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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.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1000270.
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)
doi:10.1371/journal.pmed.1000270
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
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001147.
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)
doi:10.1371/journal.pmed.1001147
PMCID: PMC3243713  PMID: 22205887
3.  Human papillomavirus genotypes detected in clinician-collected and self-collected specimens from women living in the Mississippi Delta 
Background
There are no data available on human papillomavirus (HPV) infections in women living in the Mississippi Delta, where cervical cancer incidence and mortality among African American women is among the highest in the United States. The aim of this analysis was to report the age-specific prevalence of HPV in this population.
Methods
We recruited 443 women, 26–65 years of age, from the general population of women living in the Mississippi Delta to participate; 252 women had been screened for cervical cancer within the last 3 years while 191 had not. Women underwent a pelvic exam and had clinician-collected Pap sample taken for the routine cervical cancer screening by cytology. Women were asked to collect a self-collected specimen at home and return it to the clinic. Both specimens were tested for HPV genotypes.
Results
Four hundred and six women (91.6%) had HPV genotyping results for the clinician-collected and self-collected specimens. The prevalence of carcinogenic HPV was 18.0% (95% CI: 14.4%-22.1%) for clinician-collected specimens and 26.8% (95% CI: 22.6%-31.4%) for self-collected specimens. The concordance for the detection of carcinogenic HPV between clinician-collected and self-collected specimens was only fair (kappa = 0.54). While the prevalence of carcinogenic HPV in either sample decreased sharply with increasing age (ptrend< 0.01), the prevalence of non-carcinogenic HPV did not, especially the prevalence of HPV genotypes in the alpha 3/4/15 phylogenetic group.
Conclusions
The prevalence of carcinogenic HPV in our sample of women living in the Mississippi Delta was greater than the prevalence reported in several other U.S. studies. The high carriage of HPV infection, along with lack of participation in cervical cancer screening by some women, may contribute to the high cervical cancer burden in the region.
doi:10.1186/1471-2334-13-5
PMCID: PMC3570306  PMID: 23289357
Human papillomavirus (HPV); Self-collection; Pap; Cervical intraepithelial neoplasia; Cervix
4.  Human Papillomavirus Genotype Distributions: Implications for Vaccination and Cancer Screening in the United States 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1093/jnci/djn510
PMCID: PMC2664090  PMID: 19318628
5.  Cervical Screening at Age 50–64 Years and the Risk of Cervical Cancer at Age 65 Years and Older: Population-Based Case Control Study 
PLoS Medicine  2014;11(1):e1001585.
Peter Sasieni and colleagues use a population-based case control study to assess the risk of cervical cancer in screened women aged over 65 years to help inform policy on the upper age of cervical cancer screening.
Please see later in the article for the Editors' Summary
Background
There is little consensus, and minimal evidence, regarding the age at which to stop cervical screening. We studied the association between screening at age 50–64 y and cervical cancer at age 65–83 y.
Methods and Findings
Cases were women (n = 1,341) diagnosed with cervical cancer at age 65–83 y between 1 April 2007 and 31 March 2012 in England and Wales; age-matched controls (n = 2,646) were randomly selected from population registers. Screening details from 1988 onwards were extracted from national databases. We calculated the odds ratios (OR) for different screening histories and subsequent cervical cancer. Women with adequate negative screening at age 65 y (288 cases, 1,395 controls) were at lowest risk of cervical cancer (20-y risk: 8 cancers per 10,000 women) compared with those (532 cases, 429 controls) not screened at age 50–64 y (20-y risk: 49 cancers per 10,000 women, with OR = 0.16, 95% CI 0.13–0.19). ORs depended on the age mix of women because of the weakening association with time since last screen: OR = 0.11, 95% CI 0.08–0.14 at 2.5 to 7.5 y since last screen; OR = 0.27, 95% CI 0.20–0.36 at 12.5 to 17.5 y since last screen. Screening at least every 5.5 y between the ages 50 and 64 y was associated with a 75% lower risk of cervical cancer between the ages 65 and 79 y (OR = 0.25, 95% CI 0.21–0.30), and the attributable risk was such that in the absence of screening, cervical cancer rates in women aged 65+ would have been 2.4 (95% CI 2.1–2.7) times higher. In women aged 80–83 y the association was weaker (OR = 0.49, 95% CI 0.28–0.83) than in those aged 65–69 y (OR = 0.12, 95% CI 0.09–0.17). This study was limited by an absence of data on confounding factors; additionally, findings based on cytology may not generalise to human papillomavirus testing.
Conclusions
Women with adequate negative screening at age 50–64 y had one-sixth of the risk of cervical cancer at age 65–83 y compared with women who were not screened. Stopping screening between ages 60 and 69 y in women with adequate negative screening seems sensible, but further screening may be justifiable as life expectancy increases.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Nearly one in ten cancers diagnosed 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 (mostly in developing countries) die because of cervical cancer, which occurs only after the cervix has been infected with human papillomavirus (HPV) through sexual intercourse. In the earliest stages of cervical cancer, abnormal cells begin to grow in the cervix. Cells with low-grade abnormalities (changes that often revert to normal), cells with high-grade abnormalities (which are more likely to become cancerous), and cancer cells can all be detected by collecting a few cells from the cervix and examining them under a microscope. This test forms the basis of cervical screening, which has greatly reduced cervical cancer deaths in countries with a national screening program by ensuring that cervical abnormalities are detected at an early, treatable stage. In the UK, for example, since the start of a cervical screening program in 1988 in which women aged 25–64 years are called for testing every 3–5 years, the incidence of cervical cancer (the number of new cases per year) has almost halved at a time when sexually transmitted diseases have more than doubled.
Why Was This Study Done?
Currently, there is little consensus about the age at which cervical screening should stop, and minimal evidence about the impact of cervical screening on the incidence of cervical cancer in older women. In this population-based case control study (a study that compares the characteristics of all the cases of a disease in a population with the characteristics of matched individuals without the disease), the researchers examine the association between screening in women aged 50–64 years and cervical cancer in women aged 65–83 years. They ask whether well-screened women with a history of negative results and no evidence of high-grade abnormalities are at sufficiently low risk of cervical cancer that screening can be stopped at age 65 years, and whether women who are regularly screened (at least once every 5.5 years) between the ages of 50 and 64 years are subsequently at reduced risk of cervical cancer.
What Did the Researchers Do and Find?
The researchers randomly selected two age-matched controls for every woman aged 65–83 years who was diagnosed with cervical cancer between 2007 and 2012 in England and Wales. The researchers included 1,341 women with cervical cancer and 2,646 controls. They extracted each woman's cervical screening details from national databases and calculated the association between screening history and subsequent cervical cancer. Women with adequate negative screening at age 65 years (at least three tests at age 50–64 years with the last one over age 60, the last three of which were negative, and no evidence of high-grade abnormalities) were at the lowest risk of cervical cancer (20-year risk of eight cancers per 10,000 women) compared with unscreened women (20-year risk of 49 cancers per 10,000 women). That is, women who were not screened at age 50–64 years were six times more likely to develop cervical cancer between the ages of 65 and 83 years than women who were screened. The risk of developing cervical cancer among adequately negatively screened women increased with age and with time since the last screen. Finally, the researchers estimate that in the absence of any cervical screening, the rate of cervical cancer among women aged 65–79 years would be 23 cases per 100,000 woman-years, 2.4 times higher than the current rate.
What Do These Findings Mean?
These findings show that women who exited the screening program in England and Wales with a history of adequate negative screening between the ages of 50 and 64 years were at a very low risk of being diagnosed with cervical cancer at the age of 65 years or older. The “protection” provided by screening was greatest for women aged 65–69 years and decreased steadily with increasing age and with time since the last negative screen. Because the researchers did not have any information on other characteristics that might have affected cervical cancer risk (for example, number of sexual partners), the women who were screened may have shared other characteristics that reduced their risk of developing cervical cancer. Moreover, these findings, which are based on microscopic examination of cells, may not generalise to the HPV-based screening programs that many countries are considering. Despite these limitations, the researchers conclude that, for now, it seems sensible to continue screening at least until age 60 years and not beyond age 69 years in women with adequate negative screening, but that given increasing life expectancy, screening in older women might be justified in the future.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001585.
This study is further discussed in a PLOS Medicine Perspective by Anne Rositch and colleagues
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on cervical screening (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about cervical screening
The UK National Health Service Cervical Screening Programme website has detailed information and statistics on cervical screening in England
The UK National Health Service Choices website has pages on cervical cancer (including a personal story about cervical cancer) and on cervical screening (including personal comments about screening)
Cancer Research UK provides detailed information about all aspects of cervical cancer
More information about cervical cancer and screening is available from the Macmillan cancer charity
MedlinePlus provides links to additional resources about cervical cancer and screening (in English and Spanish)
Personal stories about cervical cancer and about cervical screening are available through the charity Healthtalkonline
doi:10.1371/journal.pmed.1001585
PMCID: PMC3891624  PMID: 24453946
6.  Epidemiology of HPV 16 and Cervical Cancer in Finland and the Potential Impact of Vaccination: Mathematical Modelling Analyses 
PLoS Medicine  2006;3(5):e138.
Background
Candidate human papillomavirus (HPV) vaccines have demonstrated almost 90%-100% efficacy in preventing persistent, type-specific HPV infection over 18 mo in clinical trials. If these vaccines go on to demonstrate prevention of precancerous lesions in phase III clinical trials, they will be licensed for public use in the near future. How these vaccines will be used in countries with national cervical cancer screening programmes is an important question.
Methods and Findings
We developed a transmission model of HPV 16 infection and progression to cervical cancer and calibrated it to Finnish HPV 16 seroprevalence over time. The model was used to estimate the transmission probability of the virus, to look at the effect of changes in patterns of sexual behaviour and smoking on age-specific trends in cancer incidence, and to explore the impact of HPV 16 vaccination. We estimated a high per-partnership transmission probability of HPV 16, of 0.6. The modelling analyses showed that changes in sexual behaviour and smoking accounted, in part, for the increase seen in cervical cancer incidence in 35- to 39-y-old women from 1990 to 1999. At both low (10% in opportunistic immunisation) and high (90% in a national immunisation programme) coverage of the adolescent population, vaccinating women and men had little benefit over vaccinating women alone. We estimate that vaccinating 90% of young women before sexual debut has the potential to decrease HPV type-specific (e.g., type 16) cervical cancer incidence by 91%. If older women are more likely to have persistent infections and progress to cancer, then vaccination with a duration of protection of less than 15 y could result in an older susceptible cohort and no decrease in cancer incidence. While vaccination has the potential to significantly reduce type-specific cancer incidence, its combination with screening further improves cancer prevention.
Conclusions
HPV vaccination has the potential to significantly decrease HPV type-specific cervical cancer incidence. High vaccine coverage of women alone, sustained over many decades, with a long duration of vaccine-conferred protection, would have the greatest impact on type-specific cancer incidence. This level of coverage could be achieved through national coordinated programmes, with surveillance to detect cancers caused by nonvaccine oncogenic HPV types.
Using a mathematical model of transmission of HPV 16 infection and progression to cervical cancer, Ruanne Barnabas and colleagues show that HPV vaccination could significantly decrease HPV type-specific cervical cancer incidence.
doi:10.1371/journal.pmed.0030138
PMCID: PMC1434486  PMID: 16573364
7.  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.
doi:10.1016/j.ygyno.2009.04.035
PMCID: PMC2729751  PMID: 19464729
8.  Estimate of the global burden of cervical adenocarcinoma and potential impact of prophylactic human papillomavirus vaccination 
BMC Cancer  2013;13:553.
Background
Data on the current burden of adenocarcinoma (ADC) and histology-specific human papillomavirus (HPV) type distribution are relevant to predict the future impact of prophylactic HPV vaccines.
Methods
We estimate the proportion of ADC in invasive cervical cancer, the global number of cases of cervical ADC in 2015, the effect of cervical screening on ADC, the number of ADC cases attributable to high-risk HPV types -16, -18, -45, -31 and -33, and the potential impact of HPV vaccination using a variety of data sources including: GLOBOCAN 2008, Cancer Incidence in Five Continents (CI5) Volume IX, cervical screening data from the World Health Organization/Institut Català d'Oncologia Information Centre on HPV and cervical cancer, and published literature.
Results
ADC represents 9.4% of all ICC although its contribution varies greatly by country and region. The global crude incidence rate of cervical ADC in 2015 is estimated at 1.6 cases per 100,000 women, and the projected worldwide incidence of ADC in 2015 is 56,805 new cases. Current detection rates for HPV DNA in cervical ADC tend to range around 80–85%; the lower HPV detection rates in cervical ADC versus squamous cell carcinoma may be due to technical artefacts or to misdiagnosis of endometrial carcinoma as cervical ADC. Published data indicate that the five most common HPV types found in cervical ADC are HPV-16 (41.6%), -18 (38.7%), -45 (7.0%), -31 (2.2%) and -33 (2.1%), together comprising 92% of all HPV positive cases. Future projections using 2015 data, assuming 100% vaccine coverage and a true HPV causal relation of 100%, suggest that vaccines providing protection against HPV-16/18 may theoretically prevent 79% of new HPV-related ADC cases (44,702 cases annually) and vaccines additionally providing cross-protection against HPV-31/33/45 may prevent 89% of new HPV-related ADC cases (50,769 cases annually).
Conclusions
It is predicted that the currently available HPV vaccines will be highly effective in preventing HPV-related cervical ADC.
doi:10.1186/1471-2407-13-553
PMCID: PMC3871005  PMID: 24261839
Uterine cervical neoplasm; Adenocarcinoma; Papillomavirus infections; Human papillomavirus vaccines
9.  Human Papillomavirus Infection and Cervical Neoplasia among Migrant Women Living in Italy 
Human papillomavirus (HPV) infection is highly prevalent in women migrating from countries where cervical screening is not implemented. The variety of HPV genotypes, their prevalence and the association with cervical abnormalities has been investigated by several groups in women moving mainly from Eastern Europe, Africa, and Southern Asia to Italy. All studies are concordant on the elevated rate of HPV infection among immigrants, which is four times higher than that observed among age-matched Italian women. The HPV prevalence among short-term migrants and characterization of viral variants showed that the high prevalence of HPV reflects either individual lifestyle or high prevalence of HPV in the country of origin. The high burden of HPV infection correlates very well with the high incidence of cervical cancer in migrant women. In fact, during the years 2000–2004 the cervical cancer incidence in women from Central and Eastern Europe and living in Central Italy was 38.3 per 100,000, which is statistically significant higher than that of native Italian women (6 per 100,000). In this study, we pooled together the results of three independent studies originally designed to assess the distribution and the prevalence of HPV genotypes among 499 immigrant women living in Southern Italy. A total of 39 mucosal HPV genotypes were identified. The 12 genotypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) classified as carcinogenic to humans (group 1) accounted for >80% of all infections. HPV16 was the most common viral type in all groups with frequency rates ranging from 15.4% in Africa to 51.1% in Eastern and Southern European HPV-positive women. The high prevalence of oncogenic HPVs and cervical cancer risk among migrant women, together with the lower participation in screening programs, demands for an urgent implementation of preventive strategies to increase screening and vaccine coverage and viral monitoring of uncommon HPV genotypes potential spreading in settled population.
doi:10.3389/fonc.2014.00031
PMCID: PMC3929937  PMID: 24600587
human papillomaviruses; migrants; cervical cancer; Italy; cervical cancer screening
10.  Targeting Human Papillomavirus to Reduce the Burden of Cervical, Vulvar and Vaginal Cancer and Pre-Invasive Neoplasia: Establishing the Baseline for Surveillance 
PLoS ONE  2014;9(2):e88323.
Background
Infection with high-risk human papillomavirus (HPV) is causally related to cervical, vulvar and vaginal pre-invasive neoplasias and cancers. Highly effective vaccines against HPV types 16/18 have been available since 2006, and are currently used in many countries in combination with cervical cancer screening to control the burden of cervical cancer. We estimated the overall and age-specific incidence rate (IR) of cervical, vulvar and vaginal cancer and pre-invasive neoplasia in Denmark, Iceland, Norway and Sweden in 2004–2006, prior to the availability of HPV vaccines, in order to establish a baseline for surveillance. We also estimated the population attributable fraction to determine roughly the expected effect of HPV16/18 vaccination on the incidence of these diseases.
Methods
Information on incident cervical, vulvar and vaginal cancers and high-grade pre-invasive neoplasias was obtained from high-quality national population-based registries. A literature review was conducted to define the fraction of these lesions attributable to HPV16/18, i.e., those that could be prevented by HPV vaccination.
Results
Among the four countries, the age-standardised IR/105 of cervical, vaginal and vulvar cancer ranged from 8.4–13.8, 1.3–3.1 and 0.2–0.6, respectively. The risk for cervical cancer was highest in women aged 30–39, while vulvar and vaginal cancers were most common in women aged 70+. Age-standardised IR/105 of cervical, vulvar and vaginal pre-invasive neoplasia ranged between 138.8−183.2, 2.5−8.8 and 0.5−1.3, respectively. Women aged 20−29 had the highest risk for cervical pre-invasive neoplasia, while vulvar and vaginal pre-invasive neoplasia peaked in women aged 40−49 and 60−69, respectively. Over 50% of the observed 47,820 incident invasive and pre-invasive cancer cases in 2004−2006 can be attributed to HPV16/18.
Conclusion
In the four countries, vaccination against HPV 16/18 could prevent approximately 8500 cases of gynecological cancer and pre-cancer annually. Population-based cancer and vaccination registries are essential to assess the predicted public health effects of HPV vaccination.
doi:10.1371/journal.pone.0088323
PMCID: PMC3914976  PMID: 24505474
11.  US Geographic Distribution of Pre-Vaccine Era Cervical Cancer Screening, Incidence, Stage, and Mortality 
Background
Cervical cancer prevention programs are being reconfigured to incorporate human papillomavirus (HPV) testing and vaccination. To define priority areas for prevention efforts, we examined the geographic distribution of cervical cancer screening, incidence, stage, and mortality in the United States prior to the introduction of HPV-based prevention technologies.
Methods
County-level cervical cancer incidence data from 37 central registries were obtained from Surveillance, Epidemiology, and End Results (SEER) and North American Association of Central Cancer Registries (NAACCR) registries. A spatial- temporal model that accounted for demographic and behavioral attributes was used to generate a complete view of county-level incidence from 1995–2004, including counties with missing data. Distribution of stage at diagnosis was examined by registry. Counties with high mortality and infrequent screening were identified using vital statistics and newly available county level screening estimates.
Results
Compared to non-Hispanic whites and Asian and Pacific Islanders, incidence rates were higher among non-Hispanic black, American Indian and Alaska Native, and Hispanic women. Counties with infrequent screening often experienced elevated incidence and mortality rates and were located in states with suboptimal stage-at-diagnosis profiles. Affected areas included Appalachia, the southeastern Atlantic states, and the lower Mississippi Valley. Elevated death rates were experienced in central counties of large metropolitan areas.
Conclusions
Geographic and racial/ethnic variability were evident in cervical cancer incidence and mortality. Women living in areas with endemic poverty would benefit from access to HPV-based prevention technologies.
Impact
These findings provide a baseline for monitoring progress in cervical cancer control in the era of HPV-based prevention.
doi:10.1158/1055-9965.EPI-10-1183
PMCID: PMC3070049  PMID: 21266522
cervical cancer; geography; Human Papillomavirus (HPV); spatial-temporal modeling
12.  High-risk HPV infection after five years in a population-based cohort of Chilean women 
Background
The need to review cervical cancer prevention strategies has been triggered by the availability of new prevention tools linked to human papillomavirus (HPV): vaccines and screening tests. To consider these innovations, information on HPV type distribution and natural history is necessary. This is a five-year follow-up study of gynecological high-risk (HR) HPV infection among a Chilean population-based cohort of women.
Findings
A population-based random sample of 969 women from Santiago, Chile aged 17 years or older was enrolled in 2001 and revisited in 2006. At both visits they answered a survey on demographics and sexual history and provided a cervical sample for HPV DNA detection (GP5+/6+ primer-mediated PCR and Reverse line blot genotyping). Follow-up was completed by 576 (59.4%) women; 45 (4.6%) refused participation; most losses to follow-up were women who were unreachable, no longer eligible or had missing samples. HR-HPV prevalence increased by 43%. Incidence was highest in women < 20 years of age (19.4%) and lowest in women > 70 (0%); it was three times higher among women HR-HPV positive versus HPV negative at baseline (25.5% and 8.3%; OR 3.8, 95% CI 1.8-8.0). Type-specific persistence was 35.3%; it increased with age, from 0% in women < 30 years of age to 100% in women > 70. An enrollment Pap result ASCUS or worse was the only risk factor for being HR-HPV positive at both visits.
Conclusions
HR-HPV prevalence increased in the study population. All HR-HPV infections in women < 30 years old cleared, supporting the current recommendation of HR-HPV screening for women > 30 years.
doi:10.1186/1750-9378-6-21
PMCID: PMC3269983  PMID: 22087645
13.  HPV infection among rural American Indian women and urban white women in South Dakota: an HPV prevalence study 
BMC Infectious Diseases  2011;11:252.
Background
High-risk strains of human papillomavirus (HPV) cause cervical cancer. American Indian (AI) women in the Northern Plains of the U.S. have significantly higher incidence and mortality rates for cervical cancer than White women in the same geographical area. We compared HPV prevalence, patterns of HPV types, and infection with multiple HPV types in AI and White women living in South Dakota, U.S.
Methods
We analyzed the HPV status of cervical samples collected in 2006-2008 from women aged 18-65 years who attended two rural AI reservation clinics (n = 235) or an urban clinic in the same area serving mostly White women (n = 246). Data collection occurred before HPV vaccination was available to study participants. HPV DNA was amplified by using the L1 consensus primer system and an HPV Linear Array detection assay to identify HPV types. We used chi-square tests to compare HPV variables, with percentages standardized by age and lifetime number of sexual partners.
Results
Compared to White women, AI women were younger (p = 0.01) and reported more sexual partners (p < 0.001). A lower percentage of AI women tested negative for HPV infection compared to Whites (58% [95% CI = 51-65] vs. 77% [95% CI = 71-82]; p < 0.001), and a higher percentage of AI women were infected by oncogenic types (30% [95% CI = 25-36] vs. 16% [95% CI = 11-21]; p = 0.001). Infections among AI women showed a wider variety and very different pattern of HPV types, including a higher prevalence of mixed HPV infections (19% [95% CI = 26-38] vs. 7% [95% CI = 4-11]; p = 0.001). AI women had a higher percentage of HPV infections that were not preventable by HPV vaccination (32% [95% CI = 26-38] vs. 15% [95% CI = 11-21]; p < 0.001).
Conclusions
A higher HPV burden and a different HPV genotyping profile may contribute to the high rate of cervical cancer among AI women.
doi:10.1186/1471-2334-11-252
PMCID: PMC3190376  PMID: 21943050
cervical cancer; Pap screening; HPV genotypes; American Indians; health disparities; human papillomavirus; types
14.  HPV infection in women with and without cervical cancer in Conakry, Guinea 
British Journal of Cancer  2009;101(1):202-208.
Background:
Cervical cancer incidence in western Africa is among the highest in the world.
Methods:
To investigate human papillomavirus (HPV) infection in Guinea, we obtained cervical specimens from 831 women aged 18–64 years from the general population of the capital Conakry and from 77 locally diagnosed invasive cervical cancers (ICC). Human papillomavirus was detected using a GP5+/6+ PCR-based assay.
Results:
Among the general population, the prevalence of cervical abnormalities was 2.6% by visual inspection and 9.5% by liquid-based cytology. Fourteen of 15 high-grade squamous intraepithelial lesions were visual inspection-negative. Human papillomavirus prevalence was 50.8% (32.1% for high-risk types) and relatively constant across all age groups. Being single or reporting ⩾3 sexual partners was significantly associated with HPV positivity. HPV16 was the most common type, both among the general population (7.3%) and, notably in ICC (48.6%). HPV45 (18.6%) and HPV18 (14.3%), the next most common types in ICC, were also more common in ICC than in HPV-positive women with normal cytology from the general population.
Conclusion:
The heavy burden of HPV infection and severe cervical lesions in Guinean women calls for new effective interventions. Sixty-three per cent of cervical cancers are theoretically preventable by HPV16/18 vaccines in Guinea; perhaps more if some cross-protection exists with HPV45.
doi:10.1038/sj.bjc.6605140
PMCID: PMC2713688  PMID: 19536089
cervical cancer; human papillomavirus; prevalence; Guinea; Africa
15.  The Impact of HPV Female Immunization in Italy: Model Based Predictions 
PLoS ONE  2014;9(3):e91698.
The Human Papillomavirus (HPV) is a sexually transmitted virus that causes cervical cancer. Since 2008 a vaccination program targeting 12-year-old girls has been initiated in Italy, backing up the cervical screening program already active since 1996. We propose a mathematical model of HPV transmission dynamics with the aim of evaluating the impact of these prevention strategies. The model considers heterosexual transmission of HPV types 16 and 18, structured by sex, age and sexual activity level, where transition to sexual activity is explicitly modeled from recent survey data. The epidemiological structure is a hybrid SIS/SIR, where a fraction of individuals recovering from infection develops permanent immunity against reinfection. Infections may progress to cervical lesions and cancer and heal spontaneously or upon treatment. Women undergoing hysterectomy (either after treatment of HPV lesions or by other causes) also transmit HPV infection. The model fits well both the age-specific prevalence of HPV infections and the incidence of cervical cancers in Italy, and accurately reproduces the decreasing trend in cancer incidence due to the introduction of the screening program. The model predicts that if the screening coverage is maintained at current levels, even in the absence of vaccination, such trend will continue in the next few decades, eventually plateauing at 25% below the current level. The additional initiation of routine vaccination targeting 12-year-old girls will further reduce cervical cancer incidence by two thirds at equilibrium, under realistic assumptions of 70% coverage and a duration of protective immunity of 50 years. If catch-up immunization of 25-year-old women at first cervical screening is also introduced, about 3,000 cervical cancer cases overall can be averted, corresponding to 9.6% of all cases expected in the scenario without catch-up. We conclude that HPV vaccination in addition to cervical screening will significantly reduce the burden of cervical cancer in Italy.
doi:10.1371/journal.pone.0091698
PMCID: PMC3950270  PMID: 24618824
16.  HPV vaccination programs have not been shown to be cost-effective in countries with comprehensive Pap screening and surgery 
Pap screening combined with loop electrosurgical excision procedures (LEEP) is almost 100% effective in preventing cervical cancer mortality yet many countries with these procedures have now implemented broad HPV vaccination programs. HPV vaccines have not been demonstrated to be more effective or safer than Pap screening in the prevention of cervical cancer and Pap screening will still be required even in vaccinated women. The HPV vaccine costs Au$450 per person and it does not protect against ~30% of cancer. This investigation analyses the cost-effectiveness of using the HPV vaccine in countries where Pap screening and surgical procedures have already reduced cervical cancer mortality to very low rates. Cost-effectiveness of vaccination programs is being determined by mathematical models which are founded on many assumptions. It is necessary to examine the rigor of these assumptions to be certain of the health benefits that are predicted. In 2002 scientists concluded that HPV 16 and 18 were the central and independent cause of most cervical cancer. This conclusion was based on molecular technology. If HPV 16 and 18 infections are the central and independent cause of most cervical cancer then the incidence of HPV 16 and 18 should vary with the incidence and mortality of cervical cancer worldwide. This correlation does not exist. It is also observed that the majority of HPV 16/18 infections do not lead to cervical cancer. This indicates that other etiological or ‘risk’ factors are necessary for persistent HPV infection to progress to cancer. The benefits of HPV vaccines have been determined by using pre-cancerous lesions in young women as a surrogate for cervical cancer. This surrogate is found to be inadequate as an end-point for cervical cancer. Clinical trials have only provided speculative benefits for the efficacy of HPV vaccines against cancer and the long-term risks of the vaccine have not been established. Pap screening will still be required in vaccinated women hence HPV vaccination programs are not cost-effective, and may do more harm than good, in countries where regular Pap screening and surgery has already reduced the burden of this disease.
doi:10.1186/1750-9378-8-21
PMCID: PMC3698073  PMID: 23758803
Cervical cancer; Human papillomavirus virus (HPV); Genotype; Infectious diseases; Gardasil®; Public health policy; Vaccination programs
17.  Prevalence of HPV infection and other risk factors in a Fijian population 
Background
Cancer is among the leading contributors to morbidity and mortality in the Pacific, but the magnitude of the problem and the potential for prevention have not been comprehensively studied. Over the past decade, cervical cancer has been the most common cancer among women in Fiji with an age standardised cervical cancer incidence rate of 51 per 100,000. This rate is among the highest in the South Pacific region and in the world. This high cervical cancer incidence rate is likely linked to the low cervical screening rate, but it points also to the possibility of a high burden of human papillomavirus (HPV) infection.
Methods
We conducted a population-based survey in Fiji to provide information on human papillomavirus (HPV) prevalence, and the distribution of individual HPV types in a Fijian health-sub-district. We included 1,261 women aged between 16 and 64 years. A general primer GP5+/6+ mediatedpolymerase chain reaction (PCR) assay was used for HPV testing of 44 HPV types.
Results
The crude HPV prevalence in 1,244 women with an adequate HPV sample was 24.0% (95% confidence interval (CI), 21.7-26.4%) and the corresponding age standardised prevalence was 25.5% (95% CI, 23.1-28.1%). The prevalence of high-risk HPV types was 13.6% (95% CI, 11.8-15.6%). Among 1,192 women with adequate cytological results, 13 (1.1%) showed cervical abnormalities, the majority of which were high-grade intraepithelial lesions or worse. HPV prevalence declined from 35.8% in women aged <25 years to 18.6% in those aged 55–64 years of age. After adjustment, the only variables significantly associated with HPV-positivity were age (ranging from odds ratio (OR) 0.57 (95% CI, 0.36-0.89) for 25–34 year-old-women to OR 0.43 (95% CI, 0.20-0.89) for 55–64 year-old-women) and ‘husband’s extramarital sexual relationships’ (OR 1.69; 95% CI, 1.17-2.34).
Conclusion
These findings on HPV provide key information for future policy decisions on the most appropriate methods of cervical cancer prevention in Fiji and in the Pacific region.
doi:10.1186/1750-9378-9-14
PMCID: PMC4040509  PMID: 24891876
Human papillomavirus (HPV); HPV genotypes; Cervical neoplasia; Cervical screening; Fiji
18.  Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels 
Background
The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), the National Cancer Institute (NCI), and the North American Association of Central Cancer Registries (NAACCR) collaborate annually to provide updates on cancer incidence and death rates and trends in these outcomes for the United States. This year’s report includes incidence trends for human papillomavirus (HPV)–associated cancers and HPV vaccination (recommended for adolescents aged 11–12 years).
Methods
Data on cancer incidence were obtained from the CDC, NCI, and NAACCR, and data on mortality were obtained from the CDC. Long- (1975/1992–2009) and short-term (2000–2009) trends in age-standardized incidence and death rates for all cancers combined and for the leading cancers among men and among women were examined by joinpoint analysis. Prevalence of HPV vaccination coverage during 2008 and 2010 and of Papanicolaou (Pap) testing during 2010 were obtained from national surveys.
Results
Death rates continued to decline for all cancers combined for men and women of all major racial and ethnic groups and for most major cancer sites; rates for both sexes combined decreased by 1.5% per year from 2000 to 2009. Overall incidence rates decreased in men but stabilized in women. Incidence rates increased for two HPV-associated cancers (oropharynx, anus) and some cancers not associated with HPV (eg, liver, kidney, thyroid). Nationally, 32.0% (95% confidence interval [CI] = 30.3% to 33.6%) of girls aged 13 to 17 years in 2010 had received three doses of the HPV vaccine, and coverage was statistically significantly lower among the uninsured (14.1%, 95% CI = 9.4% to 20.6%) and in some Southern states (eg, 20.0% in Alabama [95% CI = 13.9% to 27.9%] and Mississippi [95% CI = 13.8% to 28.2%]), where cervical cancer rates were highest and recent Pap testing prevalence was the lowest.
Conclusions
The overall trends in declining cancer death rates continue. However, increases in incidence rates for some HPV-associated cancers and low vaccination coverage among adolescents underscore the need for additional prevention efforts for HPV-associated cancers, including efforts to increase vaccination coverage.
doi:10.1093/jnci/djs491
PMCID: PMC3565628  PMID: 23297039
19.  Epidemiology of HPV genotypes in Uganda and the role of the current preventive vaccines: A systematic review 
Background
Limited data are available on the distribution of human papillomavirus (HPV) genotypes in the general population and in invasive cervical cancer (ICC) in Uganda. Yet, with the advent of preventive HPV vaccines that target HPV 16 and 18 responsible for causing about 70% of ICC cases in the world, such information is crucial to predict how vaccination and HPV-based screening will influence prevention of ICC.
Methods
To review the distribution of HPV infection and prevalent genotypes, electronic databases (e.g. PubMed/MEDLINE and HINARI) were searched for peer reviewed English articles on HPV infection up to November 30, 2010. Eligible studies were selected according to the following criteria: DNA-confirmed cervical or male genital HPV prevalence and genotypes, HPV incidence estimates and HPV seroprevalence among participants.
Results
Twenty studies were included in the review. Among HIV negative adult women, the prevalence of HR-HPV infections ranged from 10.2% -40.0% compared to 37.0% -100.0% among HIV positive women. Among HIV positive young women aged below 25 years, the prevalence of HR-HPV genotypes ranged from 41.6% -75.0% compared to 23.7% -67.1% among HIV negative women. Multiple infections with non vaccine HR-HPV genotypes were frequent in both HIV positive and HIV negative women. The main risk factors for prevalent HPV infections were age, lifetime number of sexual partners and HIV infection. Incident infections with HR-HPV genotypes were more frequent among adult HIV positive than HIV negative women estimated at 17.3 and 7.0 per 100 person-years, respectively. Similarly, incident HR-HPV among young women aged below 25 years were more frequent among HIV positive (40.0 per 100 person-years) than HIV negative women (20.3 per 100 person-years) women. The main risk factor for incident infection was HIV infection. HPV 16 and 18 were the most common genotypes in ICC with HPV 16/18 contributing up to 73.5% of cases with single infections.
Among uncircumcised adult HIV positive males, HR-HPV prevalence ranged from 55.3% -76.6% compared to 38.6% -47.6% in HIV negative males. Incident and multiple HR-HPV infections were frequent in HIV positive males. Being uncircumcised was the main risk factor for both prevalent and incident HPV infection.
Conclusion
Infections with HR-HPV genotypes were very common particularly among HIV positive individuals and young women irrespective of HIV status. Given the high prevalence of HIV infection, HPV-associated conditions represent a major public health burden in Uganda. However, although the most common HPV genotypes in ICC cases in Uganda were those targeted by current preventive vaccines, there were a large number of individuals infected with other HR-HPV genotypes. Technology allowing, these other HR-HPV types should be considered in the development of the next generation of vaccines.
doi:10.1186/1750-9378-6-11
PMCID: PMC3163594  PMID: 21749691
20.  Prevalence and distribution of high-risk human papilloma virus (HPV) types in invasive squamous cell carcinoma of the cervix and in normal women in Andhra Pradesh, India 
Background
Despite the high incidence of cervical cancer reported from India, large scale population based studies on the HPV prevalence and genotype distribution are very few from this region. In view of the clinical trials for HPV vaccine taking place in India, it is of utmost importance to understand the prevalence of HPV genotypes in various geographical regions of India. We investigated the genotype distribution of high-risk HPV types in squamous cell carcinomas and the prevalence of high-risk HPV in cervicovaginal samples in the southern state of Andhra Pradesh (AP), India.
Methods
HPV genotyping was done in cervical cancer specimens (n = 41) obtained from women attending a regional cancer hospital in Hyderabad. HPV-DNA testing was also done in cervicovaginal samples (n = 185) collected from women enrolled in the cervical cancer screening pilot study conducted in the rural community, of Medchal Mandal, twenty kilometers away from Hyderabad.
Results
High-risk HPV types were found in 87.8% (n = 36/41) of the squamous cell carcinomas using a PCR-based line blot assay. Among the HPV positive cancers, the overall type distribution of the major high-risk HPV types was as follows: HPV 16 (66.7%), HPV 18 (19.4%), HPV 33 (5.6%), HPV 35 (5.6%), HPV 45 (5.6%), HPV 52 (2.8%), HPV 58(2.8%), HPV 59(2.8%) and HPV 73 (2.8%). Women participating in the community screening programme provided both a self-collected vaginal swab and a clinician-collected cervical swab for HPV DNA testing. Primary screening for high risk HPV was performed using the Digene Hybrid Capture 2 (hc2) assay. All hc2 positive samples by any one method of collection were further analyzed using the Roche PCR-based line blot for genotype determination. The prevalence of high risk HPV infection in this community-based screening population was 10.3% (19/185) using the clinician-collected and 7.0% (13/185) using the self-collected samples. The overall agreement between self-collected and clinician-collected samples was 92%; however among HPV-positive specimens, the HPV agreement was only moderate (39.1%). The most frequently detected HPV types in the Medchal community are HPV 52 and 16.
Conclusion
Our results suggest that the HPV type distribution in both cervical cancer tissues and in a general screening population from Andhra Pradesh is similar to that reported in India and other parts of the world. We also conclude that an effective vaccine targeting HPV 16 will reduce the cervical cancer burden in AP.
doi:10.1186/1471-2334-5-116
PMCID: PMC1345691  PMID: 16371167
21.  HPV Infection in Cervical and Other Cancers in Saudi Arabia: Implication for Prevention and Vaccination 
Human papillomavirus (HPV) is closely associated with cervical cancer that the incidence of this tumor is regarded as a surrogate marker for HPV infection in countries lacking epidemiological studies. HPV is also implicated in subsets of anogenital and oropharyngeal cancers. Although cervical cancer is the third most common cancer in women worldwide, its reported incidence is low in Saudi Arabia, ranking number 12 between all cancers in females and accounts only for 2.4% of all new cases, despite the lack of national screening programs. However, the limited available studies from Saudi Arabia indicate that HPV prevalence and genotypes’ distribution in invasive cervical cancer show similar pattern as in the world. Cytology screening (Pap smear) and HPV vaccinations are the two preventive measures against cervical cancer. The two available vaccines are effective against the two most common HPV genotypes (HPV-16 and -18). Since 92% of cervical tumors in the Kingdom are infected with HPV of which 78% are HPV-16 and -18 genotypes, vaccination is expected to protect against more than two-third of cervical cancers in Saudi Arabia. Nevertheless, due to its low incidence (2.1/100,000 women), a proper cost-effectiveness analysis is required to justify the implementation of a costly vaccine bearing in mind that HPV could potentially be associated with about 3% of all cancers. However, further studies are needed to ascertain the real prevalence of HPV at the population level at large, its association with various types of cancers, and also the impact of local tradition and emerging behavioral trends that could affect HPV transmission and consequently the effectiveness of applying national vaccination program.
doi:10.3389/fonc.2014.00065
PMCID: PMC3978341  PMID: 24744990
human papillomavirus; HPV genotype; HPV-16; cervical cancer; Saudi Arabia
22.  Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting  
PLoS Medicine  2008;5(1):e19.
Background
Important support functions, including promotion of tumor growth, angiogenesis, and invasion, have been attributed to the different cell types populating the tumor stroma, i.e., endothelial cells, cancer-associated fibroblasts, pericytes, and infiltrating inflammatory cells. Fibroblasts have long been recognized inside carcinomas and are increasingly implicated as functional participants. The stroma is prominent in cervical carcinoma, and distinguishable from nonmalignant tissue, suggestive of altered (tumor-promoting) functions. We postulated that pharmacological targeting of putative stromal support functions, in particular those of cancer-associated fibroblasts, could have therapeutic utility, and sought to assess the possibility in a pre-clinical setting.
Methods and Findings
We used a genetically engineered mouse model of cervical carcinogenesis to investigate platelet-derived growth factor (PDGF) receptor signaling in cancer-associated fibroblasts and pericytes. Pharmacological blockade of PDGF receptor signaling with the clinically approved kinase inhibitor imatinib slowed progression of premalignant cervical lesions in this model, and impaired the growth of preexisting invasive carcinomas. Inhibition of stromal PDGF receptors reduced proliferation and angiogenesis in cervical lesions through a mechanism involving suppression of expression of the angiogenic factor fibroblast growth factor 2 (FGF-2) and the epithelial cell growth factor FGF-7 by cancer-associated fibroblasts. Treatment with neutralizing antibodies to the PDGF receptors recapitulated these effects. A ligand trap for the FGFs impaired the angiogenic phenotype similarly to imatinib. Thus PDGF ligands expressed by cancerous epithelia evidently stimulate PDGFR-expressing stroma to up-regulate FGFs, promoting angiogenesis and epithelial proliferation, elements of a multicellular signaling network that elicits functional capabilities in the tumor microenvironment.
Conclusions
This study illustrates the therapeutic benefits in a mouse model of human cervical cancer of mechanism-based targeting of the stroma, in particular cancer-associated fibroblasts. Drugs aimed at stromal fibroblast signals and effector functions may prove complementary to conventional treatments targeting the overt cancer cells for a range of solid tumors, possibly including cervical carcinoma, the second most common lethal malignancy in women worldwide, for which management remains poor.
Douglas Hanahan and colleagues investigate a paracrine regulatory circuit centered upon PDGF receptor signaling in cancer-associated fibroblasts and pericytes of a mouse model of cervical carcinogenesis.
Editors' Summary
Background.
Cancers—disorganized, life-threatening masses of cells—develop when cells acquire genetic changes that allow them to divide uncontrollably and to move into (invade) other tissues. Interactions with ostensibly normal cells in the tissue surrounding the tumor (the stroma) support the growth of these abnormal cells. The stroma contains endothelial cells and pericytes (which line the inside and coat the outside, respectively, of blood vessels), cancer-associated fibroblasts, and some immune system cells. Together, these cells support angiogenesis (the formation of a blood supply, which feeds the tumor), produce factors that stimulate tumor cell growth, and facilitate tumor cell invasion into surrounding tissues. One type of tumor with a prominent stromal compartment is cervical cancer. Precancerous changes in the epithelial cells lining the cervix (the structure that connects the womb to the vagina) are usually triggered by infection with human papillomavirus. Some of these early lesions, which are known as cervical intraepithelial neoplasias (CINs), develop into invasive cervical cancer, which is treated by surgery followed by chemotherapy or radiotherapy.
Why Was This Study Done?
The outlook for women whose cervical cancer is detected early is good but only 15%–30% of women whose cancer has spread out of the cervix survive for five years. If, as researchers believe, the stromal compartment is important in the development and growth (neoplastic progression) of cervical cancer, it might be possible to help these women by specifically targeting the cells in the stroma. However, relatively little is known about the role that the stroma plays in the neoplastic progression of cervical cancer or how it is regulated other than that a protein called platelet-derived growth factor (PDGF), which is made by the tumor cells, might be involved in its formation. In this study, the researchers have used a mouse model of cervical cancer (HPV/E2 mice) to investigate PDGF signaling in the tumor stroma. HPV/E2 mice develop CINs before they are three months old; by five months of age, 90% of them have invasive cervical cancer.
What Did the Researchers Do and Find?
The researchers report that PDGF was expressed in the cervixes of normal and HPV/E2 mice, mainly by epithelial cells, and that PDGF receptors (cell-surface proteins that bind PDGF and send a message into the cell that alters the expression of other proteins) were expressed on cells within normal stroma and in fibroblasts and pericytes in the stroma surrounding CINs and tumors (but not on the cancer cells). The expression of PDGF and its receptors increased slightly during tumor progression. Treatment of the HPV/E2 mice with imatinib, an inhibitor of PDGF signaling, slowed the progression of precancerous lesions, impaired the growth of invasive cancers, and reduced the number of blood vessels formed in the tumors and the coverage of these vessels with pericytes. Other experiments indicate that imatinib had these effects because its inhibition of stromal PDGF receptors suppressed the expression of FGF-7 (a factor that encourages epithelial cell division) and FGF-2 (a proangiogenic factor) by cancer-associated fibroblasts. Finally, as in HPV/E2 mice, FGF-2 and PDGF receptors were expressed in the stroma of human cervical cancers whereas PDGF was expressed in the cancer cells.
What Do These Findings Mean?
These findings suggest that PDGF receptor signaling in the stromal cells associated with cervical tumors in mice has a functional role during tumor progression. More specifically, they suggest that PDGF released by the tumor cells triggers PDGF signaling in the stromal cells, which increases the expression of factors that both directly and indirectly stimulate the growth of the tumor cells. Confirmation of this scheme will require additional experiments in mouse models of cervical cancer and the careful examination of more human material. Importantly, although approaches that work in mice do not always work in people, the current findings suggest that targeted therapeutics that prevent the stromal support of tumor growth (such as inhibitors of PDGF receptor signaling) might provide a complementary approach to conventional treatments that target the cancer cells themselves.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050019.
The US National Cancer Institute provides information on all aspects of cancer, including information about cervical cancer (in English and Spanish)
The UK charity Cancerbackup also provides information on all aspects of cancer, including information on cervical cancer and on imatinib
Wikipedia has pages on platelet-derived growth factor, on PDGF receptors, and on imatinib (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050019
PMCID: PMC2214790  PMID: 18232728
23.  Human papillomavirus (HPV) vaccination for the prevention of HPV 16/18 induced cervical cancer and its precursors 
Introduction
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.
Objectives
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?
Methods
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.
Results
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.
Discussion
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.
Conclusion
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.
doi:10.3205/hta000066
PMCID: PMC3011291  PMID: 21289891
24.  Human papilloma virus vaccines 
Human papilloma viruses (HPVs) infect the skin and mucosal epithelium of both men and women. There are about 100 types of HPVs, which are differentiated by the genetic sequence of the outer capsid protein L1. More than 30 types of HPVs are sexually transmitted. Most cases of carcinoma of the cervix are caused by HPV. Cervical cancer is one of the most common forms of cancer in women is the second biggest cause of female cancer mortality worldwide. The worldwide incidence of cervical carcinoma is 529,000 per year, and mortality is 275,000, of which an estimated 88% of deaths occur in developing countries. At least 20 million people worldwide are already chronically infected. Over 80% of cases of cervical carcinoma occurs in developing countries, with 25% estimated to occur in India. At least 50% of sexually active men and women encounter genital HPV at some time in their lives. Cervical cancer is ranked as the most frequent cancer in women in India. India has a population of approximately 366 million women above 15 y of age, who are at risk of developing cervical cancer. The current estimates indicate approximately 132,000 new cases diagnosed and 74,000 deaths annually in India, accounting for nearly one-third of the global cervical cancer deaths. HPV can be prevented by vaccination. Two types of HPV vaccines are available, as Gardasil and Cervarix, both of which are highly effective at preventing HPV infection. HPV vaccine is administered in a three-dose series administered by intramuscular injection, either in the deltoid muscle or in the antero-lateral thigh. The second and third doses should be administered 2 and 6 mo after the first dose respectively. The minimum interval between the first and second doses should be 4 weeks, between the second and third dose should be 12 weeks.
doi:10.4161/hv.22063
PMCID: PMC3667952  PMID: 23108360
HPV; cervical carcinoma; wart; death; vaccines
25.  Epidemiology of cervical cancer in Colombia 
Colombia Médica : CM  null;43(4):298-304.
Worldwide, cervical cancer is the third most common cancer in women, and the first or second most common in developing countries. Cervical cancer remains in Colombia the first cause of cancer mortality and the second cause of cancer incidence among women, despite the existence of screening programs during the last 3 decades. Bucaramanga, Manizales and Cali reported rates around 20 per 100,000and Pasto 27 per 100,000. The Cali cancer registry has reported a progressive decrease in the age standardized incidence and mortality rates of cervical cancer over the past 40 years. Reasons for the decline in incidence and mortality of cervical cancer are multiple and probably include: improvement in socio-economic conditions, decrease in parity rates and some effect of screening programs.
Human papilloma Virus is the main cause of cervical cancer, HPV natural history studies have now revealed that HPVs are the commonest of the sexually transmitted infections in most populations. Most HPV exposures result in spontaneous clearance without clinical manifestations and only a small fraction of the infected persons, known as chronic or persistent carriers, will retain the virus and progress to precancerous and cancer. HPV 16 and 18 account for 70% of cervical cancer and the 8 most common types. (HPV 16, 18, 45, 33, 31, 52, 58 and 35) account for about 90% of cervical cancer. Case-control studies also allowed the identification of the following cofactors that acting together with HPV increase the risk of progression from HPV persistent infection to cervical cancer: tobacco, high parity, long term use of oral contraceptives and past infections with herpes simplex type 2 and Chlamydia trachomatis. The demonstration that infection with certain types of human papillomavirus (HPV) is not only the main cause but also a necessary cause of cervical cancer has led to great advances in the prevention of this disease on two fronts: (i) Primary prevention by the use of prophylactic HPV vaccines; and (ii) secondary prevention by increasing the accuracy of cervical cancer screening.
PMCID: PMC4001966  PMID: 24893303
Cervix uteri cancer; HPV; HPV vaccines; cancer epidemiology; Cali; Colombia

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