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Persistent HPV Infection and Cervical Cancer Risk: Is the Scientific Rationale for Changing the Screening Paradigm Enough?
... [13,14] This unfortunately has not been possible in resource-limited countries such as Nigeria, because of the poor availability screening tests and poor uptake of available screening options. [15,16] Screening ensures that cervical cancer is detected at an early stage when it can be treated more effectively. [17] Current evidence-based recommendation for cervical cancer screening supports the use of Papanicolaou (Pap) smear. ...
Background
In Nigeria, inadequate regular screening services for cervical cancer as well as poor uptake of available cervical cancer screening modalities continue to challenge cervical cancer prevention. This study seeks to assess the knowledge, attitude and practices of cervical cancer screening among female secondary school teachers whose effective role in the communication and motivation of young students have been largely documented in literature.
Methodology
This was a descriptive cross-sectional study conducted among 273 female teachers in Oshodi-Isolo Local Government Area of Lagos State selected by the multi-stage sampling method. Data was collected using self-administered questionnaire and analyzed using Epi info 7.2 statistical software. The Chi-square tests was used to determine statistical associations. A p-value of <0.05 was considered statistically significant.
Results
The mean age of the respondents was 39.7 ± 8.6. Respondents were mostly married 219(80.2%) in monogamous family setting 175(64.1%). Majority 224(80.2%) had an overall poor knowledge of cervical cancer and only 73(26.7%) could correctly link HPV as a cause of cervical cancer. Multiple sexual partners 52(19.1%), and early sexual onset 45(16.5%) were the commonest risk factors known by respondents. Although majority had a positive attitude 249(91.2%) towards cervical cancer screening, overall practice was however majorly poor 246(90.1%).
Conclusion
Our result demonstrates an overwhelming majority of female teachers had poor knowledge and poor cervical cancer screening practices. This highlights the need for effective dissemination of information on cervical cancer and screening to teachers to foster effective transmission of accurate information about cervical cancer to young students.
... Of all HPV strains, HPV16 infection is not only more likely to persist but also carried the highest risk of CIN3. The absolute risk for CIN3 was estimated as 50% at annual follow-up on HPV positive women [19]. ...
Objective:
To introduce HPV self-sampling and out-reach colposcopy clinic as interventions to improve the follow-up of HPV positive women in a community based cervical cancer screening programme.
Methods:
This was a prospective observational study conducted during October 2017 to August 2019 and 2977 women underwent cervical cancer screening using CareHPV test. Follow up colposcopy for HPV positive women were conducted at the rural health center and alternatively as out-reach clinics in their own villages and default rates were compared. HPV positive women were followed up at one-year. They were given an option of either having a follow-up HPV test performed by a health care worker (HCW) or by self-sampling. Compliance to follow up in these two modalities were compared. A validated questionnaire was given to women who had given an HPV self-sample to assess their awareness about HPV and cervical cancer.
Results:
During our initial round of cervical cancer screening using HPV as a primary screening modality, our HPV screen positive rate was 7.05% (210 out of 2977 women screened). Our colposcopy rates following an initial invitation at the rural health centre was only 28.5%. Following this, we initiated out-reach colposcopy clinics at their own villages for HPV positive women and this increased colposcopy rates from 28.5% to 45.2%. The participation rate at one-year follow-up was increased from 40.5% to 60% by the introduction of self-sampling as a follow up option and 16.2% of women who were initially positive remained HPV positive at 12-14 months follow up. All women who were offered the option of self-sampling preferred it over a HCW collected sample.
Conclusion:
Our study showed that self-sampling could also be used effectively in the follow up of HPV positive women in the community. Outreach colposcopy clinics in their own villages enabled better follow up of HPV positive women.
... Genital warts are benign epithelial cell growths caused by sexually transmitted HPV infection (21,22). Genotyping of genital HPV is of great clinical significance in terms of developing treatment plans as well as follow-up and prevention strategies (23). Low-risk HPVs are frequency associated with anogenital warts or condylomata acuminata. ...
... Genital warts are benign epithelial cell growths caused by sexually transmitted HPV infection (21,22). Genotyping of genital HPV is of great clinical significance in terms of developing treatment plans as well as follow-up and prevention strategies (23). Low-risk HPVs are frequency associated with anogenital warts or condylomata acuminata. ...
Background and objectives: Low-risk and high-risk human papillomavirus (HPV) genotypes are the main cause of anogenital warts. The present study aimed to determine prevalence of HPV genotypes in patients with anogenital warts in Gorgan, northeast of Iran.
Methods: In this cross-sectional study, 40 biopsy samples were taken from patients with anogenital warts in Gorgan, Iran. After DNA extraction, multiplex polymerase chain reaction was carried out for detecting HPV genotypes 54, 18, 16 and 6. Demographic characteristics of subjects including gender, age, education level, marital status, smoking and method of contraception were also collected. Data were analyzed in SPSS 16 software at statistical significance of 0.05.
Results: The mean age of male and female patients was 31.81±6.9 and 27.95±6.92 years, respectively. The frequency of HPV-6, HPV-16 and HPV-54 was 77%, 15% and 7.5%, respectively. In addition, HPV-18 was not detected in the collected specimens. Co-infection of HPV-54 with HPV-6 and HPV-16 was also observed in some cases. No significant association was found between HPV infection and age, gender, smocking, contraceptive method and education level.
Conclusions: Similar to previous studies in Iran and other countries, HPV type 6 is the predominant cause of genital warts in Gorgan, Iran. Further studies with a larger study population are needed to explore the role of other contributors to HPV-induced genital warts.
... [7][8][9] However, this has not been possible in most resource-limited countries, mainly because systematic screening is rarely performed. [10][11][12][13] In Ethiopia, cervical cancer ranks as the most frequent cancer among women and cause for 4,732 deaths annually. 1,[14][15][16] Among the general population, ~33.6% of women are estimated to harbor cervical human papilloma virus (HPV) infection at a given time. ...
... However, this has not been possible in most limited resource countries, mainly because systematic screening is rarely performed. 6,7 In Ethiopia, Cervical Cancer ranks as the second most frequent cancer among women between 15 and 44years of age. Every year 4648 women are diagnosed with cervical cancer, and 3,235 dies from the disease. ...
Background: Cancer of the cervix is the leading cause of cancer-related death next to
breast cancer. Cervical cancer screening is a means for early detection and treatment of the problem before it advances to a later stage. However, cervical cancer screening rate is not satisfactory in many countries including Ethiopia. Therefore, this study aimed to assess the knowledge and attitude towards cervical cancer screening and associated factors among female Hawassa University College of Medicine and health sciences students.
Methods: An institution based cross-sectional study conducted using simple random
sampling technique from April1st to 30th 2016. Three hundred eighty female students
participated in the study. Descriptive statistics and binary logistic regression used to
describe each variable and to identify the presence of an association between independent variables with outcome variable respectively. Adjusted odds ratio with 95% confidence interval and p-value<0.05 used to determine the association.
Result: A total of 380 participate in the study with the response rate of 90%. The majority,
202(53.2), of the respondents, belongs to the age group21-23 years old. Two hundred
sixteen (56.8%) Knowledgeable and 210(55.3%) had a positive attitude toward cervical
cancer screening. Age, year of study, school category, and income significantly associated with knowledge of cervical cancer screening. Age, year of study, religion, knowing Human papillomavirus as a cause for cervical cancer significantly associated with the attitude towards cervical cancer screening.
Conclusion: Half of the respondents were Knowledgeable and had a positive attitude
towards cervical cancer screening. Age, year of study, school category, and income identified as significantly associated factors for knowledge of cervical cancer screening. Age, year of study, religion, knowledge about Human papillomavirus are associated considerably with the attitude towards cervical cancer screening.
... [7][8][9] However, this has not been possible in most resource-limited countries, mainly because systematic screening is rarely performed. [10][11][12][13] In Ethiopia, cervical cancer ranks as the most frequent cancer among women and cause for 4,732 deaths annually. 1,[14][15][16] Among the general population, ~33.6% of women are estimated to harbor cervical human papilloma virus (HPV) infection at a given time. ...
Background
Cervical cancer remains a major cause of morbidity and mortality among the women in the world. Early screening for cervical cancer is a key intervention in reduction of maternal deaths. Health care workers have a significant contribution to improve cervical cancer screening practice among women. Hence, this study aimed to assess the knowledge and practice of cervical cancer screening among female health care workers in southern Ethiopia.
Methods
Institution-based cross-sectional study was conducted during March and April, 2015. All hospitals in Hawassa city administration and Sidama zone were purposively selected. A simple random sampling technique was used to draw the health centers. After proportional allocations to their respective health facilities, a total of 367 female health workers were selected by simple random sampling technique. A structured and pretested questionnaire was used to collect the data. Data were entered to SPSS version 20.0 for further analysis. Logistic regression analyses were used to see the association of different variables.
Results
Out of the total respondents, 319 (86.9%) had a good level of knowledge on cervical cancer. Similarly, a majority of them, 329 (89.6%), 321 (87.5%), and 295 (80.4%), knew about the risk factors, symptoms, and outcomes of cervical cancer, respectively. More than two thirds of the respondents, 283 (77.1%), knew that there is a procedure used to detect premalignant cervical lesions and 138 (37.6%) of them mentioned visual inspection with acetic acid as a screening method. In this study, only 42 (11.4%) of the respondents were screened for cervical cancer (confidence interval [CI]: 8.7, 13.9). Being a physician (adjusted odds ratio [AOR] =0.12, 95% CI: 0.02, 0.79) and working in a cervical cancer screening center (AOR =0.14, 95% CI: 0.03, 0.68) had a lower odds of cervical cancer screening practices.
Conclusions
Significant numbers of health care workers were knowledgeable on cervical cancer. Cervical cancer screening among health care workers in southern Ethiopia was found to be low. Being a physician and working in a screening center had lower odds of cervical cancer screening practice. In spite of having adequate knowledge on cervical cancer the reasons for low practice of cervical cancer screening among health care workers needs to be investigated.
... method in low-resource settings [6][7][8][9]. CareHPV™ is a new HPV-DNA test that is ideal for low income resource setting as it is cost-effective (lower cost per test) as compared to other HPV-DNA tests, simple to use by laboratory technical staff and can provide rapid results within 3 hours [9]. CareHPV™ can be performed on both provider-and selfcollected samples, and findings show that the clinical performance for detecting cervical intraepithelial neoplasia grade 2 or more severe diagnosis (CIN2+) was comparable to other HPV-DNA screening tests such as Hybrid Capture 2 [3,9]. ...
Vaginal self-sampling with HPV-DNA tests is a promising primary screening method for cervical cancer. However, women’s experiences, concerns and the acceptability of such tests in low-resource settings remain unknown.
In India, Nicaragua, and Uganda, a mixed-method design was used to collect data from surveys (N = 3,863), qualitative interviews (N = 72; 20 providers and 52 women) and focus groups (N = 30 women) on women’s and providers’ experiences with self-sampling, women’s opinions of sampling at home, and their future needs.
Among surveyed women, 90% provided a self- collected sample. Of these, 75% reported it was easy, although 52% were initially concerned about hurting themselves and 24% were worried about not getting a good sample. Most surveyed women preferred self-sampling (78%). However it was not clear if they responded to the privacy of self-sampling or the convenience of avoiding a pelvic examination, or both. In follow-up interviews, most women reported that they didn’t mind self-sampling, but many preferred to have a provider collect the vaginal sample. Most women also preferred clinic-based screening (as opposed to home-based self-sampling), because the sample could be collected by a provider, women could receive treatment if needed, and the clinic was sanitary and provided privacy. Self-sampling acceptability was higher when providers prepared women through education, allowed women to examine the collection brush, and were present during the self-collection process. Among survey respondents, aids that would facilitate self-sampling in the future were: staff help (53%), additional images in the illustrated instructions (31%), and a chance to practice beforehand with a doll/model (26%).
Self-and vaginal-sampling are widely acceptable among women in low-resource settings. Providers have a unique opportunity to educate and prepare women for self-sampling and be flexible in accommodating women’s preference for self-sampling.
... Another limitation is the case-control design, limiting our ability to infer PEG3 methylation as an important factor in progression. However, identifying methylation marks associated with case-control differences is a necessary step allowing for examination of this marker in longitudinal studies currently under way by several groups [23]. ...
Cytology-based screening for invasive cervical cancer (ICC) lacks sensitivity and specificity to discriminate between cervical intraepithelial neoplasia (CIN) likely to persist or progress from cases likely to resolve. Genome-wide approaches have been used to identify DNA methylation marks associated with CIN persistence or progression. However, associations between DNA methylation marks and CIN or ICC remain weak and inconsistent. Between 2008–2009, we conducted a hospital-based, case-control study among 213 Tanzania women with CIN 1/2/3 or ICC. We collected questionnaire data, biopsies, peripheral blood, cervical scrapes, Human papillomavirus (HPV) and HIV-1 infection status. We assessed PEG3 methylation status by bisulfite pyrosequencing. Multinomial logistic regression was used to estimate odds ratios (OR) and confidence intervals (CI 95%) for associations between PEG3 methylation status and CIN or ICC. After adjusting for age, gravidity, hormonal contraceptive use and HPV infection, a 5% increase in PEG3 DNA methylation was associated with increased risk for ICC (OR = 1.6; 95% CI 1.2–2.1). HPV infection was associated with a higher risk of CIN1-3 (OR = 15.7; 95% CI 5.7–48.6) and ICC (OR = 29.5, 95% CI 6.3–38.4). Infection with high risk HPV was correlated with mean PEG3 differentially methylated regions (DMRs) methylation (r = 0.34 p<0.0001), while the correlation with low risk HPV infection was weaker (r = 0.16 p = 0.047). Although small sample size limits inference, these data support that PEG3 methylation status has potential as a molecular target for inclusion in CIN screening to improve prediction of progression.
... The sensitivity of HPV-DNA for detecting CIN 2-3 ranges from 66-95% with most studies reporting values greater than 85% among women 30yrs or older (Almonte et al., 2007; Qiao et al., 2008; Sankaranarayanan et al., 2005a) because they are at the highest risk for precancerous lesions due to persistent HPV infection. New evidence also advocates the use of HPV-DNA testing as the primary technology for cervical cancer screening, both in developed and in developing countries (Franceschi et al., 2011; Franco 2010; Schiffman and Wentzensen 2010). Although HPV-DNA testing performs well when compared with other screening tests, commercially available HPV-DNA tests such as Hybrid Capture 2 (QIAGEN Inc.) is relatively expensive, complex and interpretation needs seven hours. ...
Cervical cancer remains the most frequent cancer in women from the developing world. More than 88% of deaths occur in low-income countries, and it is predicted to climb to 91.5% by 2030. Although Pap-based screening programmes have shown to be effective in reducing the disease burden in high-resource countries, implementation and sustention of cytology-based programmes is quite challenging in low-resource settings. The present paper reviews evidence-based alternatives of screening methods, triaging algorithm, treatment of cervical precancerous lesions, and age-group at screening appropriate for low-income countries. Evidence shows that visual inspection methods using diluted acid acetic or Lugol's iodine, and HPV-DNA testing are more sensitive tests than the Pap-smear screening test. Visual inspection allows an immediate result and, when appropriate, may be immediately followed by cryotherapy, the so called "screen-and-treat" approach, achieved in a single visit, by trained nurses and midwives. Examples of cervical cancer prevention programmes in India and selected low-income countries are given.
Background and objectives: Pathogenesis of human papillomaviruses (HPVs) is controlled by viral and host factors, among which human histone acetyltransferase p300 (EP300) plays an important role. This study aimed to examine single nucleotide polymorphisms (SNPs) at the EP300 binding site in patients with HPV-associated anogenital wart.
Methods: After DNA extraction, polymerase chain reaction was performed to determine HPV genotypes. Human p300 was amplified to detect SNPs using Sanger sequencing.
Results: Overall, 35.3% of HPV-6-positive patients had Ile997Val substitution at the EP300 binding site. Another SNP containing A to G point mutation leading to Glu983Gly was also detected. In addition, Ile997Val substitution of EP300 was frequently observed in the patients.
Conclusion: Our findings suggest that the EP300 genotype Ile/Val can be involved in HPV-6 pathogenesis. In addition, we introduced a new genotype (Glu983Gly) at the EP300 bromodomain site, which requires further investigation.
Background Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the eff ectiveness of cervical screening improves when HPV DNA testing is implemented.
Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types.
A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time.
For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow-up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%).
HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary.
To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions.
Randomised trial.
Population based screening programme for cervical cancer in southern Finland in 2003-5.
58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer.
Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference).
Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry.
In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers). The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended. Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17). The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended.
When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions. The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention.
Current Controlled Trials ISRCTN23885553.
Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity.
To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+).
Multinational cohort study with joint database analysis.
Seven primary HPV screening studies in six European countries.
24,295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up.
Long term cumulative incidence of CIN3+.
The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%.
A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.
Several studies suggest that HPV testing is more sensitive than cytology in primary cervical screening. These studies had different designs and were reported in different ways. Individual patient data were collected for all European and North American studies in which cytology was routinely performed and HPV testing was included as an additional parallel test. More than 60,000 women were included. The sensitivity and specificity of HPV testing were compared with routine cytology, both overall and for ages <35, 35-49 and 50+. The age-specific prevalence of high risk HPV (hr-HPV) was also analysed. HPV testing was substantially more sensitive in detecting CIN2+ than cytology (96.1% vs. 53.0%) but less specific (90.7% vs. 96.3%). The sensitivity of HPV testing was similar in all studies carried out in different areas of Europe and North America, whereas the sensitivity of cytology was highly variable. HPV sensitivity was uniformly high at all ages, whereas the sensitivity of cytology was substantially better in women over the age of 50 than in younger women (79.3% vs. 59.6%). The specificity of both tests increased with age. Positivity rates for HPV testing in women without high-grade CIN were region dependent. These results support the use of HPV testing as the sole primary screening test, with cytology reserved for women who test HPV positive. Large demonstration projects are needed to fully evaluate this strategy.
Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown.
In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group). Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy. A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group. Comprehensive registry data were used to follow the women for a mean of 4.1 years. The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated.
At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions. At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions. Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy.
The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations. (ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].).
To determine whether testing for DNA of oncogenic human papillomaviruses (HPV) is superior to the Papanicolaou (Pap) test for cervical-cancer screening, we conducted a randomized trial comparing the two methods.
We compared HPV testing, using an assay approved by the Food and Drug Administration, with conventional Pap testing as a screening method to identify high-grade cervical intraepithelial neoplasia in women ages 30 to 69 years in Montreal and St. John's, Canada. Women with abnormal Pap test results or a positive HPV test (at least 1 pg of high-risk HPV DNA per milliliter) underwent colposcopy and biopsy, as did a random sample of women with negative tests. Sensitivity and specificity estimates were corrected for verification bias.
A total of 10,154 women were randomly assigned to testing. Both tests were performed on all women in a randomly assigned sequence at the same session. The sensitivity of HPV testing for cervical intraepithelial neoplasia of grade 2 or 3 was 94.6% (95% confidence interval [CI], 84.2 to 100), whereas the sensitivity of Pap testing was 55.4% (95% CI, 33.6 to 77.2; P=0.01). The specificity was 94.1% (95% CI, 93.4 to 94.8) for HPV testing and 96.8% (95% CI, 96.3 to 97.3; P<0.001) for Pap testing. Performance was unaffected by the sequence of the tests. The sensitivity of both tests used together was 100%, and the specificity was 92.5%. Triage procedures for Pap or HPV testing resulted in fewer referrals for colposcopy than did either test alone but were less sensitive. No adverse events were reported.
As compared with Pap testing, HPV testing has greater sensitivity for the detection of cervical intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN57612064 [controlled-trials.com].).
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)‐based test which was used. The formerly HPV‐negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV‐negative and a sample of 48 of the 866 cases which were HPV‐positive in the original study. Moreover, 55 of the 66 formerly HPV‐negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR‐negative and ‐positive. Type‐specific E7 PCR for 14 high‐risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV‐negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA‐positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV‐negative on all PCR tests, as against 13 of the 21 that were inadequate ( p < 0·001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99·7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV‐negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright © 1999 John Wiley & Sons, Ltd.
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalysed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalysed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0·001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99·7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening. Copyright
Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN). We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.
Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase). Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres. During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive. During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive. Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round. The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds. Analysis was done by intention to screen. This trial is registered, number ISRCTN81678807.
In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing. 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. We also retrieved the histological diagnoses from screening done elsewhere. The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004). Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028). Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together. At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together. Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3. At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two. At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two. Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.
HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period. However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.
European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio.
In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India.
In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment.
In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women.
In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.
A recent report that 93 per cent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA. Serology for HPV 16 VLPs, E6, and E7 antibodies was performed on 49 of the 66 cases which were HPV-negative and a sample of 48 of the 866 cases which were HPV-positive in the original study. Moreover, 55 of the 66 formerly HPV-negative biopsies were also reanalyzed by a sandwich procedure in which the outer sections in a series of sections are used for histological review, while the inner sections are assayed by three different HPV PCR assays targeting different open reading frames (ORFs). No significant difference was found in serology for HPV 16 proteins between the cases that were originally HPV PCR-negative and -positive. Type-specific E7 PCR for 14 high-risk HPV types detected HPV DNA in 38 (69 per cent) of the 55 originally HPV-negative and amplifiable specimens. The HPV types detected were 16, 18, 31, 33, 39, 45, 52, and 58. Two (4 per cent) additional cases were only HPV DNA-positive by E1 and/or L1 consensus PCR. Histological analysis of the 55 specimens revealed that 21 were qualitatively inadequate. Only two of the 34 adequate samples were HPV-negative on all PCR tests, as against 13 of the 21 that were inadequate ( p< 0.001). Combining the data from this and the previous study and excluding inadequate specimens, the worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
Human papillomavirus (HPV) types 16 and 18 cause 60%-70% of cervical cancer worldwide, and other HPV types cause virtually all remaining cases. Pooled HPV testing for 13 oncogenic types, including HPV16 and 18, is currently used in clinical practice for triage of equivocal cytology and, in conjunction with Pap tests, is an option for general screening among women 30 years of age and older. It is not clear to what extent individual identification of HPV16 or HPV18 as an adjunct to pooled oncogenic HPV testing might effectively identify women at particularly high risk of cervical cancer or its immediate precursor, cervical intraepithelial neoplasia 3 (CIN3).
From April 1, 1989, to November 2, 1990, a total of 20 810 women in the Kaiser Permanente health plan in Portland, OR, enrolled in a cohort study of HPV and cervical neoplasia. Women were tested for 13 oncogenic HPV types by Hybrid Capture 2 (HC2), and those women with a positive HC2 test were tested for HPV16 and 18. Enrollment Pap smear interpretation and HPV test results were linked to histologically confirmed CIN3 and cervical cancer (> or = CIN3) occurring during 10 years of cytologic follow-up. We calculated cumulative incidence rates with 95% confidence intervals for each interval up to 122 months using Kaplan-Meier methods.
The 10-year cumulative incidence rates of > or = CIN3 were 17.2% (95% confidence interval [CI] = 11.5% to 22.9%) among HPV16+ women and 13.6% (95% CI = 3.6% to 23.7%) among HPV18+ (HPV16-) women, but only 3.0% (95% CI = 1.9% to 4.2%) among HC2+ women negative for HPV16 or HPV18. The 10-year cumulative incidence among HC2- women was 0.8% (95% CI = 0.6% to 1.1%). A subanalysis among women 30 years of age and older with normal cytology at enrollment strengthened the observed risk differences.
HPV screening that distinguishes HPV16 and HPV18 from other oncogenic HPV types may identify women at the greatest risk of > or = CIN3 and may permit less aggressive management of other women with oncogenic HPV infections.
This is a meta-analysis of studies comparing HPV testing to cytology with regard to their accuracy in the detection of underlying high grade cervical intraepithelial neoplasia in primary cervical cancer screening.
A systematic review was conducted following the Cochrane Collaboration Guidelines. A systematic search was performed in 8 electronic databases. Strict selection criteria were applied in terms of types of participants, types of interventions and methods to limit verification bias. Where possible we calculated the sensitivity, specificity, positive and negative predictive value of cytology and the HPV test, as well as sensitivity and specificity ratios for the detection of CIN2 or worse. Random effect models were used for pooling accuracy parameters. The results were displayed using forest plots.
We identified 25 studies fulfilling the inclusion criteria. The pooled sensitivity of HC2, PCR, cytology (ASCUS or worse) and cytology (LSIL or worse) was 90%, 80.9%, 72.7% and 61.6%, respectively, and the pooled specificity was 86.5%, 94.7%, 91.9% and 96.0%, respectively. The ratio of the sensitivity of HC2 to cytology (ASCUS) was 1.25 (95% CI=1.20-1.29), and the corresponding specificity ratio was 0.97 (95% CI=0.96-0.98). The ratio of the sensitivity of combination of HC2 and cytology (ASCUS) to HC2 alone was 1.05 (95% CI=1.04-1.06) and the ratio of the specificity 0.95 (95% CI=0.94-0.96). For women over 30 years, the sensitivity of HC2 was 94.8% and the specificity 86.0%.
Compared to cytology, the HC2 and PCR are substantially more sensitive for prevalent CIN2 or worse but significantly less specific. The combination of HC2 and cytology has the highest sensitivity and lowest specificity. However, reduction of the incidence of or mortality from invasive cervical cancer among HPV screened subjects compared to cytologically screened subjects has not yet been demonstrated.
Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented.
Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131.
8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups.
The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.
Diagnostic accuracy of human papillomavirus testing in primary cervical screening: a systematic review and meta-analysis of nonrandomized studies
- G Koliopoulos
- M Arbyn
- P Martin-Hirsch
- M Kyrgiou
- W Prendiville
- E Paraskevaidis
Koliopoulos G, Arbyn M, Martin-Hirsch P, Kyrgiou M, Prendiville W,
Paraskevaidis E. Diagnostic accuracy of human papillomavirus testing in
primary cervical screening: a systematic review and meta-analysis of nonrandomized studies. Gynecol Oncol. 2007;104(1):232–246.