as well as in their sexual partners and to identify the concordance of HPV genotypes among them. By using the polymerase chain reaction, we detected a 95% prevalence of HPV DNA in women with cervical intraepithelial neoplasia (CIN) compared to 18.3% in women with normal cervical epithelium, with a statistically significant difference (P < 0.001). The HPV DNA prevalence was 50% in male partners of women with CIN and 16.6% in partners of healthy women. In the control group (healthy women), only 9 couples were simultaneously infected with HPV, and only 22.2% of them had the same virus type, showing a weak agreement rate (kappa index = 0.2). Finally, we observed that HPV DNA was present in both partners in 30 couples if the women had CIN, and among them, 53.3% shared the same HPV type, showing moderate agreement, with a kappa index of 0.5. This finding supports the idea of circulation and recirculation of HPV among couples, perpetuating HPV in the sexually active population, rather than true recurrences of latent infections.
PMCID: PMC3854444  PMID: 23739745
Human papillomavirus; Neoplasia; Couples; Sexual partners; Polymerase chain reaction
To evaluate the prevalence of HPV DNA genotypes in women diagnosed with cervical intraepithelial neoplasia grade 2 or greater (CIN 2+), together with the detection of mRNA transcripts from HPV 16/18/31/33/45. In 1113 women referred to our colposcopy unit for abnormal cytology, colposcopic assessment was followed by histologic examination for final diagnosis and by presence of HPV DNA and E6/E7 mRNA transcripts. A total of 134 CIN 2+ cases were identified. Out of the 134 women with CIN 2+ cervical lesions, 115 cases (85.8%) tested positive by PCR to HR HPV DNA types, and 19 (14.2%) were HR HPV DNA negative. 68 cases (50.7%) were positive for HPV DNA 16/18/31/33/45 and of them 50 cases were E6/E7 positive, and 18 were E6/E7 negative. 47 cases (35.1%) were positive for high risk types other than 16/18/31/33/45. HPV 16 is the most frequent genotype found in histologically confirmed high grade cervical lesions in our series; HPV 31 is the second most frequent type, contributing significantly to the proportion of women with CIN 2+ lesions in our population and shows a higher prevalence than HPV 18. Out of the 979 women with lesions less than CIN 2, 588 cases tested positive by PCR to high risk HPV DNA types (60.1%), and 98 cases were E6/E7 positive from HPV 16/18/31/33/45 (10.1%). Although HPV DNA and mRNA negative results should be evaluated with caution, since they could represent “false negatives”, high risk HPV DNA positivity should be assessed carefully with colposcopy before performing excisional treatments, particularly in adolescents but also in patients who want child, since they may reflect transient situations.
PMCID: PMC3493024  PMID: 23145213
HPV infection; sexually transmitted disease; cervical cancer; HPV DNA; E6/E7 mRNA transcripts; CIN
British Journal of Cancer  2010;104(2):353-360.
High-risk human papillomavirus (H-HPV) infection is linked to cervical neoplasia but its role in detecting cervical glandular lesions (GLs) is unclear. Carbonic anhydrase IX (CA-IX) is a hypoxic biomarker that is highly expressed in neoplastic cervical GLs. The diagnostic utility of these biomarkers was evaluated by the Gynecologic Oncology Group in Japanese women with a cytological diagnosis of atypical glandular cells.
Immunostaining was used to detect CA-IX in a conventional Pap smear. Immunoreactivity of CA-IX was interpreted by a panel of pathologists blinded to the histological diagnosis. Polymerase chain reaction was used to detect H-HPV in a liquid-based cytology specimen.
Significant cervical lesions (SCLs), defined as cervical intraepithelial neoplasia (CIN2, CIN3), adenocarcinoma in situ or invasive carcinoma, were observed in 37/88 (42%) of women. CA-IX testing alone (n=88) had a sensitivity of 89, 100 or 73% for SCLs, GLs or significant squamous lesions (SLs), respectively, with a false negative rate (FNR) of 14%. Testing for H-HPV (n=84) had a sensitivity of 65, 53 or 80% for SCLs, GLs or SLs, respectively, with a FNR of 22%. The combination of CA-IX and H-HPV testing had a sensitivity of 97, 100 or 93% for SCLs, GLs or SLs, respectively, with a FNR of 5%. Among eight H-HPV-negative GLs, six (75%) had a diagnosis of lobular endocervical glandular hyperplasia (LEGH).
The combination of CA-IX and HPV testing improved the diagnostic accuracy. The low rate of H-HPV positivity in the GLs was associated with coexisting LEGH independent of H-HPV.
PMCID: PMC3031897  PMID: 21157448
CA-IX; H-HPV; AGC diagnosis; cervix
PLoS ONE  2013;8(8):e72142.
We investigated the association between alcohol consumption and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer, and determined whether these associations were modified by human papillomavirus (HPV) viral load in high-risk HPV-positive women participating in the Korean HPV cohort study (KHPV).
Among the women recruited in the KHPV (n = 1,243) from March 2006 to December 2009, we analyzed normal cytology (n = 581) as control group, CIN1 (n = 299), CIN2/3 (n = 161), or cervical cancer (n = 202). Multinomial logistic analysis was performed to estimate multivariate-adjusted odds ratios (OR).
Alcohol drinkers had an increased risk of CIN1 (OR = 2.18, 95% CI 1.22–3.89) compared with non-drinkers after adjusting for potential confounders. Subjects with more frequent alcohol consumption had a higher risk of CIN1 (p for linear trend <0.0001). Higher ethanol consumption was associated with an increased risk of CIN1 (p for linear trend = 0.0001). We also observed a synergistic effect between HPV viral load and alcohol consumption: drinkers with a high HPV viral load (≥100 RLU/PC) were associated with a significantly increased risk of CIN1 (OR = 19.1; 95% CI, 6.60–55.3, interaction p<0.001). There were no associations between alcohol drinking and CIN2/3 or cervical cancer.
HPV viral load and alcohol was associated with the risk of CIN1 among high-risk HPV-positive women. This is the first demonstration that alcohol is an independent and combined risk factor of CIN1.
PMCID: PMC3747046  PMID: 23977233
In a retrospective case-control study biopsy specimens of cervical intraepithelial neoplasia (CIN) lesions from 47 women in whom invasive cancer subsequently developed (cases) and from 94 control subjects in whom CIN was diagnosed within 6 months of the diagnosis for the matched case subject but invasive disease did not develop were tested for human papillomavirus (HPV) DNA with tissue in-situ hybridization. There were no significant differences in the frequency of detection of HPV DNA between the two groups. In a cross-sectional survey the prevalence of HPV DNA was found to be 11% in specimens without CIN, 27% in those with CIN I, 49% in those with CIN II and 56% in those with CIN III. The positivity rates for HPV 16/33 DNA increased with the severity of CIN, but this was not observed for HPV 6/11 and 18 DNA. A comparison of the results of the case-control and cross-sectional studies suggested that the younger cohort of women had higher prevalence rates of HPV DNA than the older cohort.
PMCID: PMC1451821  PMID: 2154306

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