Human Papillomavirus (HPV), Vaccination, and Cervical Cancer
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Human papillomavirus (HPV) is a common cause of infection. There are over 100 different sub-types of HPV. HPV types 16 and 18 cause 70% of cervical cancers and are also linked to cancers of the anus, vulva, vagina, penis, as well as the mouth and throat. Over time these can cause cells in the cervix to change, leading to precancerous conditions - cervical intraepithelial neoplasia (CIN), with a higher risk of developing cancer. Vaccination against HPV 16, 18 and other 'high risk' types of HPV reduces the risk of developing cervical and other HPV-related cancers.

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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Dobson SR, McNeil S, Dionne M, et al.
Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial.
JAMA. 2013; 309(17):1793-802 [PubMed]
IMPORTANCE: Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible.
OBJECTIVE: To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses.
DESIGN, SETTING, AND PATIENTS: Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%).
INTERVENTION: Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES: Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months.
RESULTS: The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36.
CONCLUSIONS AND RELEVANCE: Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00501137.


Laz TH, Rahman M, Berenson AB
Human papillomavirus vaccine uptake among 18- to 26-year-old women in the United States: National Health Interview Survey, 2010.
Cancer. 2013; 119(7):1386-92 [PubMed] Article available free on PMC after 01/04/2014
BACKGROUND: Human papillomavirus (HPV) vaccine uptake among young adult women has been reported to be very low. The authors conducted this study to provide an update on HPV vaccine uptake among 18- to 26-year-old women.
METHODS: The authors used the National Health Interview Survey 2010 data to estimate HPV vaccine coverage and their correlates.
RESULTS: Overall, 22.7% of women initiated (≥1 dose) and 12.7% completed the vaccine (≥3 doses). Thus, about 56% of women who initiated the vaccine completed it. Multivariate logistic regression analyses showed that younger age, unmarried status, Papanicolaou test, influenza vaccine, lifetime vaccines, and HPV vaccine awareness were positively associated with receiving ≥1 and ≥3 doses. In addition, uninsured women were less likely to receive ≥1 dose (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.28-0.84), and blacks (OR, 0.48; 95% CI, 0.23-0.99) and women with a family income <100% of the federal poverty level (OR, 0.40; 95% CI, 0.21-0.73) were less likely to receive ≥3 doses. Furthermore, based on vaccine initiators, blacks were less likely than whites to complete the vaccine (OR, 0.29; 95% CI, 0.16-0.55). Two thirds of unvaccinated women were not interested in future vaccination. Among those who were interested, >76.4% preferred to receive it free or at a lower cost, whereas 20% would pay the full cost of the vaccine.
CONCLUSIONS: One in 8 women completed the 3-dose HPV vaccine. Educational and vaccine financing programs are needed to improve the uptake among low-income minority women who are at increased risk for cervical cancer.


Johansson C, Schwartz S
Regulation of human papillomavirus gene expression by splicing and polyadenylation.
Nat Rev Microbiol. 2013; 11(4):239-51 [PubMed]
Human papillomaviruses (HPVs) are small DNA tumour viruses that are present in more than 99% of all cervical cancers. The ability of these viruses to cause disease is partly attributed to the strict coordination of viral gene expression with the differentiation stage of the infected cell. HPV gene expression is regulated temporally at the level of RNA splicing and polyadenylation, and a dysregulated gene expression programme allows some HPV types to establish long-term persistence, which is a risk factor for cancer. In this Review, we summarize the role of splicing and polyadenylation in the regulation of HPV gene expression and discuss the viral and cellular factors that control these processes.


Wang S, Pang T, Gao M, et al.
HPV E6 induces eIF4E transcription to promote the proliferation and migration of cervical cancer.
FEBS Lett. 2013; 587(6):690-7 [PubMed]
Increasing evidence has placed eukaryotic translation initiation factor 4E (eIF4E) at the hub of tumor development and progression. Several studies have reported that eIF4E is over-expressed in cervical cancer; however, the mechanism remains elusive. The results of this study further confirm over-expression of eIF4E in cervical cancer tumors and cell lines, and we have discovered that the transcription of eIF4E is induced by protein E6 of the human papillomavirus (HPV). Moreover, regulation of eIF4E by E6 significantly influences cell proliferation, the cell cycle, migration, and apoptosis. Therefore, eIF4E emerges as a key player in tumor development and progression and a potential target for CC treatment and prevention.


Galarowicz B, Jach R, Kidzierska J, et al.
The role of mRNA E6/E7 HPV high oncogenic risk expression in colposcopy of cervical intraepithelial neoplasia (CIN).
Przegl Lek. 2012; 69(9):651-7 [PubMed]
UNLABELLED: The aim of this paper is the evaluation of colposcopy and mRNA E6/E7 HPV detection--as the marker of persistent human papilloma virus (HPV) infection in the triage of abnormal Pap smears and in the assessment of cervical intraepithelial neoplasia progression risk. The clinical material consisted of 85 women, participating the national cervical cancer screening in the period of April 2010, and October 2010, reffered to the Outpatient Clinic of Gynecologic Oncology and Female Genital Tract Neoplasms Prophylaxy of the Jagiellonian University Medical College in Krakow, Poland. All subjects were offered gynecological evaluation, Pap smear, colposcopy, DNA HPV (Hybrid Capture2, Qiagen) and mRNA E6/E7 testing (NulciSens, Biomerieux). In case of positive tests colposcopically directed cervical biopsy with histopathologic evaluation were performed.
RESULTS: The presence of mRNA E6/E7 HPV transcripts correlated with high grade squamous intraepithelial lesions, statistically significantly. There was statistically difference between colposcopic, histologic concordance comparing to mRNA E6/E7 HPV colposcopic histologic concordance (p < 0.001).
CONCLUSIONS: The presence of mRNA E6/E7 HR HPV may be assumed as specific marker of high grade cervical lesions. The combination of mRNA E6/E7 HR HPV ewith colposcopic evaluation increases the colposcopy concordanece with final histologic findings.


Booth CN, Bashleben C, Filomena CA, et al.
Monitoring and ordering practices for human papillomavirus in cervical cytology: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 5.
Arch Pathol Lab Med. 2013; 137(2):214-9 [PubMed]
CONTEXT: The association of certain types of human papillomavirus with cervical carcinoma is well established. Human papillomavirus testing is now routinely used to screen for cervical carcinoma and precursor lesions of the cervix (cotesting and reflex testing) and these results are considered in patient triage and management.
OBJECTIVE: To provide information about current laboratory practices in human papillomavirus testing and consensus best practice statements based on results from the College of American Pathologists' laboratory-based survey funded by the Centers for Disease Control and Prevention.
DESIGN: The College of American Pathologists submitted a paper-based survey to 1245 laboratories in the United States. After review of the initial results, follow-up Web-based survey results, and a literature review by an expert working group, consensus best practice statements were constructed by working group members for presentation at a national consensus conference. These best practice statements were discussed and then voted upon by conference participants.
RESULTS: A total of 525 laboratories responded to survey questions about human papillomavirus ordering and monitoring practices, whereas 546 responded to the overall survey. In most laboratories (87.6%), the high-risk human papillomavirus test is ordered as a reflex test by providers. A minority of laboratories (11.9%) routinely bundle low- and high-risk human papillomavirus tests. Most laboratories (84.4%) do not limit testing in patients with atypical squamous cells to women older than 20 years. More than half of laboratories (53.3%) monitor human papillomavirus positive rates in Papanicolaou tests with atypical squamous cells of undetermined significance.
CONCLUSIONS: It is not appropriate for laboratories to offer low-risk human papillomavirus testing for any clinical circumstance in gynecologic cytology. Laboratories should not order human papillomavirus testing to resolve diagnostic discrepancies. It is a valuable broad measure of laboratory quality to monitor the human papillomavirus-positive rates in Papanicolaou tests with atypical squamous cells.


Chay DB, Cho H, Kim BW, et al.
Clinical significance of serum anti-human papillomavirus 16 and 18 antibodies in cervical neoplasia.
Obstet Gynecol. 2013; 121(2 Pt 1):321-9 [PubMed]
OBJECTIVE: To estimate the clinical significance of serum anti-human papillomavirus (HPV) antibodies and high-risk cervical HPV DNA in cervical neoplasia.
METHODS: The study population comprised patients who were histopathologically diagnosed with cervical intraepithelial neoplasia (CIN) 1 (n=64), CIN 2 and 3 (n=241), cervical cancer (n=170), and normal control participants (n=975). Cervical HPV DNA tests were performed through nucleic acid hybridization assay tests, and serum anti-HPV 16 and 18 antibodies were measured by competitive immunoassay. The associations of HPV DNA and anti-HPV antibodies were evaluated with demographic characteristics and compared according to the levels of disease severity. Anti-HPV antibodies were also investigated with clinicopathologic parameters, including survival data.
RESULTS: Among various demographic characteristics, factors involving sexual behavior had a higher tendency of HPV DNA positivity and HPV seropositivity. Human papillomavirus DNA mean titer and positivity were both increased in patients with cervical neoplasia compared with those with normal control participants, but there was no statistical difference among types of cervical neoplasia. Serum anti-HPV 16 antibodies were also able to differentiate cervical neoplasia from a normal control participant and furthermore distinguished CIN 1 from CIN 2 and 3 (odd ratio 2.87 [1.43-5.78], P=.002). In cervical cancer, HPV 16 seropositivity was associated with prolonged disease-free survival according to the univariable analysis (hazard ratio=0.12 [0.01-0.94], P=.044).
CONCLUSION: Serum anti-HPV 16 antibodies can distinguish cervical neoplasia from a normal control and has the advantage of identifying high-grade CIN. Moreover, in cervical cancer, HPV 16 seropositivity may be associated with a more favorable prognosis.
LEVEL OF EVIDENCE: II.


Pruski D, Fraszczak J, Iwaniec K, et al.
Assessment of frequency of regression and progression of mild cervical neoplasia - LGSIL in women with positive high-risk HPV DNA test result.
Ginekol Pol. 2012; 83(8):572-5 [PubMed]
OBJECTIVES: Assessment of frequency of regression and progression of mild cervical neoplasia in women positive for types of HPV DNA of high oncogenic potential.
MATERIALS AND METHODS: 111 women were studied. One-year-long observation of patients included cervical cytology conducted every three months, and colposcopy conducted every six months. After a period of 12 months all women were evaluated with colposcopy and directed biopsies of abnormal cervical tissue.
RESULTS: This study confirms the significant effect of age on both regression and progression of low-grade cervical intraepithelial neoplasia.
CONCLUSIONS: In the age group below 26 years, complete regression of LGSIL occurs significantly more frequently than in older women. Whereas in the over 36 age group, progression to HGSIL occurred more frequently during 12 months of follow-up.


Hall JS, Iype R, Armenoult LS, et al.
Poor prognosis associated with human papillomavirus α7 genotypes in cervical carcinoma cannot be explained by intrinsic radiosensitivity.
Int J Radiat Oncol Biol Phys. 2013; 85(5):e223-9 [PubMed]
PURPOSE: To investigate the relationship between human papillomavirus (HPV) genotype and outcome after radiation therapy and intrinsic radiosensitivity.
METHODS AND MATERIALS: HPV genotyping was performed on cervix biopsies by polymerase chain reaction using SPF-10 broad-spectrum primers, followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA25) (version 1) (n=202). PapilloCheck and quantitative reverse transcription-polymerase chain reaction were used to genotype cervix cancer cell lines (n=16). Local progression-free survival after radiation therapy alone was assessed using log-rank and Cox proportionate hazard analyses. Intrinsic radiosensitivity was measured as surviving fraction at 2 Gy (SF2) using clonogenic assays.
RESULTS: Of the 202 tumors, 107 (53.0%) were positive for HPV16, 29 (14.4%) for HPV18, 9 (4.5%) for HPV45, 23 (11.4%) for other HPV genotypes, and 22 (10.9%) were negative; 11 (5.5%) contained multiple genotypes, and 1 tumor was HPV X (0.5%). In 148 patients with outcome data, those with HPVα9-positive tumors had better local progression-free survival compared with α7 patients in univariate (P<.004) and multivariate (hazard ratio 1.54, 95% confidence interval 1.11-1.76, P=.021) analyses. There was no difference in the median SF2 of α9 and α7 cervical tumors (n=63). In the cell lines, 9 were α7 and 4 α9 positive and 3 negative. There was no difference in SF2 between α9 and α7 cell lines (n=14).
CONCLUSION: The reduced radioresponsiveness of α7 cervical tumors is not related to intrinsic radiosensitivity.


Liao SY, Rodgers WH, Kauderer J, et al.
Endocervical glandular neoplasia associated with lobular endocervical glandular hyperplasia is HPV-independent and correlates with carbonic anhydrase-IX expression: a Gynaecological Oncology Group Study.
Br J Cancer. 2013; 108(3):613-20 [PubMed] Article available free on PMC after 19/02/2014
BACKGROUND: Lobular endocervical glandular hyperplasia (LEGH) is a rare lesion of the uterine cervix. It has been proposed that LEGH may represent a precursor lesion to a group of mucinous adenocarcinoma with gastric phenotype (GA) that is independent of high-risk human papillomavirus (H-HPV) infection. Carbonic anhydrase-IX (CA-IX) is highly expressed in conventional glandular lesions (CGLs). However, expression of CA-IX in LEGH or GA has not been studied.
METHODS: In all, 12 CGLs, 7 LEGHs, 6 LEGHs with coexisting adenocarcinoma in situ (AIS, 3) and GA (3) were identified from Japanese women with a cytological diagnosis of atypical glandular cells of undetermined significance. Immunostaining was used to detect CA-IX and p16(INK)4(a) (hereafter termed p16) protein expression in the tissues and CA-IX protein expression in the Papanicolaou smears (PSs). Polymerase chain reaction was used to detect H-HPV DNA in liquid-based cytology.
RESULTS: Out of 12 (83%) CGLs, 10 were positive with H-HPV and high levels of CA-IX expression were seen in all (100%) cases. P16 protein expression was observed in 11 out of 12 (92%) cases. None of the LEGHs, LEGHs with AIS or GA were positive for H-HPV and only 8 out of 13 (62%) showed focal weak (1+) p16 expression. In contrast, all cases (100%) exhibited strong CA-IX protein expression.
CONCLUSION: Our study suggests that there are different molecular mechanisms of carcinogenesis resulting in CGLs vs LEGHs associated with AIS or GA. There is also a possible link between LEGHs and GAs. Furthermore, CA-IX expression may serve as a useful biomarker for the detection of GAs in the absence of H-HPV infection.


Hanning JE, Saini HK, Murray MJ, et al.
Lack of correlation between predicted and actual off-target effects of short-interfering RNAs targeting the human papillomavirus type 16 E7 oncogene.
Br J Cancer. 2013; 108(2):450-60 [PubMed] Article available free on PMC after 05/02/2014
BACKGROUND: When designing therapeutic short-interfering RNAs (siRNAs), off-target effects (OTEs) are usually predicted by computational quantification of messenger RNAs (mRNAs) that contain matches to the siRNA seed sequence in their 3' UTRs. It is assumed that the higher the number of predicted transcriptional OTEs, the greater the size of the actual OTE signature and the more detrimental the phenotypic consequences in target-negative cells.
METHODS: We tested this general assumption by investigating the OTEs of potential therapeutic siRNAs targeting the human papillomavirus (HPV) type-16 E7 oncogene. We studied HPV-negative squamous epithelial cells, from normal cervix (NCx) and skin (HaCaT), which would be vulnerable to 'bystander' OTEs following transfection in vivo.
RESULTS: We observed no correlation between the number of computationally predicted OTEs and the actual number of seed-dependent OTEs (P=0.76). On average only 20.5% of actual transcriptional OTEs were seed-dependent (i.e., predicted). The unpredicted OTEs included stimulation of innate immune pathways, as well as indirect (downstream) effects of other OTEs, which affected important cancer-associated pathways. Although most significant OTEs observed were seen in both NCx and HaCaT cells, only 0-5.9% of differentially expressed genes overlapped between the two cell types.
CONCLUSION: These data do not support the assumption that actual OTEs correlate well with predicted OTEs.


Carozzi F, Gillio-Tos A, Confortini M, et al.
Risk of high-grade cervical intraepithelial neoplasia during follow-up in HPV-positive women according to baseline p16-INK4A results: a prospective analysis of a nested substudy of the NTCC randomised controlled trial.
Lancet Oncol. 2013; 14(2):168-76 [PubMed]
BACKGROUND: Immunostaining for p16-INK4A (henceforth p16) is a sensitive and specific method for detection of high-grade cervical intraepithelial neoplasia (CIN) in women infected with human papillomavirus (HPV), but longitudinal data have not been obtained. We investigated the relation between p16 status and risk of CIN during 3 years of follow-up.
METHODS: Women aged 25-60 years were enrolled between June 10, 2003, and Dec 31, 2004, in a multicentre randomised trial comparing HPV testing with cytology. HPV-positive women were referred for colposcopy and, in seven of nine centres, were tested for p16 overexpression by immunostaining. If no CIN was detected, these women were followed up at yearly intervals until clearance of HPV infection. The primary endpoint was histologically confirmed CIN of grade 2 or worse (CIN of grade 2 [CIN2], CIN of grade 3 [CIN3], or invasive cervical cancer) at recruitment or during follow-up. We calculated the absolute and relative risks by p16 status at recruitment. We also calculated the longitudinal sensitivity of p16 testing. Additionally, we assessed the relative sensitivity of an alternative strategy (referral to colposcopy and follow-up of only HPV-positive, p16-positive women) versus conventional cytology in two age groups. Percentages were weighted by the inverse of the tested fraction. The trial in which this study is nested is registered, number ISRCTN81678807.
FINDINGS: Of 1042 HPV-positive women who were tested for p16 with no CIN detected during the first round of screening, 944 (91%) had further HPV tests. 793 (84%) of these 944 were followed up until detection of CIN2 or worse, HPV infection clearance, or for at least 3 years. CIN2 or worse was detected during follow-up in more p16-positive women (31 of 365, 8·8% [95% CI 5·8-11·8]) than in p16-negative women (17 of 579, 3·7% [1·9-5·4]; relative risk [RR] 2·61 [95% CI 1·49-4·59]). RR was higher in women aged 35-60 years at recruitment (3·37 [1·39-8·15]) than in those aged 25-34 years (2·15 [1·00-4·61]), but age was not a significant modifier. CIN3 or worse was detected during follow-up in more p16-positive women (16 of 365, 4·4% [2·3-6·6]) than in p16-negative women (six of 579, 1·3% [0·2-2·3]; RR 3·90 [95% CI 1·57-9·68]). Longitudinal sensitivity of p16 testing for detection of CIN3 or worse during follow-up at all ages was 77·8% (95% CI 63·9-91·6). The relative sensitivity of the alternative strategy compared with conventional cytology was 2·08 (1·13-3·56) in women aged 35-60 years and 2·86 (1·28-5·36) in those aged 25-34 years. HPV-positive, p16-negative women aged 35-60 years had a higher cumulative risk of CIN3 or worse during recruitment or follow-up (2·0%, 95% CI 0·3-3·7) than did HPV-negative women (0·01%, 0-0·04) or those who were cytologically normal (0·04%, 0·02-0·09) at recruitment.
INTERPRETATION: p16 overexpression is a marker for CIN2 or worse or for development of CIN2 or worse within 3 years in HPV-positive women, especially those aged 35-60 years. HPV-positive, p16-positive women need immediate colposcopy and, if the assessment is negative, annual follow-up. Immediate colposcopy can be avoided in HPV-positive, p16-negative women, who can be safely managed with repeat screening after 2-3 year intervals.
FUNDING: European Union; Italian Ministry of Health; Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia Romagna; and Public Health Agency of Lazio Region.


Gerli S, Bavetta F, Di Renzo GC
Antisepsis regimen in the surgical treatment of HPV generated cervical lesions: polyhexamethylene biguanide vs chlorhexidine. A randomized, double blind study.
Eur Rev Med Pharmacol Sci. 2012; 16(14):1994-8 [PubMed]
INTRODUCTION: To reduce the risk of local infections after surgical treatments for HPV infected cervical lesions, the post-operative regimen is generally based on the use of vaginal antimicrobial agents.
AIM: The efficacy and safety of polyhexamethylene biguanide-based vaginal suppositories was compared to a similar chlorhexidine-based treatment, in the post recovery regimen after surgical treatment of cervical lesions.
MATERIALS AND METHODS: 50 women who underwent to CO2 laser therapy for cervical lesions were randomly assigned to receive 10 days of antiseptic treatment with chlorhexidine digluconate vaginal suppositories, or polyhexamethylene biguanide vaginal suppositories (Monogin®/Biguanelle® ovuli, Lo.Li. Pharma, Italy). A weekly follow-up check was performed for 6 weeks.
RESULTS: Polyhexamethylene biguanide-based treatment showed improved efficacy compared to chlorhexidine, in terms of healing process and prevention of bacterial infections.
CONCLUSIONS: Due to its safety and effectiveness, the vaginal treatment with polyhexamethylene biguanide is preferred to chlorexidine, in accordance with previously reported in vitro evidences.


Chando S, Tiro JA, Harris TR, et al.
Effects of socioeconomic status and health care access on low levels of human papillomavirus vaccination among Spanish-speaking Hispanics in California.
Am J Public Health. 2013; 103(2):270-2 [PubMed]
Little is known about the effect of language preference, socioeconomic status, and health care access on human papillomavirus (HPV) vaccination. We examined these factors in Hispanic parents of daughters aged 11 to 17 years in California (n = 1090). Spanish-speaking parents were less likely to have their daughters vaccinated than were English speakers (odds ratio [OR] = 0.55; 95% confidence interval [CI] = 0.31, 0.98). Adding income and access to multivariate analyses made language nonsignificant (OR = 0.68; 95% CI = 0.35, 1.29). This confirms that health care use is associated with language via income and access. Low-income Hispanics, who lack access, need information about free HPV vaccination programs.


Guo M, Gong Y, Wang J, et al.
The role of human papillomavirus type 16/18 genotyping in predicting high-grade cervical/vaginal intraepithelial neoplasm in women with mildly abnormal Papanicolaou results.
Cancer Cytopathol. 2013; 121(2):79-85 [PubMed]
BACKGROUND: The authors compared the predictive value of type 16 and/or 18 human papillomavirus (HPV) versus non-16/18 HPV types for high-grade (grade ≥2) cervical neoplasm/vaginal intraepithelial neoplasm and carcinoma (CIN/VAIN2+) in women with mildly abnormal Papanicolaou (Pap) results (ie, atypical squamous cells of undetermined significance [ASCUS] or low-grade squamous epithelial lesion [LSIL]).
METHODS: The authors retrospectively selected Pap specimens with HPV testing results obtained from 243 women (155 with ASCUS and 88 with LSIL Pap results) in their Department of Pathology. HPV genotyping was performed using the EasyChip HPV blot assay. The Pap specimens with HPV16/18 and non-16/18 HPV types were compared with follow-up biopsy results. Follow-up duration ranged from 1 month to 58 months (mean, 26 months).
RESULTS: In total, 58 of 155 specimens (37%) that had ASCUS and 29 of 88 specimens (33%) that had LSIL were positive for HPV16/18. CIN/VAIN2+ biopsies were identified in 43 of 155 women (28%) with ASCUS and in 28 of 88 women (32%) with LSIL. Women with ASCUS and HPV16/18 had a significantly higher rate (43%) of CIN/VAIN2+ than women with ASCUS and non-16/18 HPV types (19%; P = .003; odds ratio, 3.10; 95% confidence interval, 1.48-6.53). There was no statistically significant difference in the rate of CIN/VAIN2+ between women who had LSIL and HPV16/18 (45%) and those who had LSIL and non-16/18 HPV types (29%; P = .16; odds ratio, 1.96; 95% confidence interval, 0.77-4.97).
CONCLUSIONS: HPV genotyping for HPV16/18 improved risk assessment for women with ASCUS Pap results and may be used to predict the risk of CIN/VAIN2+ to better guide follow-up management.


Stoler MH, Wright TC, Cuzick J, et al.
APTIMA HPV assay performance in women with atypical squamous cells of undetermined significance cytology results.
Am J Obstet Gynecol. 2013; 208(2):144.e1-8 [PubMed]
OBJECTIVE: The objective of the study was to determine the sensitivity and specificity of the APTIMA human papillomavirus (AHPV) assay for high-grade cervical intraepithelial neoplasia (CIN) in women 21 years old and older with atypical squamous cells of undetermined significance (ASC-US) cytology.
STUDY DESIGN: Women 21 years old and older with ASC-US cytology had colposcopy/biopsy and molecular human papillomavirus testing. Performance of the AHPV and Hybrid Capture 2 assays was compared with a clinical diagnosis of CIN grade 2, CIN grade 3, or adenocarcinoma in situ (CIN2 or greater).
RESULTS: Of 939 evaluable subjects, CIN2 or greater and CIN3 or greater prevalence was 9.7% and 4.4%, respectively. AHPV sensitivity and specificity was 86.8% and 62.9% for CIN2 or greater detection and 90.2% and 60.2% for CIN3 or greater, respectively. AHPV had a similar sensitivity to Hybrid Capture 2 but a significantly higher specificity (62.9% vs 55.8%, P < .001) for CIN2 or greater detection.
CONCLUSION: Among women with ASC-US cytology, detection of high-risk human papillomavirus E6/E7 oncogenic messenger ribonucleic acid is an effective triage method for colposcopy referral.


Ciesielska U, Nowińska K, Podhorska-Okołów M, Dziegiel P
The role of human papillomavirus in the malignant transformation of cervix epithelial cells and the importance of vaccination against this virus.
Adv Clin Exp Med. 2012 Mar-Apr; 21(2):235-44 [PubMed]
Human papillomavirus (HPV) belongs to the diverse group of sexually transmitted viruses that manifest affinity to the squamous epithelia of the skin and mucous membranes. Over 100 types of HPV have been described and identified in human tissues, and it has been proved that persistent infection with high-risk types of the virus (types 16 and 18 in particular) could lead to cervical cancer. High-risk HPV types have been found in approximately 70% of all cases of cervical cancer worldwide. The aim of this study was to describe the role of HPV in the process of neoplastic transformation in epithelial cells and to emphasize the prophylactic significance of vaccinations against the virus.


Arbyn M, Ronco G, Anttila A, et al.
Evidence regarding human papillomavirus testing in secondary prevention of cervical cancer.
Vaccine. 2012; 30 Suppl 5:F88-99 [PubMed]
More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Consistent evidence is available indicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. Several other tests show at least similar accuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. The APTIMA(®) test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only. Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®) 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older. However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Kane MA, Serrano B, de Sanjosé S, Wittet S
Implementation of human papillomavirus immunization in the developing world.
Vaccine. 2012; 30 Suppl 5:F192-200 [PubMed]
Cervical cancer is the second leading cause of cancer death in women in less developed regions of the world and the leading cause of cancer deaths in GAVI-eligible countries, where 54% of worldwide cervical cancer deaths occur. If prevention is not implemented in these countries, population growth alone will lead to a 63% increase in deaths by 2025. Human papillomavirus (HPV) vaccines are routinely used in the National Immunization Programs in most industrial countries, and the decision by the GAVI Alliance to accept applications from eligible developing countries for HPV vaccine support is the single most important opportunity for children in these countries to be protected against HPV-related diseases. As it has done for other vaccines, such as Haemophilus influenzae type b, rotavirus and pneumococcal conjugate vaccines, GAVI should strongly consider developing and funding a group dedicated to working on all aspects of HPV vaccine introduction in the developing world. Immunization in middle-income developing countries not eligible for GAVI support will depend on "tiered" pricing policies or regional procurement schemes to make vaccine available at prices significantly lower than those in industrial countries. Immunization coverage of infants has reached high levels in many of the poorest developing countries where complementary strategies for HPV control, such as adult screening and treatment, are poorly developed. Immunizing young adolescents will require expansion of immunization infrastructure to reach cohorts that currently are largely unreached, but the success of school-based strategies in industrial countries and developing country demonstration projects provides hope that relatively high coverage may be achieved in many countries. Communication and advocacy strategies for HPV control need to carefully consider local cultural attitudes toward HPV-related issues. Current strategies supported by health economic analyses call for female only immunization, but concerns have been expressed as to whether this is the optimal strategy for the developing world. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Steben M, Jeronimo J, Wittet S, et al.
Upgrading public health programs for human papillomavirus prevention and control is possible in low- and middle-income countries.
Vaccine. 2012; 30 Suppl 5:F183-91 [PubMed]
Cancer is an important cause of premature death in low- and middle-income countries (LMIC). Two preventive tools are available that have the potential together to sharply decrease the impact of cervical cancer in LMIC. The combination of human papillomavirus (HPV) vaccination and cervical cancer screening within existing programs is possible. Although there is a great deal of concern about introducing and strengthening HPV prevention efforts in LMIC, recent projects have demonstrated feasibility. Thus, with appropriate prioritization and resources, HPV prevention can be introduced and scaled up. Comprehensive HPV prevention strategies, mainly those geared at preventing cervical cancer, should include both vaccination and screening. The integration of both screening and vaccination will save the most lives, and such strategies are endorsed by many international organizations. However, some vaccine and screening programs are financed almost entirely by special externally-based programs. These more closely resemble demonstration exercises than sustainable national programs. In order for successful demonstration projects to have a broad impact on prevention, sustainable national funding based on strong commitments is essential. There may be challenges to implementing HPV prevention programs, but none should be considered insurmountable. Many LMIC have successfully adopted an HPV prevention agenda despite prevailing pessimism. Failure to act on this issue can perpetuate inequity in sexually transmitted infection and cancer prevention. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Forman D, de Martel C, Lacey CJ, et al.
Global burden of human papillomavirus and related diseases.
Vaccine. 2012; 30 Suppl 5:F12-23 [PubMed]
The worldwide prevalence of infection with human papillomavirus (HPV) in women without cervical abnormalities is 11-12% with higher rates in sub-Saharan Africa (24%), Eastern Europe (21%) and Latin America (16%). The two most prevalent types are HPV16 (3.2%) and HPV18 (1.4%). Prevalence increases in women with cervical pathology in proportion to the severity of the lesion reaching around 90% in women with grade 3 cervical intraepithelial neoplasia and invasive cancer. HPV infection has been identified as a definite human carcinogen for six types of cancer: cervix, penis, vulva, vagina, anus and oropharynx (including the base of the tongue and tonsils). Estimates of the incidence of these cancers for 2008 due to HPV infection have been calculated globally. Of the estimated 12.7 million cancers occurring in 2008, 610,000 (Population Attributable Fraction [PAF]=4.8%) could be attributed to HPV infection. The PAF varies substantially by geographic region and level of development, increasing to 6.9% in less developed regions of the world, 14.2% in sub-Saharan Africa and 15.5% in India, compared with 2.1% in more developed regions, 1.6% in Northern America and 1.2% in Australia/New Zealand. Cervical cancer, for which the PAF is estimated to be 100%, accounted for 530,000 (86.9%) of the HPV attributable cases with the other five cancer types accounting for the residual 80,000 cancers. Cervical cancer is the third most common female malignancy and shows a strong association with level of development, rates being at least four-fold higher in countries defined within the low ranking of the Human Development Index (HDI) compared with those in the very high category. Similar disparities are evident for 5-year survival-less than 20% in low HDI countries and more than 65% in very high countries. There are five-fold or greater differences in incidence between world regions. In those countries for which reliable temporal data are available, incidence rates appear to be consistently declining by approximately 2% per annum. There is, however, a lack of information from low HDI countries where screening is less likely to have been successfully implemented. Estimates of the projected incidence of cervical cancer in 2030, based solely on demographic factors, indicate a 2% increase in the global burden of cervical cancer, i.e., in balance with the current rate of decline. Due to the relative small numbers involved, it is difficult to discern temporal trends for the other cancers associated with HPV infection. Genital warts represent a sexually transmitted benign condition caused by HPV infection, especially HPV6 and HPV11. Reliable surveillance figures are difficult to obtain but data from developed countries indicate an annual incidence of 0.1 to 0.2% with a peak occurring at teenage and young adult ages. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Bosch FX, Tsu V, Vorsters A, et al.
Reframing cervical cancer prevention. Expanding the field towards prevention of human papillomavirus infections and related diseases.
Vaccine. 2012; 30 Suppl 5:F1-11 [PubMed]
The reframed paradigm of cervical cancer prevention will include strategic combinations of at least four major components: 1) routine introduction of human papillomavirus (HPV) vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. On a global scale, vaccination of newborns and infants is well established and has developed a successful working infrastructure. The hepatitis B virus (HBV) vaccination programs offer a model for HPV introduction in which newborn and infant immunization achieves a rapid reduction in the prevalence of the HBV carrier rates in immunized cohorts of children, and of liver cirrhosis and liver cancer decades later. In contrast, screening for cervical pre-cancer is largely restricted to industrialized populations and upper social classes in developing countries. The expertise gained by vaccination programs worldwide needs to be coordinated with the traditional cervical cancer prevention community of gynecologists and pathologists. Significant political and advocacy efforts at the Global level (World Health Organization, other United Nations agencies and The GAVI Alliance) need to be organized and reinforced to achieve a meaningful reduction in HPV transmission and its related health conditions and cancers. This desirable goal is now scientifically and technologically attainable, and great progress is being made in obtaining financing for global HPV immunization. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.


Leinonen MK, Nieminen P, Lönnberg S, et al.
Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland.
BMJ. 2012; 345:e7789 [PubMed] Article available free on PMC after 05/02/2014
OBJECTIVE: To compare the detection rates of precancerous and cancerous cervical lesions by human papillomavirus (HPV) DNA testing and by conventional cytology screening.
DESIGN: Prospective randomised trial. Two cohorts were followed over one screening round of five years, screened initially by primary HPV DNA testing or by primary Pap test.
SETTING: Population based programme for cervical cancer screening in Finland.
PARTICIPANTS: Women aged 25-65 years invited for screening in 2003-07 (101,678 in HPV arm; 101,747 in conventional cytology arm).
INTERVENTION: Women were randomly allocated (1:1) to primary HPV DNA screening followed by cytology triage if they had positive results, or to primary cytology screening. Screening method was disclosed at the screening visit. Trial personnel involved were aware of all test results.
MAIN OUTCOME MEASURES: Cumulative detection rates of cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive cervical cancer before the second screening (after five years) or before 31 December 2008. Lesions detected at screening and during the five year interval were included.
RESULTS: 1010 and 701 precancerous or cancerous lesions were detected during an average follow-up of 3.6 years in the HPV and cytology arms, respectively. Among invited women, the hazard ratio was 1.53 (95% confidence interval l.28 to 1.84) for CIN grade 1, 1.54 (1.33 to 1.78) for CIN 2, 1.32 (1.09 to 1.59) for CIN 3 or AIS, and 0.81 (0.48 to 1.37) for cervical cancer. In 25-34 year old participants, the cumulative hazard (or cumulative detection rate) was 0.0057 (0.0045 to 0.0072) for HPV screening versus 0.0046 (0.0035 to 0.0059) for conventional screening; corresponding data for women aged 35 years and older were 0.0022 (0.0019 to 0.0026) and 0.0017 (0.0014 to 0.0021), respectively.
CONCLUSIONS: Primary HPV DNA screening detects more cervical lesions than primary cytology within one screening round of five years. Even if the detection rate of CIN 3 or AIS increased in the HPV arm in both age groups, the absolute difference in cumulative rates in women aged 35 years or older was small. By carefully selecting age groups and screening intervals, HPV screening could increase the overall detection rate of cervical precancerous lesions only slightly. However, these findings should be interpreted in the context of the high level of opportunistic screening that occurs in Finland.
TRIAL REGISTRATION: International Standard Randomised Controlled Trial ISRCTN23885553.


Salehi M, Taheri T, Mohit E, et al.
Recombinant Leishmania tarentolae encoding the HPV type 16 E7 gene in tumor mice model.
Immunotherapy. 2012; 4(11):1107-20 [PubMed]
BACKGROUND: Cervical cancer, the third most prevalent cause of cancer in women worldwide, is associated with HPVs. The critical role of E7 protein in HPV-related malignancies has designated it as a strong contender for generating vaccines against HPV.
MATERIALS & METHODS: In this study, we developed a novel live vaccine using recombinant Leishmania tarentolae expressing E7-green fluorescent protein (GFP) fusion protein for the protection of mice against HPV-associated tumors. In order to transfect L. tarentolae with E7-GFP fusion construct, pLEXSY-neo2 system was applied. Followed by PCR, fluorescence imaging and fluorescence-activated cell sorting analysis, integration of E7-GFP gene into parasites genome was confirmed. A comparative study of six groups of C57BL/6 mice was performed to analyze antigen-specific humoral and cellular immune responses against E7 encoding live and DNA vaccines. Furthermore, the anti-tumor protective effect of L. tarentolae-E7-GFP was compared to other vaccination strategies, namely pcDNA-E7 as the DNA vaccine and pcDNA-E7/L. tarentolae-E7-GFP as the prime-boost regimen.
RESULTS: We found that E7-GFP expressing recombinant L. tarentolae induces significant levels of IgG2a and IFN-γ, while there is no significant IL-5 production compared with that of other strategies and control groups before and after challenge with TC-1 tumor cells. It is noteworthy that the designed live vaccine showed the best protection and minimum tumor size among all groups against TC-1-induced tumors.
CONCLUSION: Overall, the results obtained revealed that the E7-GFP recombinant L. tarentolae could be a potential live vaccine for induction of immune responses in vivo.


Torné A, Fusté P, Rodríguez-Carunchio L, et al.
Intraoperative post-conisation human papillomavirus testing for early detection of treatment failure in patients with cervical intraepithelial neoplasia: a pilot study.
BJOG. 2013; 120(4):392-9 [PubMed]
OBJECTIVE: To evaluate the feasibility and utility of intraoperative post-conisation human papillomavirus (IOP-HPV) testing and cytology to detect treatment failure in patients with cervical intraepithelial neoplasia grades 2-3 (CIN2-3).
DESIGN: Prospective observational pilot study.
SETTING: Barcelona, Spain.
POPULATION: A cohort of 132 women treated for CIN2-3 by loop electrosurgical conisation.
METHODS: An endocervical sample was obtained intraoperatively with a cytobrush from the cervix remaining after the conisation. The material was kept in PreservCyt medium and processed for Hybrid Capture 2 and cytology. Patients were followed-up for 24 months. The performance of IOP-HPV testing and IOP cytology was compared with conventional indicators of recurrence (cone margin, endocervical curettage, and HPV testing and cytology at 6 months).
MAIN OUTCOME MEASURE: Treatment failure (i.e. recurrent CIN2-3 during follow-up).
RESULTS: Treatment failure was identified in 12 women (9.1%). IOP-HPV testing for sensitivity, specificity, and positive and negative predictive values for treatment failure were 91.7, 78.3, 62.2, and 96.0%, respectively, which are similar to the figures for conventional HPV testing at 6 months (91.7, 76.0, 64.0, and 95.1%, respectively), and are better than the values of other conventional predictive factors (cone margin, endocervical curettage, and cytology intraoperative at 6 months). IOP-HPV was strongly associated with treatment failure in the multivariate analysis (OR 15.40, 95% CI 1.58-150.42).
CONCLUSION: IOP-HPV testing is feasible, and accurately predicts treatment failure in patients with CIN2-3. This new approach may allow an early identification of patients with treatment failure, thereby facilitating the scheduling of an attenuated follow-up for negative patients who are at very low risk of persistent disease.


Balbi G, Napolitano A, Giordano F, et al.
Role of the association of high-risk HPV identified by real-time PCR in cervical preneoplastic lesions.
Eur J Gynaecol Oncol. 2012; 33(5):467-71 [PubMed]
OBJECTIVE: To evaluate the effects of infection in multiple types of high-risk human papilloma virus (HPV) in cervical preneoplastic lesions in patients undergoing colposcopy following a diagnosis of atypical squamous cells of unknown significance (ASCUS) and low-grade squamous intraepithelial (LSIL) cytology.
MATERIALS AND METHODS: Between 2009 and 2010, 2,500 patients were recruited with a mean age of 35 +/- 5 years. Screening for cervical cancer was performed and in case of ASCUS and LSIL the patients underwent colposcopy. The tests for the detection and typing of viral DNA (HPV - DNA test) were performed on cervical swab with real-time PCR amplification.
RESULTS: The prevalence of infection was 70% (1579/2256) in the patients recruited. In relation to the degree of preneoplastic lesions some high-risk HPV viral genotypes were identified: HPV 16 (319/1466), HPV 18 (164/1466), HPV 45 (76/1466), HPV 31 (215/1466), HPV 52 (145/1466), HPV 58 (55/1466) HPV 56 (79/1466), HPV 51 (110/1466), HPV 6(138/1466), HPV 11 (88/1466), HPV 42 (34/1466), HPV 53 (43/1466). In case of high-grade lesions of CIN (CIN2 and CIN3) a greater HPV co-infection was detected and in particular the association from 16 to 18 (70%), 16-33 (18%) and 16 to 52 (12%).
CONCLUSIONS: Infection caused by the simultaneous presence of multiple HPV genotypes appears to be associated with a significantly increased risk of high-grade lesions of CIN or invasive cancer than the presence of single viral infections. The infection with multiple HPV types is a significant risk factor for high-grade lesions of CIN in women undergoing colposcopy for ASCUS cytology/LSIL. The use of real-time PCR has shown the ability not only to identify the different types of HPV, but also to monitor quantitatively the same over time, and during the study phase, to evaluate the sensitivity and specificity of the method in comparison with other techniques.


Oscarsson MG, Hannerfors AK, Tydén T
Young women's decision-making process for HPV vaccination.
Sex Reprod Healthc. 2012; 3(4):141-6 [PubMed]
OBJECTIVES: To explore young women's decision-making process for HPV vaccination and to identify their beliefs about HPV vaccination.
METHODS: This study employs a qualitative design. Data was collected by audio-taped interviews with 16 HPV vaccinated Swedish women, 17-26 years old. The data was analysed using latent content analysis.
RESULTS: Three themes emerged from the data: "Fear of cancer", "Reliance on vaccination" and "Mother--the main motivational factor". One of the major reasons for taking the decision to be HPV vaccinated was fear of cancer: vaccination was seen as a way to protect oneself against this. The young women's decision-making surrounding HPV vaccination was based on reliance on vaccination and trust in health care. Support from the mothers of the young women and mothers' sponsorship of costs initiated HPV vaccination. Other motivational factors were advertisements and friends. Despite having been vaccinated, the young women were unaware of the relation between cervical cancer, sexual behaviour and HPV.
CONCLUSION: These HPV vaccinated young women had limited knowledge about HPV. Therefore it is important that health professionals provide comprehensible information about HPV vaccination in attaining informed consent. In order to avoid misunderstandings, health care professionals in youth clinics and schools need to initiate discussion with young women, clarifying the relation between cervical cancer, HPV and sexual transmission.


Cox JT, Castle PE, Behrens CM, et al.
Comparison of cervical cancer screening strategies incorporating different combinations of cytology, HPV testing, and genotyping for HPV 16/18: results from the ATHENA HPV study.
Am J Obstet Gynecol. 2013; 208(3):184.e1-184.e11 [PubMed]
OBJECTIVE: The objective of the study was to compare 9 cervical cancer screening strategies to the current screening standard (cytology with human papillomavirus [HPV] triage of atypical squamous cells of undetermined significance) for the detection of high-grade cervical disease.
STUDY DESIGN: Women (n = 34,254) aged 30 years or older from the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study underwent screening with cytology and HPV testing with simultaneous HPV16/18 genotyping; those with atypical squamous cells of undetermined significance cytology or greater or HPV-positive status were referred for colposcopy.
RESULTS: In general, screening strategies that offered greater sensitivity also required more referral to colposcopy. HPV testing was more sensitive than cytology for detection of cervical intraepithelial neoplasia grade 2 or greater, but strategies that depended on cytology for triage of HPV-positive women decreased this sensitivity. Various strategies of cotesting with cytology increased sensitivity but did so by increasing testing. Strategies that included integrated HPV16/18 testing provided more efficient referral to colposcopy.
CONCLUSION: Strategies that maximize detection of women at greatest risk of cervical intraepithelial neoplasia grade 3 or greater by immediate referral to colposcopy, with follow-up testing of women at intermediate risk, maximize the benefits of cervical cancer screening while decreasing the potential harm. Incorporating screening with HPV and triage of HPV-positive women by a combination of genotyping for HPV16/18 and cytology provided a good balance between maximizing sensitivity (benefit) and specificity by limiting the number of colposcopies (potential harm).


Ogilvie GS, Krajden M, van Niekerk DJ, et al.
Primary cervical cancer screening with HPV testing compared with liquid-based cytology: results of round 1 of a randomised controlled trial -- the HPV FOCAL Study.
Br J Cancer. 2012; 107(12):1917-24 [PubMed] Article available free on PMC after 05/02/2014
BACKGROUND: Round 1 data of human papillomavirus (HPV) FOCAL, a three-arm, randomised trial, which aims to establish the efficacy of HPV DNA testing as a primary screen for cervical cancer, are presented.
METHODS: The three arms are: Control arm - liquid based cytology with atypical squamous cells of unknown significance (ASC-US) triage with hrHPV testing; Intervention Arm - hrHPV at entry with liquid-based cytology (LBC) triage of hrHPV positives, with exit screen at 4 years; Safety check arm - hrHPV at entry with LBC triage of hrHPV positives with exit screen at 2 years.
RESULTS: A total of 6154 women were randomised to the control arm and 12 494 to the HPV arms (intervention and safety check). In the HPV arm, the baseline cervical intraepithelial neoplasia (CIN)2+ and CIN3+ rate was 9.2/1000 (95%CI; 7.4, 10.9) and 4.8/1000 (95%CI; 3.6, 6.1), which increased to 16.1/1000 (95%CI 13.2, 18.9) for CIN2+ and to 8.0/1000 (95%CI; 5.9, 10.0) for CIN3+ after subsequent screening of HPV-DNA-positive/cytology-negative women. Detection rate in the control arm remained unchanged after subsequent screening of ASC-US-positive/hrHPV DNA-negative women at 11.0/1000 for CIN2+ and 5.0/1000 for CIN3+.
CONCLUSION: After subsequent screening of women who were either hrHPV positive/cytology negative or ASC-US positive/HPV negative, women randomised to the HPV arms had increased CIN2+ detection compared with women randomised to the cytology arm.


Jensen KE, Schmiedel S, Norrild B, et al.
Parity as a cofactor for high-grade cervical disease among women with persistent human papillomavirus infection: a 13-year follow-up.
Br J Cancer. 2013; 108(1):234-9 [PubMed] Article available free on PMC after 15/01/2014
BACKGROUND: Several environmental factors have been associated with increased risks for cervical cancer. We examined whether reproductive history, contraceptive use, or sexual behaviour increase the risk for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among women with persistent human papillomavirus (HPV) infection.
METHODS: A population-based cohort of women participated in a personal interview and underwent a gynaecological examination at which cervical specimens were obtained for HPV DNA testing. Follow-up information (~13 years) on cervical lesions was obtained from the Danish Pathology Data Bank. Women who had a high-risk HPV infection comprised the overall study population (n=1353). A subgroup of women with persistent high-risk HPV infection (n=312) was identified. Hazard ratios (HRs) for a diagnosis of CIN3+ and the corresponding 95% confidence intervals (CIs) were calculated.
RESULTS: Women with persistent HPV infection who had given birth had a significantly increased risk for CIN3+ (HR=1.78; 95% CI: 1.07-2.94). No association was found with pregnancy, use of intrauterine devices, or sexual behaviour. Based on small numbers, women with persistent HPV infection had a decreased risk for CIN3+ with any use of oral contraceptives (HR=0.54; 95% CI: 0.29-1.00).
CONCLUSION: Childbirth increases the risk for subsequent CIN3+ among women with persistent HPV infection.


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