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1.  A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt 
PLoS Medicine  2010;7(5):e1000270.
Analysis of a telephone survey by Gina Ogilvie and colleagues identifies the parental factors associated with HPV vaccine uptake in a school-based program in Canada.
Information on factors that influence parental decisions for actual human papillomavirus (HPV) vaccine receipt in publicly funded, school-based HPV vaccine programs for girls is limited. We report on the level of uptake of the first dose of the HPV vaccine, and determine parental factors associated with receipt of the HPV vaccine, in a publicly funded school-based HPV vaccine program in British Columbia, Canada.
Methods and Findings
All parents of girls enrolled in grade 6 during the academic year of September 2008–June 2009 in the province of British Columbia were eligible to participate. Eligible households identified through the provincial public health information system were randomly selected and those who consented completed a validated survey exploring factors associated with HPV vaccine uptake. Bivariate and multivariate analyses were conducted to calculate adjusted odds ratios to identify the factors that were associated with parents' decision to vaccinate their daughter(s) against HPV. 2,025 parents agreed to complete the survey, and 65.1% (95% confidence interval [CI] 63.1–67.1) of parents in the survey reported that their daughters received the first dose of the HPV vaccine. In the same school-based vaccine program, 88.4% (95% CI 87.1–89.7) consented to the hepatitis B vaccine, and 86.5% (95% CI 85.1–87.9) consented to the meningococcal C vaccine. The main reasons for having a daughter receive the HPV vaccine were the effectiveness of the vaccine (47.9%), advice from a physician (8.7%), and concerns about daughter's health (8.4%). The main reasons for not having a daughter receive the HPV vaccine were concerns about HPV vaccine safety (29.2%), preference to wait until the daughter is older (15.6%), and not enough information to make an informed decision (12.6%). In multivariate analysis, overall attitudes to vaccines, the impact of the HPV vaccine on sexual practices, and childhood vaccine history were predictive of parents having a daughter receive the HPV vaccine in a publicly funded school-based HPV vaccine program. By contrast, having a family with two parents, having three or more children, and having more education was associated with a decreased likelihood of having a daughter receive the HPV vaccine.
This study is, to our knowledge, one of the first population-based assessments of factors associated with HPV vaccine uptake in a publicly funded school-based program worldwide. Policy makers need to consider that even with the removal of financial and health care barriers, parents, who are key decision makers in the uptake of this vaccine, are still hesitant to have their daughters receive the HPV vaccine, and strategies to ensure optimal HPV vaccine uptake need to be employed.
Please see later in the article for the Editors' Summary
Editors' Summary
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, globally, more than a quarter of a million women die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse. There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Although most people become infected with HPV at some time in their life, most never know they are infected. However, some HPV types cause harmless warts on the skin or around the genital area and several—in particular, HPV 16 and HPV 18, so-called high-risk HPVs—can cause cervical cancer. HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries in recent decades by detecting the cancer early when it can be treated; but it would be better to prevent cervical cancer ever developing. Because HPV is necessary for the development of cervical cancer, vaccination of girls against HPV infection before the onset of sexual activity might be one way to do this. Scientists recently developed a vaccine that prevents infection with HPV 16 and HPV 18 (and with two HPVs that cause genital warts) and that should, therefore, reduce the incidence of cervical cancer. Publicly funded HPV vaccination programs are now planned or underway in several countries; but before girls can receive the HPV vaccine, parental consent is usually needed, so it is important to know what influences parental decisions about HPV vaccination. In this study, the researchers undertake a telephone survey to determine the uptake of the HPV vaccine by 11-year-old girls (grade 6) in British Columbia, Canada, and to determine the parental factors associated with vaccine uptake; British Columbia started a voluntary school-based HPV vaccine program in September 2008.
What Did the Researchers Do and Find?
In early 2009, the researchers contacted randomly selected parents of girls enrolled in grade 6 during the 2008–2009 academic year and asked them to complete a telephone survey that explored factors associated with HPV vaccine uptake. 65.1% of the 2,025 parents who completed the survey had consented to their daughter receiving the first dose of HPV vaccine. By contrast, more than 85% of the parents had consented to hepatitis B and meningitis C vaccination of their daughters. Nearly half of the parents surveyed said their main reason for consenting to HPV vaccination was the effectiveness of the vaccine. Conversely, nearly a third of the parents said concern about the vaccine's safety was their main reason for not consenting to vaccination and one in eight said they had been given insufficient information to make an informed decision. In a statistical analysis of the survey data, the researchers found that a positive parental attitude towards vaccination, a parental belief that HPV vaccination had limited impact on sexual practices, and completed childhood vaccination increased the likelihood of a daughter receiving the HPV vaccine. Having a family with two parents or three or more children and having well-educated parents decreased the likelihood of a daughter receiving the vaccine.
What Do These Findings Mean?
These findings provide one of the first population-based assessments of the factors that affect HPV vaccine uptake in a setting where there are no financial or health care barriers to vaccination. By identifying the factors associated with parental reluctance to agree to HPV vaccination for their daughters, these findings should help public-health officials design strategies to ensure optimal HPV vaccine uptake, although further studies are needed to discover why, for example, parents with more education are less likely to agree to vaccination than parents with less education. Importantly, the findings of this study, which are likely to be generalizable to other high-income countries, indicate that there is a continued need to ensure that the public receives credible, clear information about both the benefits and long-term safety of HPV vaccination.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about HPV
The UK National Health Service Choices website has pages on cervical cancer and on HPV vaccination
More information about cervical cancer and HPV vaccination is available from the Macmillan cancer charity
ImmunizeBC provides general information about vaccination and information about HPV vaccination in British Columbia
MedlinePlus provides links to additional resources about cervical cancer (in English and Spanish)
PMCID: PMC2864299  PMID: 20454567
2.  Sex-Specific Immunization for Sexually Transmitted Infections Such as Human Papillomavirus: Insights from Mathematical Models 
PLoS Medicine  2011;8(12):e1001147.
Johannes Bogaards and colleagues use mathematical models to investigate whether vaccinating females only, males only, or both sexes is the best way to achieve the most effective reduction in the population prevalence of sexually-transmitted infections
Sex-specific differences regarding the transmissibility and the course of infection are the rule rather than the exception in the epidemiology of sexually transmitted infections (STIs). Human papillomavirus (HPV) provides an example: disease outcomes differ between men and women, as does the potential for transmission to the opposite sex. HPV vaccination of preadolescent girls was recently introduced in many countries, and inclusion of boys in the vaccination programs is being discussed. Here, we address the question of whether vaccinating females only, males only, or both sexes is the most effective strategy to reduce the population prevalence of an STI like HPV.
Methods and Findings
We use a range of two-sex transmission models with varying detail to identify general criteria for allocating a prophylactic vaccine between both sexes. The most effective reduction in the population prevalence of infection is always achieved by single-sex vaccination; vaccinating the sex with the highest prevaccine prevalence is the preferred strategy in most circumstances. Exceptions arise only when the higher prevaccine prevalence is due to a substantially lower rate of natural immunity, or when natural immunity is lifelong, and a prolonged duration of infectiousness coincides with increased transmissibility. Predictions from simple models were confirmed in simulations based on an elaborate HPV transmission model. Our analysis suggests that relatively inefficient genital transmission from males to females might render male vaccination more effective in reducing overall infection levels. However, most existing HPV vaccination programs have achieved sufficient coverage to continue with female-only vaccination.
Increasing vaccine uptake among preadolescent girls is more effective in reducing HPV infection than including boys in existing vaccination programs. As a rule, directing prophylactic immunization at the sex with the highest prevaccine prevalence results in the largest reduction of the population prevalence.
Please see later in the article for the Editors' Summary
Editors' Summary
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, more than a quarter of a million women (85% of them in developing countries) die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse (HPV is one of more than thirty sexually transmissable organisms that, globally, cause many millions of sexually transmitted infections every year). There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Most people become infected with HPV at some time during their life, but most never know they have been infected. Some HPV types cause harmless warts on the skin or around the genital area, and several—in particular HPV16 and HPV18, so-called high-risk HPVs—can cause cervical cancer (and some other cancers, including anal, penile, head, and neck cancers). HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries by detecting the cancer early, when it can be treated. However, it would be better to prevent cervical cancer ever developing. Moreover, most women in developing countries do not have access to screening. Because infection with specific HPV types can cause the development of some types of cervical cancer, vaccination of girls against HPV before the onset of sexual activity might be one way to prevent cervical cancer. Scientists recently developed a vaccine that prevents infection with HPV16 and HPV18, and HPV vaccination programs have been introduced in several countries. These programs are currently directed only at girls because HPV-related illness and death are higher among women than men, but should boys also be included in HPV vaccination programs? Men would benefit directly from immunization against HPV-related diseases, but, in addition, vaccination of boys might help to reduce the circulation of HPV in the population, thereby indirectly improving the protection of women through so-called “herd immunity.” In this study, the researchers used mathematical models to investigate whether vaccinating girls only, boys only, or both sexes is the most effective way to reduce the population prevalence of HPV infection (the proportion of the population infected with HPV).
What Did the Researchers Do and Find?
The researchers first used a range of standard two-sex mathematical models of infection and transmission in heterosexual populations to identify general criteria for allocating an HPV vaccine between the sexes. They found that the most effective reduction in the population prevalence of HPV infection was always achieved by single-sex vaccination and that, in most situations, the preferred strategy was to vaccinate the sex with the highest prevaccine prevalence of HPV infection. The researchers confirmed these predictions using a more elaborate HPV transmission model that incorporated differences among individuals in age and level of sexual activity. Importantly, this second analysis also suggested that for existing girl-only vaccination programs, increasing coverage of vaccination among girls would bolster herd immunity more effectively than switching to a policy of vaccinating both sexes.
What Do These Findings Mean?
The findings of this study suggest that increasing vaccine uptake among preadolescent girls is a more effective way to reduce HPV infection than including boys in existing vaccination programs. They also suggest that directing HPV vaccination at the sex with the highest prevaccine prevalence of infection will reduce the population prevalence of HPV most effectively. Although the accuracy of these findings is dependent on the assumptions included in the mathematical transmission models used by the researchers, these findings support a policy of increasing female HPV vaccine coverage as far as possible, within the limits set by vaccine acceptance and economic constraints. More generally, these findings suggest that single-sex preventative interventions might be the best way to reduce heterosexual transmission of other sexually transmitted infections and that targeting the sex with the highest prevalence of infection might achieve the most effective reduction in the population prevalence of these common diseases.
Additional Information
Please access these websites via the online version of this summary at
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and HPV
The UK National Health Service Choices website has pages on cervical cancer and HPV vaccination (available in several languages and including a short video of girls talking about HPV vaccination)
The PREHDICT project investigates health-economic modeling of prevention strategies for HPV-related diseases in European countries; information about this project is available from the European Cervical Cancer Association
More information about cervical cancer and HPV vaccination is available from Macmillan Cancer Support
Personal stories about cervical cancer are available through the charity Healthtalkonline
MedlinePlus provides links to additional resources about cervical cancer and other sexually transmitted infections (in English and Spanish)
PMCID: PMC3243713  PMID: 22205887
3.  Decision-analytic modeling to evaluate the long-term effectiveness and cost-effectiveness of HPV-DNA testing in primary cervical cancer screening in Germany 
Persistent infections with high-risk types of human papillomavirus (HPV) are associated with the development of cervical neoplasia. Compared to cytology HPV testing is more sensitive in detecting high-grade cervical cancer precursors, but with lower specificity. HPV based primary screening for cervical cancer is currently discussed in Germany. Decisions should be based on a systematic evaluation of the long-term effectiveness and cost-effectiveness of HPV based primary screening.
Research questions
What is the long-term clinical effectiveness (reduction in lifetime risk of cervical cancer and death due to cervical cancer, life years gained) of HPV testing and what is the cost-effectiveness in Euro per life year gained (LYG) of including HPV testing in primary cervical cancer screening in the German health care context? How can the screening program be improved with respect to test combination, age at start and end of screening and screening interval and which recommendations should be made for the German health care context?
A previously published and validated decision-analytic model for the German health care context was extended and adapted to the natural history of HPV infection and cervical cancer in order to evaluate different screening strategies that differ by screening interval, and tests, including cytology alone, HPV testing alone or in combination with cytology, and HPV testing with cytology triage for HPV-positive women. German clinical, epidemiological and economic data were used. In the absence of individual data, screening adherence was modelled independently from screening history. Test accuracy data were retrieved from international meta-analyses. Predicted outcomes included reduction in lifetime-risk for cervical cancer cases and deaths, life expectancy, lifetime costs, and discounted incremental cost-effectiveness ratios (ICER). The perspective of the third party payer and 3% annual discount rate were adopted. Extensive sensitivity analyses were performed in order to evaluate the robustness of results and identify areas of future research.
In the base case analysis screening resulted in a 53% to 97% risk reduction for cervical cancer with a discounted ICER between 2,600 Euro/LYG (cytology alone every five years) and 155,500 Euro/LYG (Annual cytology age 20 to 29 years, and annual HPV age 30 years and older). Annual cytology, the current recommended screening strategy in Germany, was dominated. In sensitivity analyses variation in the relative increase in the sensitivity of HPV testing as compared to cytology, HPV test costs, screening adherence, HPV incidence, and annual discount rate influenced the ICER results. Variation in the screening start age also influenced the ICER. All cytology strategies were dominated by HPV screening strategies, when relative sensitivity increase by HPV testing compared to cytology was higher (scenario analysis with data for test accuracy from German studies). HPV testing every one, two or three years was more effective than annual cytology. With increased screening adherence a longer screening interval and with low screening adherence a shorter interval would be more cost-effective. With a reduction in HPV incidence of more than 70% triennial HPV screening in women aged 30 years and older (and biennial Pap screening in women aged 20 to 29 years) is cost-effective. The discounted ICER increases with increasing annual discount rate. Increasing screening start age to 25 years had no relevant loss in effectiveness but resulted in lower costs. An optimal strategy may be biennial HPV testing age 30 years and older with biennial cytology at age 25 to 29 years (ICER of 23,400 Euro/LYG).
Based on these results, HPV-based cervical cancer screening is more effective than cytology and could be cost-effective if performed at intervals of two years or greater. Increasing the age at screening start to 25 years causes no relevant loss in effectiveness but saves resources. In the German context an optimal screening strategy could be biennial HPV testing at age 30 years and older with biennial cytology at the age of 25 to 29 years. An extension to a three-yearly screening interval requires substantially improved screening adherence or a higher relative increase in the sensitivity of HPV testing as compared to cytology. The implementation of an organised screening program for quality-controlled introduction of HPV-screening and -vaccination with continued systematic outcome evaluation is recommended.
PMCID: PMC3010885  PMID: 21289878
cervix; cervix of uterus; cervical carcinoma; carcinoma; cancer; cytology; human papillomavirus; HPV; DNA; HPV-DNA diagnosis; diagnosis; early finding; screening; primary screening; test; decision-analytical modelling; Markov model; effectiveness; systematic review; meta-analysis; Health Technology Assessment; long-term effectiveness; cost-effectiveness; health economic evaluation
4.  Anal Dysplasia Screening 
Executive Summary
This review considered the role of the anal Pap test as a screening test for anal dysplasia in patients at high risk of anal SCC. The screening process is now thought to be improved with the addition of testing for the human papillomavirus (HPV) in high-risk populations. High-resolution anoscopy (a method to view the rectal area, using an anoscope, a lighted instrument inserted into the rectum) rather than routine anoscopy-guided biopsy, is also now considered to be the diagnostic standard.
Clinical Need: Target Population and Condition
Anal cancer, like cervical cancer, is a member of a broader group of anogenital cancers known to be associated with sexually transmitted viral HPV infection. Human papillomavirus is extremely prevalent, particularly in young, sexually active populations. Sexual practices involving receptive anal intercourse lead to significantly elevated risk for anal dysplasia and cancer, particularly in those with immune dysfunctions.
Anal cancer is rare. It occurs at a rate of about 1 to 2 per 100,000 in the general population. It is the least common of the lower gastrointestinal cancers, representing about 4% of them, in contrast to colorectal cancers, which remain the third most commonly diagnosed malignancy. Certain segments of the population, however, such as HIV-positive men and women, other chronic immune-suppressed patients (e.g., after a transplant), injection drug users, and women with genital dysplasia /cancer, have a high susceptibility to anal cancer.
Those with the highest identified risk for anal cancer are HIV-positive homosexual and bisexual men, at a rate of 70 per 100,000 men. The risk for anal cancer is reported to be increasing dramatically in HIV-positive males and females, particularly since the introduction of highly active antiretroviral therapy in the mid-1990s. The introduction of effective viral therapy has been said to have transformed the AIDS epidemic in developed countries into a chronic disease state of long-term immunosuppression. In Ontario, there are about 25,000 people living with HIV infection; more than 6,000 of these are women. About 28% of the newly diagnosed HIV infections are in women, a doubling since 1999. It has also been estimated that 1 of 3 people living with HIV do no know it.
Health Technology Description
Anal Pap test screening involves the blind insertion of a swab into the anal canal and fixing cells either on a slide or in fluid for cytological examination. Anal cytology classified by the standardized Bethesda System is the same classification used for cervical cytology. It has 4 categories: normal, atypical squamous cells of uncertain significance, or squamous intraepithelial lesions which are further classified into low- or high-grade lesions. Abnormal cytological findings are subjected to further evaluations by high-resolution anoscopy, a technique similar to cervical colposcopy, and biopsy. Several HPV deoxyribonucleic acid detection technologies such as the Hybrid 11 Capture and the polymerase chain reaction are available to detect and differentiate HPV viral strains.
Unlike cervical cancer, there are no universally accepted guidelines or standards of care for anal dysplasia. Moreover, there are no formal screening programs provincially, nationally, or internationally. The New York State Department of Health AIDS Institute has recently recommended (March 2007) annual anal pap testing in high-risk groups. In Ontario, reimbursement exists only for Pap tests for cervical cancer screening. That is, there is no reimbursement for anal Pap testing in men or women, and HPV screening tests for cervical or anal cancer are also not reimbursed.
The scientific evidence base was evaluated through a systematic literature review. Assessments of current practices were obtained through consultations with various agencies and individuals including the Ministry of Health and Long-Term Care AIDS Bureau; Public Health Infectious Diseases Branch, Ministry of Health and Long-Term Care; Cancer Care Ontario; HIV/AIDS researchers; pathology experts; and HIV/AIDS clinical program directors. An Ontario-based budget impact was also done.
No direct evidence was found for the existence of controlled studies evaluating the effectiveness of anal Pap test screening programs for impact on anal cancer morbidity or mortality. In addition, no studies were found on the use of HPV DNA testing in the screening or diagnostic setting for anal dysplasia. The reported prevalence of HPV infection in high-risk groups, particularly HIV-positive males, however, was sufficiently high to preclude any utility of HPV testing as an adjunct to anal Pap testing.
Nine reports involving studies in the United States, United Kingdom, and Canada were identified that evaluated the performance characteristics of anal Pap test screening for anal dysplasia. All involved hospital-based specialty HIV/AIDS care clinics with mainly HIV-positive males. All studies involved experienced pathologists, so the results generally represent best-case scenarios. Estimates of anal Pap test sensitivity and specificity were highly variable, and depended on the varying prevalence of cytology abnormality and differential thresholds for abnormality for both cytology and histopathology.
In the largest study of HIV-positive males, sensitivity varied from 46% (95% confidence interval [CI], 36%–56%) to 69% (95% CI, 60%–78%). Specificity ranged from 59% (95% CI, 53%–65%) to 81% (95% CI, 76%–85%). In the only study of HIV-negative males, sensitivity ranged from 26% (95% CI, 5%-47%) to 47% (95% CI, 26%–68%). Specificity ranged from 81% (95% CI, 76%–85%) to 92% (95% CI, 89%–95%).
In comparison, cervical Pap testing has also been evaluated mainly in settings where there is a high prevalence of the disease, and estimates of sensitivitykij and specificity were also low and highly variable. In a systematic review involving cervical Pap testing, sensitivity ranged from 30% to 87% (mean, 47%) and specificity from 86% to 100% (mean, 95%).
No direct evidence exists to support the effectiveness of an anal Pap test screening program to reduce anal cancer mortality or morbidity. There are, however, strong parallels with cervical pap testing for cervical cancer. Sexually transmitted HPV viral infection is currently the acknowledged common causative agent for both anal and cervical cancer. Anal cancer rates in high-risk populations are approaching those of cervical cancer before the implementation of Pap testing.
The anal Pap test, although it has been mainly evaluated only in HIV-positive males, has similar operating characteristics of sensitivity and specificity as the cervical Pap test. In general, the treatment options for precancer dysplasia in the cervix and the anus are similar, but treatment involving a definitive surgical resection in the anus is more limited because of the higher risk of complications. A range of ablative therapies has been applied for anal dysplasia, but evidence on treatment effectiveness, tolerability and durability, particularly in the HIV-positive patient, is limited.
PMCID: PMC3377578  PMID: 23074504
5.  Cervical Cancer-Related Knowledge, Attitudes, and Practices of Health Professionals Working in Brazil’s Network of Primary Care Units 
The Oncologist  2014;19(4):375-382.
The authors surveyed coordinators and health professionals from 1,600 primary health care units across Brazil regarding their knowledge, attitudes, and practices related to cervical cancer and human papillomavirus vaccination. Results showed that overscreening may be impeding efforts to increase cervical cancer screening coverage among the eligible target population of women aged 25–64 years and that educational efforts may be needed to increase knowledge about targeting age-appropriate groups for human papillomavirus vaccination.
Brazil’s national strategy for cervical cancer screening includes using the Papanicolaou (Pap) test every 3 years among women aged 25–64 years. Comprehensive primary care services are provided through a network of primary health units, but little is known about cervical cancer-related knowledge, attitudes, and practices among health professionals and coordinators working in these facilities.
In 2011, we conducted a cross-sectional nationally representative phone survey of 1,600 primary health care units to interview one unit coordinator and one health care professional per unit (either nurse, physician, or community health worker). Responses were obtained from 1,251 coordinators, 182 physicians, 347 nurses, and 273 community health workers. Questionnaires were administered to assess health units’ characteristics and capacity for cervical cancer-related services as well as health professionals’ perceived effectiveness of the Pap test, preparedness to talk to women about cervical cancer, adherence with screening guidelines, and willingness to recommend human papillomavirus (HPV) vaccination to females.
Most units conducted screening (91.9%), used home visits to conduct recruitment and outreach (83.4%), and provided follow-up to women who did not return to discuss Pap test results (88.1%). Approximately 93% of health professionals stated that Pap testing was effective in decreasing death rates from cervical cancer and 65% stated that national guidelines for cervical cancer screening are very influential; 93% of nurses and physicians reported screening women annually and 75% reported beginning to screen women younger than 25 years old. Regarding HPV vaccination, almost 90% of nurses and physicians would recommend the HPV vaccine to their females patients if it were available. A larger proportion of physicians and nurses recommended the HPV vaccine to older girls (13–18 years) and women (19–26 years and even older than 26 years) than to younger girls (12 years or younger).
Although Brazil’s network of primary care units has significantly increased access to cervical cancer screening, effective strategies are needed to ensure that women get screened at the appropriate ages and intervals. Additionally, this study’s baseline data on HPV vaccination may be useful as Brazil embarks on a national HPV vaccination program in 2014.
PMCID: PMC3983817  PMID: 24668334
Cervical cancer screening in Brazil; Global health; HPV vaccination; Cervical cancer knowledge
6.  Prevalence and Molecular Epidemiology of Human Papillomavirus Infection in Italian Women with Cervical Cytological Abnormalities 
Human papillomavirus (HPV) infection is the most common sexually transmitted infection and high-risk HPV types are a necessary cause for the development of cervical cancer. The present study investigated the HPV-type specific prevalence in 650 women, aged 15-76 years, with cytological abnormalities and the association between HPV infection and cervical disease in a subset of 160 women for whom cytological results for Pap-Test were available, during the period 2008-2011 in Cagliari (Southern Italy).
Design and Methods
HPV-DNA extraction was performed by lysis and digestion with proteinase K and it was typed by using the INNOLiPA HPV Genotyping Assay.
Overall the HPV prevalence was 52.6%; high-risk genotypes were found in 68.9% of women and multiple-type infection in 36.1% of HPV-positive women. The commonest types were HPV-52 (23.4%), HPV-53 (15.7%), HPV-16 (15.4%) and HPV-6 (12.4%). Among the women with cytological diagnosis, any-type of HPV DNA was found in 49.4% of the samples and out of these 93.7% were high-risk genotypes. Genotype HPV 53 was the commonest type among women affected by ASCUS lesions (21.4%), genotype 52 in positive L-SIL cases (22.5%), genotype 16 H-SIL (27.3%).
This study confirmed the high prevalence of HPV infection and high-risk genotypes among women with cervical abnormalities while, unlike previously published data, genotype HPV-52 was the most common type in our series. These data may contribute to increase the knowledge of HPV epidemiology and designing adequate vaccination strategies.
Significance for public healthHuman papillomavirus (HPV) is the most common sexually-transmitted agent, which can cause cervical lesions and cancer in females. Efforts to reduce the burden of cervical cancer with cytology screening in the last years have had limited success. HPV infection and disease imposes a substantial burden of direct costs on the Italian National Health Service that have never been fully quantified. Monitoring HPV prevalence could represent a tool to follow the evolution of the infection in the vaccination and post-vaccination era, to understand the impact of HPV types in cervical diseases in Italy. Our survey shows an high frequency of infections sustained by HPV 52. Given the recent implementation of a widespread immunization program with vaccines not containing HPV 52, it has been relevant to prove the high prevalence of this HPV genotype from the beginning of the vaccination campaign, to avoid ascribing to the vaccination program a possible selection effect and the importance of non-vaccine HPV types in the burden of cervical disease, in order to assess the opportunity to realize new vaccine including other types.
PMCID: PMC4140382  PMID: 25170506
HPV epidemiology; cervical abnormalities; HPV prevalence
7.  Prevalence of HPV Infection And Cervical Intraepithelial Neoplasia And Attitudes towards HPV Vaccination among Chinese Women Aged 18-25 in Jiangsu Province 
Few data are available on the epidemiology of HPV and cervical cancer among Chinese women younger than 25 years old. This study aimed to estimate the HPV infection rate and the prevalence of cervical intraepithelial neoplasia (CIN) in women aged 18-25, as well as their knowledge of and attitudes towards HPV vaccination.
A population-based cervical cancer screening study was conducted on women aged 18-25 in Jiangsu province in 2008. Participants provided socio-demographic, reproductive and behavioral information and completed a survey about their knowledge of and attitudes towards HPV vaccination. Women then underwent a gynecologic exam to provide two cervical exfoliated cell samples for high risk HPV DNA testing and liquid-based cytology (LBC) as well as visual inspection with acetic acid (VIA). Women testing positive for any test were referred to colposcopy and biopsy. The gold standard for diagnosis of cervical lesions was directed or random biopsies.
Within the sample of 316 women, 3.4% of them were diagnosed with CIN grade 2 or worse lesions and 17.1% were found to be positive for HPV DNA. Among these young women, extra-marital sexual behavior of them (OR=2.0, 95%CI: 1.1-3.8) or their husbands (OR=2.6, 95%: 1.4-4.7) were associated with an increased risk of HPV positivity. Although overall HPV awareness was low, after a brief educational intervention, 98.4% reported they would electively receive HPV vaccination and would also recommend that their daughters be vaccinated. However, most urban and rural women reported their ideal maximum out-of-pocket contribution for HPV vaccination to be less than 500 RMB and 50-100 RMB, respectively.
Our study indicates cervical disease burden is relatively high among sampled Chinese women aged 18-25. Appropriate educational interventions for female adolescents and strategies to subsidize vaccine costs are definitely needed to ensure the effectiveness of vaccination campaigns in China.
PMCID: PMC3587523  PMID: 23467401
Cervical cancer; Cervical intraepithelial neoplasia; Human papillomavirus; Knowledge; Attitude
8.  Human papillomavirus (HPV) vaccination for the prevention of HPV 16/18 induced cervical cancer and its precursors 
Essential precondition for the development of cervical cancer is a persistent human papillomavirus (HPV) infection. The majority - approximately 70% - of cervical carcinomas is caused by two high-risk HPV types (16 and 18). Recently, two vaccines have been approved to the German market with the potential to induce protection against HPV 16 and HPV 18 among additional low-risk virus types.
To analyse whether HPV vaccination is effective with regard to the reduction of cervical cancer and precursors of cervical carcinoma (CIN), respectively? Does HPV vaccination represent a cost-effective alternative or supplement to present screening practice? Are there any differences concerning cost-effectiveness between the two available vaccines? Should HPV vaccination be recommended from a health economic point of view? If so, which recommendations can be conveyed with respect to a (re)organization of the German vaccination strategy? Which ethical, social and legal implications have to be considered?
Based on a systematic literature review, randomized controlled trials (RCT) looking at the effectiveness of HPV vaccination for the prevention of cervical carcinoma and its precursors - cervical intraepithelial neoplasia - have been identified. In addition, health economic models were identified to address the health economic research questions. Quality assessment of medical and economic literature was assured by application of general assessment standards for the systematic and critical appraisal of scientific studies.
Vaccine efficacy in prevention of CIN 2 or higher lesions in HPV 16 or HPV 18 negative women, who received all vaccination doses, ranges between 98% and 100%. Side effects of the vaccination are mainly associated with injection site reactions (redness, turgor, pain). No significant differences concerning serious complications between the vaccination- and the placebo-groups were reported. Results of base case scenarios in the identified health economic modeling analyses range from approximately 3,000 Euro to 40,000 Euro per additional QALY (QALY = Quality-adjusted life year) and approximately 9,000 Euro to 65,000 Euro per additional life year (LYG), respectively.
The included studies show that both available HPV vaccines are effective in preventing HPV 16 and HPV 18 infections and probable resulting premalignant lesions of the cervix. However, the duration of protection is currently unclear. With regard to side effects, the vaccination can be considered as secure. Nevertheless, the number of cases within the clinical studies is not sufficient to determine the occurrence of rarely occurring (severe) adverse events in a reliable way. A reduction in the incidence and induced mortality through cervical cancer in Germany is not only depending on the vaccine’s clinical efficacy. Effects of the new technology on the overall participation rate in screening programs and the resulting vaccination rate and immunization status are also important factors. The results of identified health economic models vary substantially due to the heterogeneity of methodological approaches as well as chosen input parameters. However, almost all model-based analyses reached the conclusion that the implementation of a vaccination with lifelong protection can be considered as cost-effective, if the present screening practice continues. A comparison of the two vaccines shows, that the cost effectiveness ratios are more favorable with the quadrivalent vaccine than with the bivalent alternative when considering QALY as primary outcome parameter. The reason for this finding might be that in the case of the quadrivalent vaccine the prevention of genital warts can also be incorporated into the analysis. Variations of the duration of protection as well as the discounting rate were identified as the primary influencing factors of cost-effectiveness results.
Implementation of HPV vaccination might lead to a reduction of cervical cancer in immunized women. However, uptake of immunization should be accompanied by further studies in order to assess long-term effectiveness and safety aiming at an optimization of possible implementation processes. High numbers of participants are of particular importance regarding immunization. This has to be backed up by programs to optimize early detection – as this affects even those women who already underwent immunization. Since cost-effectiveness evidence might be significantly affected by the unclear duration of protective benefits, a final verdict on the vaccination’s cost-effectiveness in the German setting is not possible. Hence, risk-sharing-agreements between third-party payers and manufacturers would pose an option to balance the consequences of uncertainty towards the duration of protection on cost-effectiveness.
PMCID: PMC3011291  PMID: 21289891
9.  Primary care providers human papillomavirus vaccine recommendations for the medically underserved: A pilot study in U.S. Federally Qualified Health Centers 
Vaccine  2014;32(42):5432-5435.
In the United States, Federally Qualified Health Centers (FQHCs) are safety-net clinics that provide cervical cancer screening and human papillomavirus (HPV) vaccination to medically underserved women, some of whom may be at risk for developing cervical cancer. National guidelines recommend against using screening test results or sexual history to determine vaccine eligibility. Documenting HPV vaccine recommendations and beliefs of primary care providers in FQHCs may aid in promoting evidence-based practices and prioritizing health interventions for vulnerable populations.
Between 2009 and 2010, we collected data from 98 primary care providers in 15 FQHC clinics in IL, USA using a cross-sectional survey. Questions assessed provider and practice characteristics, HPV vaccine recommendations, and provider’s belief about whether their screening and management procedures would change for women who were vaccinated.
93% of providers recommended the HPV vaccine, most frequently for females aged 13–26 years (98%). Some providers reported sometimes to always using HPV test results (12%), Pap test results (7%), and number of sexual partners (33%) to determine vaccine eligibility. More than half of providers (55%) reported they will not change their screening and management practices for vaccinated females, yet believe vaccination will yield fewer abnormal Pap tests (71%) and referrals for colposcopy (74%).
Study providers routinely recommended the HPV vaccine for their patients. However, providers made fewer recommendations to vaccinate females ages 9–12 years (which includes the target age for vaccination) compared to older females, and used pre-vaccination assessments not recommended by U.S. guidelines, such as screening test results and number of sexual partners. In order to maximize the public health benefit of the HPV vaccine to prevent cervical cancer, adherence to guidelines is necessary, especially in settings that provide care to medically underserved women.
PMCID: PMC4480766  PMID: 25131744
HPV vaccine; Cervical cancer screening; Federally Qualified Health Center (FQHC); Underserved; Low-income
10.  Human Papillomavirus-Type Distribution in Women With and Without Cervical Neoplasia in North India 
Our objective was to determine the human papillomavirus (HPV)-type prevalence in cervical samples in women with and without cervical neoplasia in an opportunistic hospital-based cancer-screening program.
A cross-sectional study of 524 women presenting from January 2003 through June 2005 with symptoms of persistent vaginal discharge, intermenstrual bleeding, and postcoital bleeding or detected to have an unhealthy cervix underwent HPV genotyping by consensus polymerase chain reaction and reverse line-blot hybridization assay, conventional Pap smear, and colposcopy, with directed biopsy from all lesions detected.
The prevalence rates of HPV infection among women with normal, low-grade cervical neoplasia (CIN 1) and high-grade CIN (>CIN2) were found to be 7.6%, 42.3%, and 87.5%, respectively. Seventeen high-risk and 6 low-risk HPV types were identified by the reverse line-blot assay. Multiple infections were seen in 20% of women. In normal women, the 6 commonest types were HPV-16, HPV-89, HPV-39, HPV-52, HPV-62, and HPV-18, whereas in high-grade disease, these were all high-risk types HPV-16, HPV-18, HPV-33, HPV-39, HPV-35, and HPV-56. HPV-16 was the commonest type in all groups, seen in 49.4% cases overall and in 74.3% of high-grade squamous intraepithelial lesion. It was followed by HPV-18 (7.4%) and HPV-33 and HPV-39 (4.9% each). HPV-89 was the commonest low-risk type (9.9%). HPV-16/18 were associated with 34.3% of normal, 45.4% of low-grade and 65.7% of high-grade lesions. A wide spectrum of HPV types is seen in north Indian women, with the majority being HPV-16 in all grades of histology. A vaccine against HPV-16 and HPV-18 could prevent two thirds of cases of high-grade cervical neoplasia.
PMCID: PMC4156035  PMID: 18580322
11.  Human Papillomavirus Infection in HIV-1 Infected Women in Catalonia (Spain): Implications for Prevention of Cervical Cancer 
PLoS ONE  2012;7(10):e47755.
High-risk human Papillomavirus infection is a necessary factor for cervical squamous intraepithelial lesions and invasive cervical cancer. In HIV-1-infected women, HPV infection is more prevalent and a higher risk of cervical cancer has been identified. We aimed to calculate the prevalence of infection by HR-HPV, determine the factors associated with this infection and abnormal cytology findings and to describe the history of cervical cancer screening in HIV-1-infected women.
We enrolled 479 HIV-1–infected women from the PISCIS cohort. Each patient underwent a gynecological check-up, PAP smear, HPV AND Hybrid capture, HPV genotyping, and colposcopy and biopsy, if necessary. We applied questionnaires to obtain information on sociodemographic, behavioral, clinical, and cervical screening variables. We present a cross-sectional analysis.
Median age was 42 years. The prevalence of HR-HPV infection was 33.2% and that of high-grade squamous intraepithelial lesions (HSIL) was 3.8%. The most common genotypes were 16(23%), 53(20.3%), and 52(16.2%). The factor associated with HR-HPV infection was age <30 years (odds ratio[OR],2.5; 95%confidence interval[CI],1.1–5.6). The factors associated with the presence of HSIL or low-grade squamous intraepithelial lesions (LSIL) were CD4T-lymphocyte count <200cells/mm3 versus >500cells/mm3 (OR,8.4; 95%CI,3.7–19.2), HIV-1 viral load >10,000copies/mL versus <400copies/mL (OR,2.1; 95%CI,1.0–4.4), and use of oral contraceptives (OR,2.0; 95%CI,1.0–3.9). Sixty percent of HIV-1–infected women had had one Pap smear within the last 2 years.
The high prevalence of HPV infection and cervical lesions in the HIV-1–infected population in Catalonia, as well as the low coverage and frequency of screening in this group, means that better preventive efforts are necessary and should include vaccination against HPV, better accessibility to screening programs, training of health care professionals, and specific health education for HIV-1–infected women.
PMCID: PMC3484159  PMID: 23118894
12.  Prevalence of human papillomavirus infection in women in Benin, West Africa 
Virology Journal  2011;8:514.
Cervical cancer ranks as the first most frequent cancer among women in Benin. The major cause of cervical cancer now recognized is persistent infection of Human Papillomavirus (HPV). In Benin there is a lack of screening programs for prevention of cervical cancer and little information exists regarding HPV genotype distribution.
Cervical cells from 725 women were examined for the presence of viral DNA by means of a polymerase chain reaction (PCR) multiplex-based assay with the amplification of a fragment of L1 region and of E6/E7 region of the HPV genome, and of abnormal cytology by Papanicolaou method. The association between HPV status and Pap test reports was evaluated. Socio-demographic and reproductive characteristics were also related.
A total of 18 different HPV types were identified, with a prevalence of 33.2% overall, and 52% and 26.7% among women with and without cervical lesions, respectively. Multiple HPV infections were observed in 40.2% of HPV-infected women. In the HPV-testing group, the odds ratio for the detection of abnormal cytology was 2.98 (95% CI, 1.83-4.84) for HPV positive in comparison to HPV negative women. High risk types were involved in 88% of infections, most notably HPV-59, HPV-35, HPV-16, HPV-18, HPV-58 and HPV-45. In multiple infections of women with cytological abnormalities HPV-45 predominated.
This study provides the first estimates of the prevalence of HPV and type-specific distribution among women from Benin and demonstrates that the epidemiology of HPV infection in Benin is different from that of other world regions. Specific area vaccinations may be needed to prevent cervical cancer and the other HPV-related diseases.
PMCID: PMC3231975  PMID: 22074103
human papillomavirus; cervical cancer; Benin; Pap test; prevention
13.  Baseline prevalence and type distribution of human papillomavirus in healthy Chinese women aged 18–25 years enrolled in a clinical trial 
Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine ( registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18–25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18–25 years underlines the importance of early HPV vaccination in this population.
What's new?
In China, cervical cancer is the second most frequent cancer among women aged 15–44 years. The authors collected baseline data on prevalence and type distribution of human papillomavirus (HPV) from more than 6,000 healthy Chinese women aged 18–25 years participating in a large vaccine efficacy trial. Regardless of cytology, 15.3% of women were positive for high-risk HPV types, with HPV-52 (4.0%), HPV-16 (3.7%), HPV-51 (1.7%) and HPV-58 (1.5%) being the most frequently detected. This high baseline prevalence of high-risk HPV types underscores the importance of early vaccination among Chinese women.
PMCID: PMC4277334  PMID: 24740547
human papillomavirus; China; women; prevalence; type distribution
14.  Primary Screening for Cervical Cancer Based on High-Risk Human Papillomavirus (HPV) Detection and HPV 16 and HPV 18 Genotyping, in Comparison to Cytology 
PLoS ONE  2015;10(3):e0119755.
The objective of the present study is to assess the performance of a high-risk human papillomavirus (HR-HPV) DNA test with individual HPV-16/HPV-18 genotyping as a method for primary cervical cancer screening compared with liquid-based cytology (LBC) in a population of Greek women taking part in routine cervical cancer screening.
The study, conducted by the “HEllenic Real life Multicentric cErvical Screening” (HERMES) study group, involved the recruitment of 4,009 women, aged 25–55, who took part in routine cervical screening at nine Gynecology Departments in Greece. At first visit cervical specimens were collected for LBC and HPV testing using the Roche Cobas 4800 system. Women found positive for either cytology or HPV were referred for colposcopy, whereas women negative for both tests will be retested after three years. The study is ongoing and the results of the first screening round are reported herein.
Valid results for cytology and HPV testing were obtained for 3,993 women. The overall prevalence of HR-HPV was 12.7%, of HPV-16 2.7% and of HPV-18 1.4%. Of those referred for colposcopy, cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was detected in 41 women (1.07%). At the threshold of CIN2+, cytology [atypical squamous cells of undetermined significance (ASC-US) or worse] and HPV testing showed a sensitivity of 53.7% and 100% respectively, without change between age groups. Cytology and HPV testing showed specificity of 96.8% and 90.3% respectively, which was increased in older women (≥30) in comparison to younger ones (25–29). Genotyping for HPV16/18 had similar accuracy to cytology for the detection of CIN2+ (sensitivity: 58.5%; specificity 97.5%) as well as for triage to colposcopy (sensitivity: 58.5% vs 53.7% for cytology).
HPV testing has much better sensitivity than cytology to identify high-grade cervical lesions with slightly lower specificity. HPV testing with individual HPV-16/HPV-18 genotyping could represent a more accurate methodology for primary cervical cancer screening in comparison to liquid-based cytology, especially in older women.
PMCID: PMC4368762  PMID: 25793281
15.  Cost-effectiveness of vaccination with a quadrivalent HPV vaccine in Germany using a dynamic transmission model 
Persistent infections with human papillomavirus (HPV) are a necessary cause of cervical cancer and are responsible for important morbidity in men and women. Since 2007, HPV vaccination has been recommended and funded for all girls aged 12 to 17 in Germany. A previously published cost-effectiveness analysis, using a static model, showed that a quadrivalent HPV vaccination programme for 12-year-old girls in Germany would be cost effective. Here we present the results from a dynamic transmission model that can be used to evaluate the impact and cost-effectiveness of different vaccination schemas.
We adapted a HPV dynamic transmission model, which has been used in other countries, to the German context. The model was used to compare a cervical cancer screening only strategy with a strategy of combining vaccination of females aged 12–17 years old and cervical cancer screening, based on the current recommendations in Germany. In addition, the impact of increasing vaccination coverage in this cohort of females aged 12–17 years old was evaluated in sensitivity analysis.
The results from this analysis show that the current quadrivalent HPV vaccination programme of females ages 12 to 17 in Germany is cost-effective with an ICER of 5,525€/QALY (quality adjusted life year). The incremental cost-effectiveness ratio (ICER) increased to 10,293€/QALY when the vaccine effects on HPV6/11 diseases were excluded. At steady state, the model predicted that vaccinating girls aged 12 to 17 could reduce the number of HPV 6/11/16/18-related cervical cancers by 65% and genital warts among women and men by 70% and 48%, respectively. The impact on HPV-related disease incidence and costs avoided would occur relatively soon after initiating the vaccine programme, with much of the early impact being due to the prevention of HPV6/11-related genital warts.
These results show that the current quadrivalent HPV vaccination and cervical cancer screening programmes in Germany will substantially reduce the incidence of cervical cancer, cervical intraepithelial neoplasia (CIN) and genital warts. The evaluated vaccination strategies were all found to be cost-effective. Future analyses should include more HPV-related diseases.
PMCID: PMC3575401  PMID: 23009387
Cervical cancer; Cervical intraepithelial neoplasia; Genital warts; Human papillomavirus; Quadrivalent HPV vaccine; Cost-effectiveness analysis; Dynamic transmission model
16.  Distribution of Human Papillomavirus Genotypes among HIV-Positive and HIV-Negative Women in Cape Town, South Africa 
Objective: HIV-positive women are known to be at high-risk of human papillomavirus (HPV) infection and its associated cervical pathology. Here, we describe the prevalence and distribution of HPV genotypes among HIV-positive and -negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN).
Methods: We report data on 1,371 HIV-positive women and 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies in Cape Town, South Africa, conducted among women who had no history of cervical cancer screening recruited from the general population. All women were tested for HIV. Cervical samples were tested for high-risk HPV DNA (Hybrid Capture 2) with positive samples tested to determine the specific genotype (Line Blot). CIN status was determined based on colposcopy and biopsy.
Results: The HPV prevalence was higher among HIV-positive women (52.4%) than among HIV-negative women (20.8%) overall and in all age groups. Younger women, aged 17–19 years, had the highest HPV prevalence regardless of HIV status. HIV-positive women were more likely to have CIN 2 or 3 than HIV-negative women. HPV 16, 35, and 58 were the most common high-risk HPV types with no major differences in the type distribution by HIV status. HPV 18 was more common in older HIV-positive women (40–65 years) with no or low grade disease, but less common in younger women (17–29 years) with CIN 2 or 3 compared to HIV-negative counterparts (p < 0.03). Infections with multiple high-risk HPV types were more common in HIV-positive than HIV-negative women, controlling for age and cervical disease status.
Conclusion: HIV-positive women were more likely to have high-risk HPV than HIV-negative women; but, among those with HPV, the distribution of HPV types was similar by HIV status. Screening strategies incorporating HPV genotyping and vaccination should be effective in preventing cervical cancer in both HIV-positive and -negative women living in sub-Saharan Africa.
PMCID: PMC3953716  PMID: 24672770
HIV-infections; HPV; genotype; HPV vaccine; cervical cancer screening
17.  Human Papillomavirus Genotype Distributions: Implications for Vaccination and Cancer Screening in the United States 
Limited data are available describing human papillomavirus (HPV) genotype distributions in cervical cancer in the United States. Such studies are needed to predict how HPV vaccination and HPV-based screening will influence cervical cancer prevention.
We used the New Mexico Surveillance, Epidemiology, and End Results Registry to ascertain cases of in situ (n = 1213) and invasive (n = 808) cervical cancer diagnosed during 1985–1999 and 1980–1999, respectively, in the state of New Mexico. HPV genotyping was performed using two polymerase chain reaction–based methods on paraffin-embedded tissues from in situ and invasive cancers and on cervical Papanicolaou test specimen from control subjects (ie, women aged 18–40 years attending clinics for routine cervical screening [n = 4007]). Relative risks for cervical cancer were estimated, and factors associated with age at cancer diagnosis and the prevalence of HPV genotypes in cancers were examined.
The most common HPV genotypes detected in invasive cancers were HPV type 16 (HPV16, 53.2%), HPV18 (13.1%), and HPV45 (6.1%) and those in in situ cancers were HPV16 (56.3%), HPV31 (12.6%), and HPV33 (8.0%). Invasive cancer case subjects who were positive for HPV16 or 18 were diagnosed at younger ages than those who were positive for other carcinogenic HPV genotypes (mean age at diagnosis: 48.1 [95% confidence interval {CI} = 46.6 to 49.6 years], 45.9 [95% CI = 42.9 to 49.0 years], and 52.3 years [95% CI = 50.0 to 54.6 years], respectively). The proportion of HPV16-positive in situ and invasive cancers, but not of HPV18-positive cancers, declined with more recent calendar year of diagnosis, whereas the proportion positive for carcinogenic HPV genotypes other than HPV18 increased.
HPV16 and 18 caused the majority of invasive cervical cancer in this population sample of US women, but the proportion attributable to HPV16 declined over the last 20 years. The age at diagnosis of HPV16- and HPV18-related cancers was 5 years earlier than that of cancers caused by carcinogenic HPV genotypes other than HPV16 and 18, suggesting that the age at initiation of cervical screening could be delayed in HPV-vaccinated populations.
PMCID: PMC2664090  PMID: 19318628
18.  An epidemiological study assessing the prevalence of human papillomavirus types in women in the Kingdom of Bahrain 
BMC Cancer  2014;14:905.
Persistent infection with high-risk (HR) human papillomavirus (HPV) causes cervical cancer, the fourth most frequent cancer in the Kingdom of Bahrain, with an annual incidence of four per 100,000 women. The aim of this study was to assess the prevalence and type distribution of HPV in Bahraini and non-Bahraini women attending routine screening. HPV prevalence was assessed by risk factors and age distribution. Health-related behaviors and HPV awareness were also studied.
This observational study was conducted between October 2010 and November 2011 in the Kingdom of Bahrain (NCT01205412). Women aged either ≥20 years attending out-patient health services for routine cervical screening or ≥16 years attending post-natal check-ups were enrolled. Cervical samples were collected and tested for HPV-DNA by polymerase chain reaction and typed using the SPF10 DEIA/LiPA25 system. All women completed two questionnaires on health-related behavior (education level, age at first marriage, number of marital partners, parity and smoking status) and HPV infection awareness.
HPV DNA was detected in 56 of the 571 women included in the final analysis (9.8%); 28 (4.9%), 15 (2.6%) and 13 (2.3%) women were infected with single, multiple and unidentifiable HPV types, respectively. The most prevalent HPV types among the HPV positive women were HR-HPV-52 in eight (1.4%), HR-HPV-16, -31 and -51 in six women each (1.1%); low-risk (LR)-HPV-6 in four (0.7%); and LR-HPV-70, -74 in three women each (0.5%). Co-infection with other HR-HPV types was observed in 50% HPV-16-positive women (with HPV-31, -45 and -56) and in both HPV-18-positive women (with HPV-52). None of the health-related risk factors studied were associated with any HR-HPV infection. More than half of women (68.7%) had never heard about HPV, but most women (91.3%) in our study were interested in HPV-vaccination.
HPV prevalence in Bahraini women was 9.8%. The most frequently observed HPV types were HR-HPV-52, -16, -31 and -51 and LR-HPV-6, -70 and -74. These are useful baseline data for health authorities to determine the potential impact of preventive measures including the use of prophylactic vaccines to reduce the burden of cervical cancer.
PMCID: PMC4265506  PMID: 25466757
Epidemiology; Human papillomavirus; Kingdom of Bahrain; Prevalence; Type distribution
19.  Factors Associated with Colposcopy-Histopathology Confirmed Cervical Intraepithelial Neoplasia among HIV-Infected Women from Rio De Janeiro, Brazil 
PLoS ONE  2011;6(3):e18297.
Despite the availability of preventive strategies (screening tests and vaccines), cervical cancer continues to impose a significant health burden in low- and medium-resourced countries. HIV-infected women are at increased risk for infection with human papillomavirus (HPV) and thus development of cervical squamous intraepithelial neoplasia (CIN).
Study participants included HIV-infected women enrolling the prospective open cohort of Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation (IPEC/FIOCRUZ). At cohort entry, women were subjected to conventional Papanicolaou test, HPV-DNA test and colposcopy; lesions suspicious for CIN were biopsied. Histopathology report was based on directed biopsy or on specimens obtained by excision of the transformation zone or cervical conization. Poisson regression modeling was used to assess factors associated with CIN2+ diagnosis.
The median age of the 366 HIV-infected women included in the study was 34 years (interquartile range: 28–41 years). The prevalence of CIN1, CIN2 and CIN3 were 20.0%, 3.5%, and 2.2%, respectively. One woman was found to have cervical cancer. The prevalence of CIN2+ was 6.0%. Factors associated with CIN2+ diagnosis in the multivariate model were age < years compared to ≥35 years (aPR  =  3.22 95%CI 1.23–8.39), current tobacco use (aPR  =  3.69 95%CI 1.54–8.78), nadir CD4 T-cell count <350 cells/mm3 when compared to ≥ 350 cells/mm3 (aPR  =  6.03 95%CI 1.50–24.3) and concomitant diagnosis of vulvar and/or vaginal intraepithelial lesion (aPR  =  2.68 95%CI 0.99–7.24).
Increased survival through wide-spread use of highly active antiretroviral therapy might allow for the development of cervical cancer. In Brazil, limited cytology screening and gynecological care adds further complexity to the HIV-HPV co-infection problem. Integrated HIV care and cervical cancer prevention programs are needed for the prevention of cervical cancer mortality in this group of women.
PMCID: PMC3068170  PMID: 21479179
20.  Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection: Role of Persistence 
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.
PMCID: PMC2950170  PMID: 20841605
21.  Clinical Human Papillomavirus Detection Forecasts Cervical Cancer Risk in Women Over 18 Years of Follow-Up 
Journal of Clinical Oncology  2012;30(25):3044-3050.
To describe the long-term (≥ 10 years) benefits of clinical human papillomavirus (HPV) DNA testing for cervical precancer and cancer risk prediction.
Cervicovaginal lavages collected from 19,512 women attending a health maintenance program were retrospectively tested for HPV using a clinical test. HPV positives were tested for HPV16 and HPV18 individually using a research test. A Papanicolaou (Pap) result classified as atypical squamous cells of undetermined significance (ASC-US) or more severe was considered abnormal. Women underwent follow-up prospectively with routine annual Pap testing up to 18 years. Cumulative incidence rates (CIRs) of ≥ grade 3 cervical intraepithelial neoplasia (CIN3+) or cancer for enrollment test results were calculated.
A baseline negative HPV test provided greater reassurance against CIN3+ over the 18-year follow-up than a normal Pap (CIR, 0.90% v 1.27%). Although both baseline Pap and HPV tests predicted who would develop CIN3+ within the first 2 years of follow-up, only HPV testing predicted who would develop CIN3+ 10 to 18 years later (P = .004). HPV16- and HPV18-positive women with normal Pap were at elevated risk of CIN3+ compared with other HPV-positive women with normal Pap and were at similar risk of CIN3+ compared with women with a low-grade squamous intraepithelial Pap.
HPV testing to rule out cervical disease followed by Pap testing and possibly combined with the detection of HPV16 and HPV18 among HPV positives to identify those at immediate risk of CIN3+ would be an efficient algorithm for cervical cancer screening, especially in women age 30 years or older.
PMCID: PMC3732003  PMID: 22851570
22.  Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials 
Human papillomavirus (HPV) is now known to be a necessary cause of cervical cancer, and prophylactic HPV vaccines aimed at preventing genital warts, precancerous cervical lesions and cervical cancer are now available. To gauge the potential impact on disease burden, we performed a systematic review of the evidence from randomized controlled trials.
We conducted a systematic search of the literature to identify all randomized controlled trials of prophylactic HPV vaccination. Reports in 5 electronic databases covering 1950 to June 2007 (MEDLINE, MEDLINE in process, EMBASE, the Cochrane Central Registry of Controlled Trials and the Cochrane Library), bibliographies of all included studies and of narrative reviews (2006–2007), clinical trial registries, Google Scholar, public health announcements, selected conference proceedings (2004–2007) and manufacturers' information on unpublished data or ongoing trials were screened against predefined eligibility criteria by 2 independent reviewers. Vaccines had to contain coverage against at least 1 oncogenic HPV strain. The primary outcome of interest was the frequency of high-grade cervical lesions (high-grade squamous intraepithelial lesion, or grade 2 or 3 cervical intraepithelial neoplasia). The secondary outcomes were persistent HPV infection, low-grade cervical lesions (low-grade squamous intraepithelial lesion or grade 1 cervical intraepithelial neoplasia), external genital lesions, adverse events and death. Meta-analysis of the data was done in all cases where adequate clinical and methodological homogeneity existed.
Of 456 screened reports, 9 were included in the review (6 were reports of randomized controlled trials and 3 were follow-up reports of initial trials). Findings from the meta-analysis showed that prophylactic HPV vaccination was associated with a reduction in the frequency of high-grade cervical lesions caused by vaccine-type HPV strains compared with control groups: Peto odds ratio 0.14 (95% confidence interval [CI] 0.09–0.21) from combined per-protocol analyses, and 0.52 (95% CI 0.43–0.63) from modified intention-to-treat analyses. Vaccination was also highly efficacious in preventing other HPV-related infection and disease outcomes, including persistent HPV infection, low-grade lesions and genital warts. The majority of adverse events were minor. The incidence of serious adverse events and death were balanced between the vaccine and control groups.
Among women aged 15–25 years not previously infected with vaccine-type HPV strains, prophylactic HPV vaccination appears to be highly efficacious in preventing HPV infection and precancerous cervical disease. Long-term follow-up is needed to substantiate reductions in cervical cancer incidence and mortality.
PMCID: PMC1950172  PMID: 17671238
23.  Cervical cancer screening: A never-ending developing program 
With the term “oncological screening”, we define the overall performances made to detect early onset of tumors. These tests are conducted on a population that does not have any signs or symptoms related to a neoplasm. The whole population above a certain age, only one sex, only subjects with a high risk of developing cancer due to genetic, professional, discretionary reasons may be involved. Screening campaigns should be associated, when risk factors that can be avoided are known, with campaigns for the prevention of cancer by means of suitable behavior. The goal of cancer screening cannot however be limited to the diagnosis of a greater number of neoplasms. Screening will be useful only if it leads to a reduction in overall mortality or at least in mortality related to the tumor. Screening should then allow the diagnosis of the disease at a stage when there is a possibility of healing, possibility that is instead difficult when the disease is diagnosed at the appearance of signs or symptoms. This is the reason why not all campaigns of cancer screening have the same effectiveness. In Italy, every year there are about 150000 deaths due to cancer. Some of these tumors can be cured with a very high percentage of success if diagnosed in time. Cervical cancer can be diagnosed with non-invasive tests. The screening test used all over the world is Papanicolaou (Pap) test. This test may be carried out over the entire healthy population potentially exposed to the risk of contracting cancer. Public health has begun the screening campaigns in the hope of saving many of the approximately 270000 new cases of cancer reported each year. Screening is done following protocols that guarantee quality at the national level: these protocols are subject to change over time to reflect new realities or to correct any errors in the system. A simplified sketch of a possible route of cancer screening is as follows: (1) after selecting the target population, for example all women between 25 and 64 years (in the case of monitoring of cervical cancer), an invitation letter with the date and time of the appointment, planned according to the acceptance capacity of the hospital, is sent to all individuals; (2) an examination, which depending on the individual and the type of cancer to be monitored, for example, can be a Pap smear, is performed and the patient can go home; (3) once available the results of examinations, if negative, they shall be communicated to the person concerned that will be notified by mail and will be recalled for a second test at a few years of distance, in the case of non-negativity, instead, the patient is contacted by telephone and informed of the need to carry out further examinations: it is said that the patient is in the “phase two” of the screening pathway; (4) in phase two, reached by only a small portion of the interested parties (usually less than 3%-5%), more in-depth tests are carried out, which, depending on the individual and the type of cancer, can be: cytological and colposcopic examinations, the removal of a fragment of tissue (biopsy) and subsequent histological examination, additional tests such as ultrasound, radiography, or others such as computerized tomography, magnetic resonance imaging, positron emission tomography, etc., in case of negativity, the concerned person will be called for new control tests at a a few years of distance, in case of non-negativity, it will be proposed instead an oncologic therapeutic plan and/or surgery to treat the diagnosed tumor; and (5) once the treatment plan is completed, the individual enters the follow-up protocol, which is monitored over time to see if the tumor has been completely removed or if instead it is still developing. Cervical cancer is undoubtedly the most successful example of a cancer screening campaign. Paradoxically, its effectiveness is one of the strongest reasons to criticize the usefulness of vaccination against human papillomavirus (HPV) in countries where the screening service with Pap test is organized in an efficient manner. Cervical cancer screening protocols are directed to sexually active women aged 25-64 years: they provide the Pap test performed by examining under a microscope or by staining with a specific “thin prep” the material taken from the cervix with a small spatula and a brush. It is recommended to repeat the test every two or three years. It is important to emphasize that women vaccinated against HPV must continue the screening with Pap test. Although some screening programs (e.g., Pap smears) have had remarkable success in reducing mortality from a specific cancer, any kind of screening is free from inherent limitations. The screening methods are in fact applied to large parts of the apparently healthy population. In particular, the limits for certain cancers may be as obvious as to prohibit the introduction of an organized screening program. Potential limitations of organized screenings are basically of two types: organizational and medical. The limits of organizational type relate to the ability of a program to recruit the whole target population. Although well organized, a screening program will hardly be able to exceed a coverage of 70%-80% of the target population, and in fact the results of the current programs are often much smaller. The limits of medical type are represented by the possibility of reducing the overall mortality, or specific mortality, using a specific screening campaign.
PMCID: PMC4517336  PMID: 26244153
Cervical cancer; Screening; Papanicolaou test; Human papillomavirus test; Vaccination
24.  Genotypic distribution of human papillomavirus (HPV) and cervical cytology findings in 5906 Thai women undergoing cervical cancer screening programs 
Cervical cancer is the major cause of morbidity and mortality in Thai women. Nevertheless, the preventive strategy such as HPV vaccination program has not been implemented at the national level. This study explored the HPV prevalence and genotypic distribution in a large cohort of Thai women.
A hospital-based cervical cancer screening program at Chulabhorn Hospital, Bangkok and a population-based screening program at a rural Pathum Thani Province were conducted using liquid-based cytology and HPV genotyping.
Of 5906 women aged 20–70 years, Pap smear was abnormal in 4.9% and the overall HPV prevalence was 15.1%, with 6.4% high-risk (HR), 3.5% probable high-risk (PR), and 8.4% low-risk (LR) HPV. The prevalence and genotypic distribution were not significantly different between the two cohorts. Among HR-HPV genotypes, HPV52 was the most frequent (1.6%), followed by HPV16 (1.4%), HPV51 (0.9%), HPV58 (0.8%), HPV18 (0.6%), and HPV39 (0.6%). Among LR-HPV genotypes, HPV72 and HPV62 were the most frequent while HPV6 and HPV11 were rare. HPV infection was found to be proportionately high in young women, aged 20–30 years (25%) and decreasing with age (11% in women aged >50). The more severe abnormal cytology results, the higher positivity of HR-HPV infection was observed.
In conclusion, HPV52, HPV16, and HPV51 were identified as the most common HR-HPV genotypes in Thai women. This study contributes genotypic evidence that should be essential for the development of appropriate HPV vaccination program as part of Thailand’s cervical cancer prevention strategies.
PMCID: PMC4347911  PMID: 25737740
Cervical cancer; Cancer screening; HPV genotypes; Cervical cytology; Thailand
25.  Age-Appropriate Use of Human Papillomavirus Vaccines in the U.S.* 
Gynecologic oncology  2009;114(2):365-369.
Cervical infections by approximately 15 cancer-associated (carcinogenic) human papillomavirus (HPV) genotypes cause virtually all cervical cancer and its immediate precursor lesions worldwide. Prophylactic vaccines against human papillomavirus (HPV) types HPV16 and HP18, which cause 70% of cervical cancer worldwide, hold great promise for reducing the burden of cervical cancer worldwide. However, current HPV vaccines prevent future infections and related cervical abnormalities and do not treat pre-existing HPV infections. In the U.S., HPV vaccine introduction should be considered in the context of a very successful cervical cancer screening program that has reduced the rates of cervical cancer by 75% or more. Thus, HPV vaccines will only prevent an incremental number of additional cervical cancers in the U.S. The introduction of HPV vaccines can also prevent other HPV-related sequelae, most importantly cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3), which precede the development of cervical cancer and require clinical follow-up and treatment. Examining data from 7 clinical centers in the U.S., the median age of CIN2/3 is typically between 25-30 years of age in 2007; if screen-detected CIN2/3 develops on average 5-10 years after the causal infection is acquired, HPV vaccination will only prevent a significant proportion of CIN2/3 if it is given to women before the age of 26 and more so if given to women 18 and younger. It is increasingly evident that prophylactic HPV vaccines will provide the greatest public health or population benefit only when delivered to adolescent women.
PMCID: PMC2729751  PMID: 19464729

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