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1.  Suitability of self-collected vaginal samples for cervical cancer screening in peri-urban villages in Andhra Pradesh, India 
Objectives:
Our aim was to determine if (1) Hybrid Capture 2 and a PCR-based method were comparable for detection of high-risk HPVs, (2) clinician-collected and self-collected samples were equally efficient to detect HPV and cervical cancer precursor lesions and (3) if participation rates improved with home-based vs. clinic-based self collection.
Methods:
Samples were selected from women participating in a cervical cancer screening study according to human papillomavirus (HPV), visual inspection with acetic acid (VIA), or Pap smear screening results. From 432 of 892 selected women, split sample aliquots were tested for HPV DNA using both the Hybrid Capture 2 assay and the Roche prototype line blot assay. Women from a subset of villages were recruited at two separate time points for clinic-based self-collection and home-based self-collection, and participation rates were compared.
Results:
Pairwise agreement between self- and clinician-collected samples was high by both hc2 (90.8% agreement, kappa=0.7) and PCR (92.6% agreement, kappa=0.8), with significantly increased high-risk HPV detection in clinician-collected specimens (McNemar's p<0.01). Ability to detect precursor lesions was highest by PCR testing of clinician-collected samples and lowest by Hybrid Capture 2 testing of self-collected samples (11/11 and 9/11 cases of cervical intraepithelial neoplasia grade 2/3 and cancer detected, respectively). Participation in home-based screening was significantly higher than clinic-based screening (71.5% and 53.8%, respectively; p<0.001) among women 30-45 years old.
Conclusion:
The combination of improved screening coverage and a high single test sensitivity afforded by HPV DNA testing of home-based self-collected swabs may have a greater programmatic impact on cervical cancer mortality reduction compared to programs requiring a pelvic exam.
doi:10.1158/1055-9965.EPI-08-1171
PMCID: PMC2762740  PMID: 19423518
2.  A Cohort Effect of the Sexual Revolution May Be Masking an Increase in Human Papillomavirus Detection at Menopause in the United States 
The Journal of Infectious Diseases  2013;207(2):272-280.
Background. Cohort effects, new sex partnerships, and human papillomavirus (HPV) reactivation have been posited as explanations for the bimodal age-specific HPV prevalence observed in some populations; no studies have systematically evaluated the reasons for the lack of a second peak in the United States.
Methods. A cohort of 843 women aged 35–60 years were enrolled into a 2-year, semiannual follow-up study. Age-specific HPV prevalence was estimated in strata defined by a lower risk of prior infection (<5 self-reported lifetime sex partners) and a higher risk of prior infection (≥5 lifetime sex partners). The interaction between age and lifetime sex partners was tested using likelihood ratio statistics. Population attributable risk (PAR) was estimated using Levin's formula.
Results. The age-specific prevalence of 14 high-risk HPV genotypes (HR-HPV) declined with age among women with <5 lifetime sex partners but not among women with ≥5 lifetime sex partners (P = .01 for interaction). The PAR for HR-HPV due to ≥5 lifetime sex partners was higher among older women (87.2%), compared with younger women (28.0%). In contrast, the PAR associated with a new sex partner was 28% among women aged 35–49 years and 7.7% among women aged 50–60 years.
Conclusions. A lower cumulative probability of HPV infection among women with a sexual debut before the sexual revolution may be masking an age-related increase in HPV reactivation in the United States.
doi:10.1093/infdis/jis660
PMCID: PMC3532829  PMID: 23242540
Human Papillomavirus; menopause; perimenopause; sexual revolution; cervical cancer; reactivation; cohort effect; age
3.  Nitric Oxide Induces Early Viral Transcription Coincident with Increased DNA Damage and Mutation Rates in Human Papillomavirus–Infected Cells 
Cancer research  2009;69(11):10.1158/0008-5472.CAN-08-4695.
High-risk human papillomavirus (HPV) infections are necessary but insufficient causes of cervical cancers. Other risk factors for cervical cancer (e.g., pregnancy, smoking, infections causing inflammation) can lead to high and sustained nitric oxide (NO) concentrations in the cervix, and high NO levels are related to carcinogenesis through DNA damage and mutation. However, the effects of NO exposure in HPV-infected cells have not been investigated. In this study, we used the NO donor DETA-NO to model NO exposure to cervical epithelium. In cell culture media, 24-hour exposure to 0.25 to 0.5 mmol/L DETA-NO yielded a pathologically relevant NO concentration. Exposure of cells maintaining episomal high-risk HPV genomes to NO increased HPV early transcript levels 2- to 4-fold but did not increase viral DNA replication. Accompanying increased E6 and E7 mRNA levels were significant decreases in p53 and pRb protein levels, lower apoptotic indices, increased DNA double-strand breaks, and higher mutation frequencies when compared with HPV-negative cells. We propose that NO is a molecular cofactor with HPV infection in cervical carcinogenesis, and that modifying local NO cervical concentrations may constitute a strategy whereby HPV-related cancer can be reduced.
doi:10.1158/0008-5472.CAN-08-4695
PMCID: PMC3820841  PMID: 19487298
4.  Looking ahead: a case for HPV testing of self-sampled vaginal specimens as a cervical cancer screening strategy 
Even in the era of highly effective HPV prophylactic vaccines, substantial reduction in worldwide cervical cancer mortality will only be realized if effective early detection and treatment of the millions of women already infection and the millions who may not receive vaccination in the next decade can be broadly implemented through sustainable cervical cancer screening programs. Effective programs must meet three targets: 1) at least 70% of the targeted population should be screened at least once in a lifetime, 2) screening assays and diagnostic tests must be reproducible and sufficiently sensitive and specific for the detection of high-grade precursor lesions (i.e., CIN2+), and 3) effective treatment must be provided. We review the evidence that HPV DNA screening from swabs collected by the women in their home or village is sufficiently sound for consideration as a primary screening strategy in the developing world, with sensitivity and specificity for detection of CIN2+ as good or better than Pap smear cytology and VIA. A key feature of a self-collected HPV testing strategy (SC-HPV) is the move of the primary screening activities from the clinic to the community. Efforts to increase the affordability and availability of HPV DNA tests, community education and awareness, development of strong partnerships between community advocacy groups, health care centers and regional or local laboratories, and resource appropriate strategies to identify and treat screen-positive women should now be prioritized to ensure successful public health translation of the technologic advancements in cervical cancer prevention.
doi:10.1002/ijc.25974
PMCID: PMC3782104  PMID: 21384341
5.  Risk of precancer determined by HPV genotype combinations in women with minor cytologic abnormalities 
Background
Studies suggest that testing for individual HPV genotypes can improve risk stratification in women with minor cytological abnormalities. We evaluated genotyping for HPV16, HPV16/18, and HPV16/18/45 in carcinogenic HPV-positive women with atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology.
Methods
For women enrolled in the ASCUS-LSIL Triage Study (ALTS), we calculated the age-stratified (<30 and 30+ years) positivity, and cumulative risk over two years of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) when testing positive or negative for three genotype combinations: HPV16, HPV16/18, and HPV16/18/45.
Results
Among women with ASCUS cytology, HPV16 positivity was 17.1% and increased to 22.0% (P<.001) for HPV16/18 and 25.6% (P<.001) for HPV16/18/45. Among women with LSIL cytology, HPV16 positivity was 21.1% and increased to 30.0% (P<.001) for HPV16/18 and 34.0% (P=.017) for HPV16/18/45. Regardless of cytology and age group, the greatest risk difference between test-positives and test-negatives was observed for HPV16 with decreasing risk stratification for HPV16/18 and HPV16/18/45. However, testing negative for any of the three combinations while being positive for another carcinogenic type still implied a 2-year risk of CIN3+ of 7.8% or greater.
Conclusions
Although genotyping for HPV16, 18, and 45 provided additional risk stratification in carcinogenic HPV-positive women with minor cytological abnormalities, the risk among genotype-negative women was still high enough to warrant immediate colposcopy referral.
Impact
HPV genotyping in HPV-positive women with minor cytological abnormalities will likely not alter clinical management. Adding HPV45 to genotyping assays is not warranted.
doi:10.1158/1055-9965.EPI-12-1455
PMCID: PMC3687215  PMID: 23603204
HPV testing; cervical intraepithelial neoplasia; cervical cytology; risk stratification
6.  High risk human papillomavirus viral load and persistence among heterosexual HIV-negative and HIV-positive men 
Sexually transmitted infections  2014;90(4):337-343.
Objectives
High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men.
Methods
HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semi-quantitative measure of HPV shedding by hybridization band intensity (graded:1–4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV.
Results
HR-HPV genotypes with high viral load (grade:3–4) at baseline were more likely to persist than HR-HPV genotypes with low viral load (grade:1–2) among HIV-negative men (month 6: adjPRR=1.83, 95%CI:1.32–2.52; month 12: adjPRR=2.01, 95%CI:1.42–3.11), and HIV-positive men (month 6: adjPRR=1.33, 95%CI:1.06–1.67; month 12: adjPRR=1.73, 95%CI:1.18–2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared to HIV-negative men (month 24: adjPRR=2.27, 95%CI: 1.47–3.51). Persistence of newly detected HR-HPV at the 6 and 12 month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95%CI 0.88–3.16).
Conclusions
HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission.
doi:10.1136/sextrans-2013-051230
PMCID: PMC4030299  PMID: 24482488
Human papillomavirus (HPV); human immunodeficiency virus (HIV); male circumcision; Uganda; penile cancer; sexually transmitted infections; viral shedding; viral load; linear array band intensity
7.  Combined Oral Contraceptive Use Increases HPV Persistence but Not New HPV Detection in a Cohort of Women From Thailand 
The Journal of Infectious Diseases  2011;204(10):1505-1513.
Background. Women diagnosed with cervical cancer report longer duration and more recent use of combined oral contraceptives (COCs). It is unclear how COC use impacts risk of cervical carcinogenesis.
Methods. We estimated the risk of new human papillomavirus (HPV) DNA detection and persistence among 1135 human immunodeficiency virus (HIV)–negative women aged 20–37 years from Thailand who were followed for 18 months at 6-month intervals. Type-specific HPV DNA, demographic information, hormonal contraceptive use, sexual behavior, genital tract coinfection, and Papanicolaou test results were assessed at baseline and each follow-up.
Results. Women who reported current COC use during follow-up were less likely to clear HPV infection compared with nonusers, independent of sexual behavior, and Papanicolaou test diagnosis (AHR: 0.67 [95% CI: .49–.93]). Similar associations were not observed among women reporting current use of depomedroxyprogesterone acetate (DMPA). Neither COC nor DMPA use was significantly associated with new HPV DNA detection.
Conclusions. These data do not support the hypothesis that contraceptive use is associated with cervical cancer risk via increased risk of HPV acquisition. The increased risk of HPV persistence observed among current COC users suggests a possible influence of female sex hormones on host response to HPV infection.
doi:10.1093/infdis/jir560
PMCID: PMC3222104  PMID: 21964399
8.  High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease 
Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (≥CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of ∼2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent ≥CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4–83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1–39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident ≥CIN2; non-16 carcinogenic high viral load was not associated with incident ≥CIN2 (OR = 0.7, 95% CI = 0.2–1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident ≥CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent ≥CIN2; however HPV16 was uniquely associated with incident ≥CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident ≥CIN2.
doi:10.1002/ijc.23012
PMCID: PMC3962984  PMID: 17722112
human papillomavirus; viral load; genotype; screening
9.  High-risk human papillomavirus prevalence is associated with HIV infection among heterosexual men in Rakai, Uganda 
Sexually transmitted infections  2012;89(2):122-127.
Objectives
Human papillomavirus (HPV) infection causes genital warts, penile cancer and cervical cancer. Africa has one of the highest rates of penile and cervical cancers, but there are little data on high-risk human papillomavirus (HR-HPV) prevalence in heterosexual men. Knowledge of HR-HPV prevalence, risk factors and genotype distribution among heterosexual men is important to establish risk-reduction prevention strategies.
Methods
1578 uncircumcised men aged 15–49 years who enrolled in male circumcision trials in Rakai, Uganda, were evaluated for HR-HPV from swabs of the coronal sulcus/glans using Roche HPV Linear Array. Adjusted prevalence risk ratios (adjPRRs) were estimated using modified Poisson multivariable regression.
Results
HPV prevalence (either high risk or low risk) was 90.7% (382/421) among HIV-positive men and 60.9% (596/978) among HIV-negative men (PRR 1.49, 95% CI 1.40 to 1.58). HIV-positive men had a significantly higher risk of infection with three or more HR-HPV genotypes (PRR = 5.76, 95% CI 4.27 to 7.79). Among HIV-positive men, high-risk sexual behaviours were not associated with increased HR-HPV prevalence. Among HIV-negative men, HR-HPV prevalence was associated with self-reported genital warts (adjPRR 1.57, 95% CI 1.07 to 2.31). Among all men (both HIV negative and HIV positive), HR-HPV prevalence was associated with more than 10 lifetime sexual partners (adjPRR 1.30, 95% CI 1.01 to 1.66), consistent condom use (adjPRR 1.31, 95% CI 1.08 to 1.60) and HIV infection (adjPRR 1.80, 95% CI 1.60 to 2.02). HR-HPV prevalence was lower among men who reported no sexual partners during the past year (adjPRR 0.47, 95% CI 0.23 to 0.94).
Conclusion
The burden of HR-HPV infection is high among heterosexual men in sub-Saharan Africa and most pronounced among the HIV-infected individuals.
doi:10.1136/sextrans-2012-050524
PMCID: PMC3640492  PMID: 22628661
10.  Cervical Cancer Screening in Older Women: New Evidence and Knowledge Gaps 
PLoS Medicine  2014;11(1):e1001586.
Anne Rositch and colleagues discuss the study by Peter Sasieni and colleagues on cervical cancer screening in older women and describe the further information needed to help inform decisions about whether to extend screening programs beyond 65 years for women with adequate negative screening.
Please see later in the article for the Editors' Summary
doi:10.1371/journal.pmed.1001586
PMCID: PMC3891623  PMID: 24453947
11.  Determinants of VIA (Visual Inspection of the Cervix After Acetic Acid Application) Positivity in Cervical Cancer Screening of Women in a Peri-Urban Area in Andhra Pradesh, India 
Objectives
Visual inspection of the cervix after acetic acid application (VIA) is widely recommended as the method of choice in cervical cancer screening programs in resource-limited settings because of its simplicity and ability to link with immediate treatment. In testing the effectiveness of VIA, human papillomavirus DNA testing, and Pap cytology in a population-based study in a peri-urban area in Andhra Pradesh, India, we found the sensitivity of VIA for detection of cervical intraepithelial neoplasia grade 2 and worse (CIN2+) to be 26.3%, much lower than the 60% to 90% reported in the literature. We therefore investigated the determinants of VIA positivity in our study population.
Methods
We evaluated VIA positivity by demographics and reproductive history, results of clinical examination, and results from the other screening methods.
Results
Of the 19 women diagnosed with CIN2+, only 5 were positive by VIA (positive predictive value, 3.1%). In multivariate analysis, VIA positivity (12.74%) was associated with older age, positive Pap smear, visually apparent cervical inflammation, and interobserver variation. Cervical inflammation of unknown cause was present in 21.62% of women. In disease-negative women, cervical inflammation was associated with an increase in VIA positivity from 6.1% to 15.5% (P < 0.001). Among the six gynecologists who performed VIA, the positivity rate varied from 4% to 31%.
Conclusions
The interpretation of VIA is subjective and its performance cannot be readily evaluated against objective standards.
Impact
VIA is not a robust screening test and we caution against its use as the primary screening test in resource-limited regions.
doi:10.1158/1055-9965.EPI-09-1282
PMCID: PMC2913449  PMID: 20447927
12.  THE CORRELATION BETWEEN HPV POSITIVITY AND ABNORMAL CERVICAL CYTOLOGY DIFFERS BY AGE AMONG PERIMENOPAUSAL WOMEN 
Objectives
We explored the age-stratified correlates and correlations between HR-HPV infection and cervical abnormalities in perimenopausal women.
Materials and methods
HPV testing and Pap smear screening were performed at baseline on 841 routinely screened women age 35–60 years in the HPV in Perimenopause (HIP) cohort. Demographic, behavioral and medical information was collected through telephone administered questionnaires. Descriptive analyses were used to examine the correlation between HR-HPV infection and cervical abnormalities by age. Logistic regression was used to determine correlates of HPV and abnormalities in women under and over 45 years of age.
Results
The prevalence of HPV, HR-HPV and cervical abnormalities decreased significantly with increasing age, as did the correlation between HR-HPV and cervical abnormalities. The prevalence of HR-HPV was 50% among younger women with abnormalities but this decreased steadily to 20% HR-HPV detection among 50–54 year old, and no abnormalities were detected in 55–60 year old women. Different correlates of HR-HPV infection and abnormalities were observed in women ≥45 years, a pattern not seen in the younger women.
Conclusions
Although the relative proportion of low and high-grade abnormalities did not change with age, we saw a loss of concordance between HR-HPV detection and cytological abnormalities with increasing age. Current guidelines for cervical cancer screening group together all women age 30 and above. Our data raise important questions about the interpretation of HPV and Pap test results in this age group and suggest that ongoing surveillance of HPV and cytology in cervical cancer screening programs consider a third age stratification among older women.
doi:10.1097/LGT.0b013e3182503402
PMCID: PMC3499667  PMID: 22885643
perimenopausal women; menopause; human papillomavirus; HPV; cervical lesions; cytology; cervical cancer; screening; guidelines
13.  Correlates of Cervicovaginal Human Papillomavirus Detection in Perimenopausal Women 
Journal of Women's Health  2009;18(9):1341-1346.
Abstract
Objective
The aim of this research was to determine correlates of prevalent cervicovaginal human papillomavirus (HPV) infection in perimenopausal women.
Methods
A total of 178 women, ages 40–60, were recruited from four clinics in the metropolitan area of Baltimore, Maryland. A self-collected cervicovaginal specimen and questionnaire were completed following enrollment and consent. HPV was detected by L1 consensus polymerase chain reaction (PCR) and genotyped using a prototype line blot assay. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CIs) from Poisson regression models with robust variance identified correlates of prevalent HPV infection.
Results
Prevalence of any HPV genotype at baseline among 172 women with complete data was 20% (6% for high-risk HPV). HPV prevalence was higher among single compared to married women (aPR = 4.3 [95% CI: 2.0, 9.5]), and among women with ≥2 sex partners in the last six months compared to women who reported none (aPR = 4.9 [1.7, 13.9]) after adjustment for confounders. Menopausal stage was also associated with HPV detection, with increased prevalence among perimenopausal compared to premenopausal women (aPR 2.3 [1.1, 5.1]), after adjustment for confounders. Age was moderately correlated with menopausal staging (r = 0.57).
Conclusions
Our observations suggest the independent associations of sexual behavior and hormones on prevalent HPV in perimenopausal women. Age was not a good surrogate for menopausal stage, as it was only moderately correlated with menopausal stage.
doi:10.1089/jwh.2008.1223
PMCID: PMC2825723  PMID: 19702476
14.  Contributions of recent and past sexual partnerships on incident human papillomavirus detection: acquisition and reactivation in older women 
Cancer research  2012;72(23):6183-6190.
Understanding the fraction of newly detected human papillomavirus (HPV) infections due to acquisition and reactivation has important implications on screening strategies and prevention of HPV-associated neoplasia. Information on sexual activity and cervical samples for HPV DNA detection using Roche Linear Array were collected semi-annually for two years from 700 women age 35–60 years. Incidence and potential fraction of HPV infections associated with new and lifetime sexual partnerships were estimated using Poisson models. Cox frailty models were used to estimate hazard ratios (HR) for potential risk factors of incident HPV detection. Recent and lifetime numbers of sexual partners were both strongly associated with incident HPV detection. However, only 13% of incident detections were attributed to new sexual partners whereas 72% were attributed to ≥5 lifetime sexual partners. Furthermore, 155 out of 183 (85%) incident HPV detections occurred during periods of sexual abstinence or monogamy, and were strongly associated with cumulative lifetime sexual exposure (HR: 4.1, 95% CI: 2.0, 8.4). This association increased with increasing age. These data challenge the 20 paradigm that incident HPV detection is driven by current sexual behavior and new viral acquisition in older women. Our observation that most incident HPV infection was attributable to past, not current, sexual behavior at older ages supports a natural history model of viral latency and reactivation. As the highly exposed baby-boomer generation of women with sexual debut after the sexual revolution transition to menopause, the implications of HPV reactivation at older ages on cervical cancer risk and screening recommendations should be carefully evaluated.
doi:10.1158/0008-5472.CAN-12-2635
PMCID: PMC3513486  PMID: 23019223
human papillomavirus; HPV; sexual behavior; older women; reactivation; incidence; acquisition; perimenopause; aging
15.  HPV infection and increased risk of HIV acquisition. A systematic review and meta-analysis 
AIDS (London, England)  2012;26(17):10.1097/QAD.0b013e328358d908.
doi:10.1097/QAD.0b013e328358d908
PMCID: PMC3831022  PMID: 22874522
papillomavirus infections; HIV; meta-analysis; human papillomavirus; risk factors
16.  Comparison of normalization methods for measuring immune markers in cervical secretion specimens☆ 
Journal of immunological methods  2012;382(0):10.1016/j.jim.2012.05.012.
Ophthalmic sponges are used to collect undiluted cervical secretions for assessment of markers of genital tract immunity. Heterogeneity in absorbed and extracted sample volumes requires normalization in order to make valid inter-individual comparisons. We evaluated the performance of adjustment by weight and total protein on normalizing inter-individual variability of immune marker measurement due to differences in volume collection. Normalization to total protein resulted in a minimal loss of usable specimens and a significant reduction in the correlation of immune marker concentration to specimen weight compared to weight adjustment. Total protein normalization appeared to be more effective than weight adjustment in reducing the dependence of cervical immune marker concentrations on differences in specimen volume.
doi:10.1016/j.jim.2012.05.012
PMCID: PMC3831520  PMID: 22677266
Cytokines; Cervical secretions; Ophthalmic sponges; Weight adjustment; Protein adjustment
17.  Differences in the concentration and correlation of cervical immune markers among HPV positive and negative perimenopausal women 
Cytokine  2011;56(3):10.1016/j.cyto.2011.09.012.
Introduction
Women ≥45 years of age with persistent HPV infections have distinct peripheral circulating immune profiles. Few studies have comprehensively evaluated the cervical immunologic microenvironment in HPV-positive and HPV-negative perimenopausal women.
Methods
We collected cervical secretion specimens from 34 high risk HPV (HR-HPV) positive and 44 HR-HPV negative women enrolled in an ongoing prospective cohort assessing the natural history of HPV across the menopausal transition. We used these specimens to quantify concentrations of 27 different immune markers using multiplexed bead-based immunoassays.
Results
HR-HPV positive women had significantly higher median concentrations of IL-5 (0.11 ng/mgtotal protein vs. 0.08 ng/mgtotal protein), IL-9 (2.7 ng/mgtotal protein vs. 2.1 ng/mgtotal protein), IL-13 (2.1 ng/mgtotal protein vs. 0.9 ng/mgtotal protein), IL-17 (2.9 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), EOTAXIN (4.1 ng/mgtotal protein vs. 1.1 ng/mgtotal protein), GM-CSF (4.3 ng/mgtotal protein vs. 3.3 ng/mgtotal protein), and MIP-1α (3.5 ng/mgtotal protein vs. 1.9 ng/mgtotal protein) compared to HR-HPV negative women. A shift in the correlation of T-cell and pro-inflammatory cytokines (IFN-γ, IL-5, IL-9, IL-10, IL-12, IL-13, IL-15, and TNF-α) from IL-2 to EOTAXIN was observed between HR-HPV negative and positive women.
Conclusions
Higher local concentrations of anti-inflammatory and allergy associated markers, with a shift in T-cell associated cytokine correlation from IL-2 to EOTAXIN, are associated with HPV infection among older women.
doi:10.1016/j.cyto.2011.09.012
PMCID: PMC3831521  PMID: 22015106
Human papillomavirus; Interleukin-2; EOTAXIN; Menopause
18.  The association between cervical HPV infection and HIV acquisition among women in Zimbabwe 
AIDS (London, England)  2010;24(7):1035-1042.
Background
The prevalence of HPV is higher among HIV+ women, but the prevalence of HPV prior to HIV acquisition has not been carefully evaluated.
Objective
This study evaluated whether HPV infection is independently associated with heterosexual HIV acquisition in a cohort of Zimbabwean women.
Design
Case-control study nested within a large multi-center cohort study (HC-HIV).
Methods
Cases consisted of Zimbabwean women with incident HIV infection observed during follow-up (n=145). HIV-uninfected controls were selected and matched to cases (n=446). The prevalence of cervical HPV infections was compared at the visit prior to HIV infection in the cases and at the same follow-up visit in the matched controls.
Results
The odds of acquiring HIV were 2.4 times higher in women with prior cervical HPV infection after adjustment for behavioral and biologic risk factors. There was no statistically significant difference in the risk of HIV acquisition between women infected with high versus low risk HPV types. Loss of detection of at least one HPV DNA type was significantly associated with HIV acquisition (OR =5.4 [95%CI, 2.9–9.9] (p<.0001).
Conclusion
Cervical HPV infection is associated with HIV acquisition among women residing in a region with a high prevalence of both infections. Further studies are required to evaluate whether the observed association is causal.
PMCID: PMC3831602  PMID: 20397287
HPV; heterosexual HIV transmission; HIV prevention; cervical HPV; STI
19.  Can human papillomavirus DNA testing of self-collected vaginal samples compare with physician-collected cervical samples and cytology for cervical cancer screening in developing countries? 
Cancer epidemiology  2009;33(6):10.1016/j.canep.2009.10.013.
Background
To determine human papillomavirus (HPV) types by polymerase chain reaction (PCR)-reverse line blot assay and examine the concordance between HPV by Hybrid Capture 2 (HC2) and PCR on self-collected vaginal and physician-collected cervical samples and cytology.
Methods
This was a cross-sectional study of 546 sexually active women aged ≥30 years with persistent vaginal discharge, intermenstrual or postcoital bleeding or an unhealthy cervix. Participants self-collected vaginal samples (HPV-S) and physicians collected cervical samples for conventional Pap smear and HPV DNA (HPV-P) testing and performed colposcopy, with directed biopsy, if indicated. HPV testing and genotyping was done by HC2 and PCR reverse line blot assay. Concordance between HC2 and PCR results of self- and physician-collected samples was determined using a Kappa statistic (κ) and Chi-square test.
Results
Complete data were available for 512 sets with 98% of women providing a satisfactory self-sample. PCR detected oncogenic HPV in 12.3% of self- and 13.0% of physician-collected samples. Overall, there was 93.8% agreement between physician-collected and self-samples (κ = 76.31%, 95% confidence interval [CI]: 64.97–82.29%, p = 0.04)—complete concordance in 473 cases (57 positive, 416 negative), partial concordance in seven pairs and discordance in 32 pairs. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of self-sampling for detection of cervical intraepithelial neoplasia (CIN)2+ disease were 82.5%, 93.6%, 52.4% and 98.4%, respectively; for physician-sampling they were 87.5%, 93.2%, 52.2% and 98.9%, respectively; and for cytology they were 77.5%, 87.3%, 34.1% and 97.9%, respectively. Concordance between HC2 and PCR was 90.9% for self-samples (κ = 63.7%, 95% CI: 55.2–72.2%) and 95.3% for physician-collected samples (κ = 80.4%, 95% CI: 71.8–89.0%).
Conclusions
Self-HPV sampling compares favourably with physician-sampling and cytology. A rapid, affordable, HPV self-test kit can be used as the primary method of cervical cancer screening in low-resource situations.
doi:10.1016/j.canep.2009.10.013
PMCID: PMC3816517  PMID: 19931499
HPV types; Self-sampling; Screening; Hybrid Capture 2; PCR; CIN; Genotyping
20.  Evolution and Taxonomic Classification of Alphapapillomavirus 7 Complete Genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70 
PLoS ONE  2013;8(8):e72565.
Background
The species Alphapapillomavirus 7 (alpha-7) contains human papillomavirus genotypes that account for 15% of invasive cervical cancers and are disproportionately associated with adenocarcinoma of the cervix. Complete genome analyses enable identification and nomenclature of variant lineages and sublineages.
Methods
The URR/E6 region was sequenced to screen for novel variants of HPV18, 39, 45, 59, 68, 70, 85 and 97 from 1147 cervical samples obtained from multiple geographic regions that had previously been shown to contain an alpha-7 HPV isolate. To study viral heterogeneity, the complete 8 kb genome of 128 isolates, including 109 sequenced for this analysis, were annotated and analyzed. Viral evolution was characterized by constructing phylogenic trees using maximum-likelihood and Bayesian algorithms. Global and pairwise alignments were used to calculate total and ORF/region nucleotide differences; lineages and sublineages were assigned using an alphanumeric system. The prototype genome was assigned to the A lineage or A1 sublineage.
Results
The genomic diversity of alpha-7 HPV types ranged from 1.1% to 6.7% nucleotide sequence differences; the extent of genome-genome pairwise intratype heterogeneity was 1.1% for HPV39, 1.3% for HPV59, 1.5% for HPV45, 1.6% for HPV70, 2.1% for HPV18, and 6.7% for HPV68. ME180 (previously a subtype of HPV68) was designated as the representative genome for HPV68 sublineage C1. Each ORF/region differed in sequence diversity, from most variable to least variable: noncoding region 1 (NCR1) / noncoding region 2 (NCR2) > upstream regulatory region (URR) > E6 / E7 > E2 / L2 > E1 / L1.
Conclusions
These data provide estimates of the maximum viral genomic heterogeneity of alpha-7 HPV type variants. The proposed taxonomic system facilitates the comparison of variants across epidemiological and molecular studies. Sequence diversity, geographic distribution and phylogenetic topology of this clinically important group of HPVs suggest an independent evolutionary history for each type.
doi:10.1371/journal.pone.0072565
PMCID: PMC3745470  PMID: 23977318
21.  Human papillomavirus incidence and clearance among HIV-positive and HIV-negative men in Rakai, Uganda 
AIDS (London, England)  2012;26(12):1555-1565.
Objectives
High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men.
Design
HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15–49 who participated in male circumcision trials in Rakai, Uganda.
Methods
Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRR) and clearance risk ratios (adjRR).
Results
HR-HPV incidence was 66.5/100 py in HIV-positive men and 32.9/100 py among HIV-negative men (IRR=2.0, 95%CI 1.7–2.4). Incidence was higher with non-marital status (adjIRR=1.7, 95%CI 1.2–2.5), and decreased with age (adjIRR=0.6, 95%CI 0.4–1.0) and male circumcision (adjIRR=0.7, 95%CI 0.6–0.9). HR-HPV clearance was 114.7/100 py for HIV-positive men and 170.2/100 py for HIV-negative men (RR=0.7, 95%I 0.6–0.8). Clearance in HIV-negative men was increased with circumcision (adjRR=1.5, 95%CI 1.3–1.7), HSV-2 infection (adjRR=1.2, 95%CI 1.0–1.4), and symptoms of urethral discharge (adjRR=1.4, 95%CI 1.1–1.7).
Conclusions
HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and HPV vaccination is critical in sub-Saharan Africa.
doi:10.1097/QAD.0b013e328353b83c
PMCID: PMC3442933  PMID: 22441255
Human papillomavirus (HPV); HIV; male circumcision; Uganda
22.  Differences in patterns of high-risk human papillomavirus infection between urban and rural low-resource settings: cross-sectional findings from Mali 
BMC Women's Health  2013;13:4.
Background
The burden of cervical cancer is disproportionately high in low-resource settings. With limited implementation of human papillomavirus (HPV) vaccines on the horizon in the developing world, reliable data on the epidemiology of high-risk HPV (HR-HPV) infection in distinct geographic populations is essential to planners of vaccination programs. The purpose of this study was to determine whether urban patterns of HR-HPV occurrence can be generalized to rural areas of the same developing country, using data from Mali, West Africa, as an example.
Methods
Urban and rural women in Mali participated in a structured interview and clinician exam, with collection of cervical samples for HPV DNA testing, to determine HR-HPV prevalence and correlates of infection. Correlates were assessed using bivariate analysis and logistic regression.
Results
A total of 414 women (n=202 urban women; n=212 rural women) were recruited across both settings. The prevalence of HR-HPV infection in rural women was nearly twice that observed in urban women (23% v. 12%). Earlier age of sexual debut and fewer pregnancies were associated with HR-HPV infection among urban women, but not rural women. Twenty-six percent of urban women who had sexual intercourse by age 14 had an HR-HPV infection, compared to only 9% of those who had later sexual debut (p<0.01). Overall, age, income, and polygamy did not appear to have a relationship with HR-HPV infection.
Conclusions
Compared to urban women, rural women were significantly more likely to be infected with high-risk HPV. The patterns and risk factors of HR-HPV infection may be different between geographic areas, even within the same developing country. The high prevalence in both groups suggests that nearly all rural women and most urban women in Mali will be infected with HR-HPV during their lifetime, so the effects of risk factors may not be statistically apparent. To control HPV and cervical cancer in West Africa and the rest of the developing world, planners should prioritize vaccination in high-burden areas.
doi:10.1186/1472-6874-13-4
PMCID: PMC3599375  PMID: 23388094
Uterine cervical cancer; Reproductive health; HPV prevalence; Mali
23.  Frequent Detection of HPV before and after Initiation of Antiretroviral Therapy among HIV/HSV-2 Co-Infected Women in Uganda 
PLoS ONE  2013;8(1):e55383.
Objectives
Most data on HPV and antiretroviral therapy (ART) come from high-resource countries with infrequent sampling for HPV pre- and post-ART initiation. Therefore, we examined the frequency of cervical HPV DNA detection among HIV/HSV-2 co-infected women followed monthly for 6 months both before and after initiation of ART in Rakai, Uganda.
Methods
Linear Array was used to detect 37 HPV genotypes in self-collected cervicovaginal swabs from 96 women who initiated ART. Random-effects log-binomial regression was used to compare the prevalence of HPV detection in the pre- and post-ART periods and determine other potential risk factors, including CD4 counts and HIV viral load.
Results
Nearly all women had detectable HPV in the 6 months preceding ART initiation (92%) and the cumulative prevalence remained high following initiation of therapy (90%). We found no effect of ART on monthly HPV DNA detection (prevalence ratio: 1.0; 95% confidence interval: 0.96, 1.08), regardless of immune reconstitution or HIV viral suppression. Older age and higher pre-ART CD4 counts were associated with a significantly lower risk of HPV DNA detection.
Conclusions
ART did not impact HPV detection within 6 months of therapy initiation, highlighting the importance of continued and consistent screening, even after ART-initiation and immune reconstitution.
doi:10.1371/journal.pone.0055383
PMCID: PMC3558485  PMID: 23383171
24.  Human papillomavirus genotypes detected in clinician-collected and self-collected specimens from women living in the Mississippi Delta 
Background
There are no data available on human papillomavirus (HPV) infections in women living in the Mississippi Delta, where cervical cancer incidence and mortality among African American women is among the highest in the United States. The aim of this analysis was to report the age-specific prevalence of HPV in this population.
Methods
We recruited 443 women, 26–65 years of age, from the general population of women living in the Mississippi Delta to participate; 252 women had been screened for cervical cancer within the last 3 years while 191 had not. Women underwent a pelvic exam and had clinician-collected Pap sample taken for the routine cervical cancer screening by cytology. Women were asked to collect a self-collected specimen at home and return it to the clinic. Both specimens were tested for HPV genotypes.
Results
Four hundred and six women (91.6%) had HPV genotyping results for the clinician-collected and self-collected specimens. The prevalence of carcinogenic HPV was 18.0% (95% CI: 14.4%-22.1%) for clinician-collected specimens and 26.8% (95% CI: 22.6%-31.4%) for self-collected specimens. The concordance for the detection of carcinogenic HPV between clinician-collected and self-collected specimens was only fair (kappa = 0.54). While the prevalence of carcinogenic HPV in either sample decreased sharply with increasing age (ptrend< 0.01), the prevalence of non-carcinogenic HPV did not, especially the prevalence of HPV genotypes in the alpha 3/4/15 phylogenetic group.
Conclusions
The prevalence of carcinogenic HPV in our sample of women living in the Mississippi Delta was greater than the prevalence reported in several other U.S. studies. The high carriage of HPV infection, along with lack of participation in cervical cancer screening by some women, may contribute to the high cervical cancer burden in the region.
doi:10.1186/1471-2334-13-5
PMCID: PMC3570306  PMID: 23289357
Human papillomavirus (HPV); Self-collection; Pap; Cervical intraepithelial neoplasia; Cervix
25.  Concordant Oral-Genital HPV Infection in South Africa Couples: Evidence for Transmission 
Frontiers in Oncology  2013;3:303.
Objective: Cervical cancer is a leading cause of cancer mortality in South Africa. However, little is known about oral human papillomavirus (HPV) infection in high human immunodeficiency virus (HIV) seroprevalence settings.
Method: Thirty-four adult heterosexual couples attending an HIV testing center in Soweto, South Africa were enrolled. Each participant provided an oral rinse sample and genital swab, which were tested for 37 types of HPV DNA, and completed a risk behavior survey.
Results: Median age was 31 years and 9% (3/34) of men and 29% (10/34) of women enrolled tested HIV-positive; median CD4 count was 437 cells/mm3. Oral HPV prevalence was similar in women and men (12 vs. 18%, p = 0.48), and was non-significantly higher in HIV-infected vs. HIV-uninfected (23 vs. 13%, p = 0.34) subjects. Most men (82%) and women (84%) reported ever performing oral sex. Median number of lifetime sexual partners was “2–5” while median number of lifetime oral sex partners was 1. Oncogenic HPV subtypes were detected in 4% of oral, 26% of penile, and 74% of vaginal samples, including HPV16 in 1, 12, and 21% of these samples respectively. Genital HPV prevalence was significantly higher than oral HPV prevalence (75 vs. 15%, p ≤ 0.001). Thirty-five percent of couples (12/34) had at least one type-specific concordant vaginal-penile HPV infection but only one of nine couples with oral HPV had concordant oral–oral infection. However, 67% (4/6) of men and 25% (1/4) of women with oral HPV infection had partners with concordant genital HPV infection.
Implications and Impact: Oral–oral HPV concordance between couples is low, but oral-genital and genital–genital HPV concordance is higher, including concordance of male oral HPV infection with their partners’ vaginal HPV infection. This data is consistent with possible transmission of vaginal HPV infection to the oral cavity of sexual partners performing oral sex.
doi:10.3389/fonc.2013.00303
PMCID: PMC3860183  PMID: 24377087
HIV; oral sex; South Africa; HPV; oral; genital; concordance; transmission

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