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1.  Rationale and design of a multicenter prospective cohort study for the eVALuation and monitoring of HPV infections and relATEd cervical diseases in high-risk women (VALHIDATE study) 
BMC Cancer  2012;12:204.
Pap screening, an effective method for cervical cancer prevention, is now supported by molecular human papillomavirus (HPV) testing. Recently commercialised preventive vaccines also provide new tools for the primary prevention of cervical cancer. To determine appropriate prevention strategies, the Health General Direction, Lombardy Region, funded a project that aims to characterize and monitor HPV infections and related cervical diseases in high-risk women.
VALHIDATE is a 5-year multicentre open prospective cohort study. It will recruit 7000 consenting women aged 13–65 years to provide information about the local biomolecular epidemiology of HPV infection and cervical diseases in high-risk women recruited from nine clinical centres and one faith-based organisation. The study will estimate the overall and type-specific prevalence of HPV infection and cervical abnormalities. It also aims to compare standard Pap screening with biomolecular screening, and to assist in the design of targeted regional prevention programs directed specifically at high-risk groups. Three groups of high-risk women: 1000 HIV-infected women (aged 26–65 years), 1000 recent migrant women (aged 26–65 years) and 3000 young women (aged 13–26 years) and 1 control group: 2000 women (aged 26–45 years) attending a spontaneous screening program, will be recruited. Sample sizes will be revised after the first year. Adult participants will undergo conventional cervical cytology, HPV DNA screening and genotyping. Paediatric participants will undergo HPV DNA testing and genotyping of urine samples. HPV DNA, cytological abnormalities and HPV types will be analysed according to demographic, epidemiological, behavioural, and clinical data collected in an electronic case report form. Overall and stratified prevalences will be estimated to analyse the associations between HPV infection and selected characteristics. Logistic regression models will be used to estimate crude and adjusted odds ratios. Cox proportional hazard models will be used to estimate hazard ratios over time and between groups.
Discussion/main expected results
This study will provide substantial insight into HPV infections and related cervical diseases in high-risk groups and will help determine appropriate regional cervical cancer prevention strategies.
PMCID: PMC3512493  PMID: 22646512
Cervical cancer; Prevention; HPV; Epidemiology; Cytology screening; Molecular screening
2.  Human Papillomavirus Testing in the Prevention of Cervical Cancer 
Strong evidence now supports the adoption of cervical cancer prevention strategies that explicitly focus on persistent infection with the causal agent, human papillomavirus (HPV). To inform an evidence-based transition to a new public health approach for cervical cancer screening, we summarize the natural history and cervical carcinogenicity of HPV and discuss the promise and uncertainties of currently available screening methods. New HPV infections acquired at any age are virtually always benign, but persistent infections with one of approximately 12 carcinogenic HPV types explain virtually all cases of cervical cancer. In the absence of an overtly persistent HPV infection, the risk of cervical cancer is extremely low. Thus, HPV test results predict the risk of cervical cancer and its precursors (cervical intraepithelial neoplasia grade 3) better and longer than cytological or colposcopic abnormalities, which are signs of HPV infection. The logical and inevitable move to HPV-based cervical cancer prevention strategies will require longer screening intervals that will disrupt current gynecologic and cytology laboratory practices built on frequent screening. A major challenge will be implementing programs that do not overtreat HPV-positive women who do not have obvious long-term persistence of HPV or treatable lesions at the time of initial evaluation. The greatest potential for reduction in cervical cancer rates from HPV screening is in low-resource regions that can implement infrequent rounds of low-cost HPV testing and treatment.
PMCID: PMC3046952  PMID: 21282563
3.  Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland 
British Journal of Cancer  2007;96(3):514-518.
Phase III trials have demonstrated the efficacy of human papillomavirus (HPV) vaccines in preventing transient and persistent high-risk (hr) HPV infection and precancerous lesions. A mathematical model of HPV type 16 infection and progression to cervical cancer, parameterised to represent the infection in Finland, was used to explore the optimal age at vaccination and pattern of vaccine introduction. In the long term, the annual proportion of cervical cancer cases prevented is much higher when early adolescents are targeted. Vaccinating against hr HPV generates greater long-term benefits if vaccine is delivered before the age at first sexual intercourse. However, vaccinating 12 year olds delays the predicted decrease in cervical cancer, compared to vaccinating older adolescents or young adults. Vaccinating males as well as females has more impact on the proportion of cases prevented when vaccinating at younger ages. Implementing catch-up vaccination at the start of a vaccination programme would increase the speed with which a decrease in HPV and cervical cancer incidence is observed.
PMCID: PMC2360033  PMID: 17245341
HPV; vaccination; modelling
4.  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
5.  Review of Gardasil 
Journal of vaccines & vaccination  2010;1(107):1000107.
Human papillomavirus (HPV) is necessary for the development of cervical cancer. Cervical cancer is the second most common cancer in women worldwide but 80% occurs in developing countries, not countries with Pap screening programs. Pap screening programs in industrialized countries have reduced the incidence of cervical cancer to 4–8/100,000 women. HPV vaccines may be a promising strategy for cervical cancer in women without access to screening programs. In industrialized countries, the benefit of HPV vaccines focuses on individual abnormal Pap test reduction not cancer prevention.
The focus of this review is to cover the side effects of Gardasil in perspective with the limited population benefit cervical cancer reduction in countries with organized Pap screening programs. In addition, information about Gardasil benefits, risks and unknowns for individual patient decision making for vaccination is presented.
Gardasil offers protection against CIN 2+ lesions caused by HPV 16/18 and against genital warts caused by HPV 6/11 for at least 5 years. Combining Gardasil with repeated cytology screenings may reduce the proportion of abnormal cytology screens and hence reduce the associated morbidity with the subsequent colposcopies and excisional procedures.
PMCID: PMC3690661  PMID: 23805398
Adverse effects; Cervical cancer; Duration of efficacy; HPV vaccine immunology; Gardasil
6.  Knowledge of HPV Among United States Hispanic Women: Opportunities and Challenges for Cancer Prevention 
Journal of health communication  2010;15(0 3):10.1080/10810730.2010.522695.
In the United States, Hispanic women contribute disproportionately to cervical cancer incidence and mortality. This disparity, which primarily reflects lack of access to, and underutilization of, routine Pap smear screening may improve with increased availability of vaccines to prevent Human Papillomavirus (HPV) infection, the principal cause of cervical cancer. However, limited research has explored known determinants of HPV vaccine acceptability among Hispanic women. The current study examines two such determinants, HPV awareness and knowledge, using data from the 2007 Health Interview National Trends Survey (HINTS) and a cross-section of callers to the National Cancer Institute’s (NCI) Cancer Information Service (CIS). Study data indicate that HPV awareness was high in both samples (69.5% and 63.8% had heard of the virus) but that knowledge of the virus and its association with cervical cancer varied between the two groups of women. The CIS sample, which was more impoverished and less acculturated than their HINTS counterparts, were less able to correctly identify that HPV causes cervical cancer (67.1% vs. 78.7%) and that it is a prevalent sexually transmitted infection (STI; 66.8% vs. 70.4%). Such findings imply that future research may benefit from disaggregating data collected with Hispanics to reflect important heterogeneity in this population subgroup’s ancestries, levels of income, educational attainment, and acculturation. Failing to do so may preclude opportunity to understand, as well as to attenuate, cancer disparity.
PMCID: PMC3858859  PMID: 21154081
7.  Human papillomavirus and vaccination: knowledge, attitudes, and behavioural intention in adolescents and young women in Italy 
British Journal of Cancer  2008;99(2):225-229.
This study assesses knowledge, attitudes, and behavioural intention towards human papillomavirus (HPV) infection and vaccination in a random sample of 1348 adolescents and young women aged 14–24 years in Italy. A self-administered anonymous questionnaire covered demographics; knowledge about HPV infection, cervical cancer, and HPV vaccine; the perceived risk for contracting HPV infection and/or for developing cervical cancer, the perceived benefits of a vaccination to prevent cervical cancer, and willingness to receive an HPV vaccine. Only 23.3% have heard that HPV is an infection of the genital mucosa and about cervical cancer. Those older, with at least one parent who is a health care professional, with personal, familiar, or friendly history of cervical cancer, and having underwent a health checkup in the last year with information about HPV vaccination were significantly more knowledgeable. Risk perception scores (range: 1–10) of contracting HPV infection and of developing cervical cancer were 5.8 and 6.5. Older age, not having a parent who is a health care professional, having had a personal, familiar, or friendly history of cervical cancer, and need of additional information were predictors of the perceived susceptibility of developing cervical cancer. The vast majority professed intent to receive an HPV vaccine and the significant predictors were having at least one parent who is a health care professional, a high perceived risk of contracting HPV infection and of developing cervical cancer, and a high belief towards the utility of a vaccination for preventing cervical cancer. Knowledge about HPV infection and cervical cancer should be improved with more attention to the benefit of HPV vaccination.
PMCID: PMC2480983  PMID: 18628763
attitudes; behavioural intention; cervical cancer; human papillomavirus; Italy
8.  Invited Commentary: Is Monitoring of Human Papillomavirus Infection for Viral Persistence Ready for Use in Cervical Cancer Screening? 
American Journal of Epidemiology  2008;168(2):138-144.
Persistent cervical infections by approximately 15 carcinogenic genotypes of human papillomavirus (HPV) cause virtually all cases of cervical cancer and its immediate precancerous precursor, cervical intraepithelial neoplasia grade 3 or carcinoma in situ. As is shown in a meta-analysis by Koshiol et al. (Am J Epidemiol 2008;168:123–137), detection of carcinogenic HPV viral persistence could be used to identify women at the greatest risk of cervical precancer. Specifically, women who have carcinogenic HPV infection that persists for at least 1 year versus those whose infections clear are at significantly elevated risk of having or developing cervical precancer. However, before detection of HPV persistence can be used in cervical cancer screening, several considerations need to be addressed: 1) validation and Food and Drug Administration approval of a reliable HPV genotyping test, 2) rational clinical algorithms based on risk of precancer and cancer for the clinical management of HPV persistence, 3) clinician and patient acceptability of monitoring of HPV infections (including not responding excessively to the first positive HPV test and waiting 1–2 years for infections to either persist or resolve), and 4) patient compliance with recommended follow-up. Investigators will need to address these and other key issues in order to realize the potential utility of HPV viral monitoring for improving the accuracy of cervical cancer screening.
PMCID: PMC2443359  PMID: 18483124
human papillomavirus 16; human papillomavirus 18; longitudinal studies; papillomavirus infections; uterine cervical neoplasms
9.  DNA vaccines targeting human papillomavirus-associated diseases: progresses in animal and clinical studies 
Human papillomavirus (HPV) infection is a major cause of cervical cancer and its precancerous diseases. Cervical cancer is the second deadliest cancer killer among women worldwide. Moreover, HPV is also known to be a causative agent of oral, pharyngeal, anal and genital cancer. Recent application of HPV structural protein (L1)-targeted prophylactic vaccines (Gardasil® and Cervarix®) is expected to reduce the incidence of HPV infection and cervical cancer, and possibly other HPV-associated cancers. However, the benefit of the prophylactic vaccines for treating HPV-infected patients is unlikely, underscoring the importance of developing therapeutic vaccines against HPV infection. In this regard, numerous types of therapeutic vaccine approaches targeting the HPV regulatory proteins, E6 and E7, have been tested for their efficacy in animals and clinically. In this communication, we review HPV vaccine types, in particular DNA vaccines, their designs and delivery by electroporation and their immunologic and antitumor efficacy in animals and humans, along with the basics of HPV and its pathogenesis.
PMCID: PMC3710918  PMID: 23858401
Cervical cancer; Cervical intraepithelial neoplasia; DNA vaccines; Electroporation; Human papillomavirus
10.  A Population-based Study of HPV Genotype Prevalence in the United States: Baseline Measures Prior to Mass HPV Vaccination 
Currently, two prophylactic human papillomavirus (HPV) vaccines targeting HPV 16 and 18 have been shown to be highly efficacious for preventing precursor lesions, although the effectiveness of these vaccines in real world clinical settings must still be determined. Toward this end, an ongoing statewide surveillance program was established in New Mexico to assess all aspects of cervical cancer preventive care. Given that the reduction in cervical cancer incidence is expected to take several decades to manifest, a systematic population-based measurement of HPV type-specific prevalence employing an age- and cytology-stratified sample of 47,617 women attending for cervical screening was conducted prior to widespread HPV vaccination. A well-validated PCR method for 37 HPV genotypes was used to test liquid-based cytology specimens. The prevalence for any of the 37 HPV types was 27.3% overall with a maximum of 52% at age 20 years followed by a rapid decline at older ages. The HPV 16 prevalence in women aged ≤ 20 years, 21-29 years, or ≥ 30 years was 9.6%, 6.5%, and 1.8%, respectively. The combined prevalence of HPV 16 and 18 in these age groups was 12.0%, 8.3% and 2.4%, respectively. HPV 16 and/or HPV 18 were detected in 54.5% of high-grade squamous intraepithelial (cytologic) lesions (HSIL) and in 25.0% of those with low-grade SIL (LSIL). These baseline data enable estimates of maximum HPV vaccine impact across time and provide critical reference measurements important to assessing clinical benefits and potential harms of HPV vaccination including increases in non-vaccine HPV types (i.e., type replacement).
PMCID: PMC3852415  PMID: 22532127
population-based HPV prevalence; HPV vaccine impact
11.  Cervical Human Papillomavirus (HPV) Infection and HPV Type 16 Antibodies in South African Women▿  
Journal of Clinical Microbiology  2007;46(2):732-739.
There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.
PMCID: PMC2238115  PMID: 18077644
12.  Therapeutic human papillomavirus vaccines: current clinical trials and future directions 
Cervical cancer is the second largest cause of cancer deaths in women worldwide. It is now evident that persistent infection with high-risk human papillomavirus (HPV) is necessary for the development and maintenance of cervical cancer. Thus, effective vaccination against HPV represents an opportunity to restrain cervical cancer and other important cancers. The FDA recently approved the HPV vaccine Gardasil for the preventive control of HPV, using HPV virus-like particles (VLP) to generate neutralizing antibodies against major capsid protein, L1. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and HPV-associated lesions. Furthermore, due to the considerable burden of HPV infections worldwide, it would take decades for preventive vaccines to affect the prevalence of cervical cancer. Thus, in order to speed up the control of cervical cancer and treat current infections, the continued development of therapeutic vaccines against HPV is critical. Therapeutic HPV vaccines can potentially eliminate pre-existing lesions and malignant tumors by generating cellular immunity against HPV-infected cells that express early viral proteins such as E6 and E7.
This review discusses the future directions of therapeutic HPV vaccine approaches for the treatment of established HPV-associated malignancies, with emphasis on current progress of HPV vaccine clinical trials.
Relevant literature is discussed.
Though their development has been challenging, many therapeutic HPV vaccines have been shown to induce HPV-specific antitumor immune responses in preclinical animal models and several promising strategies have been applied in clinical trials. With continued progress in the field of vaccine development, HPV therapeutic vaccines may provide a potentially promising approach for the control of lethal HPV-associated malignancies.
PMCID: PMC3074340  PMID: 18352847
clinical trials; HPV; human papillomavirus; therapeutic; vaccines
13.  Reducing HPV-associated Cancer Globally 
Human papillomavirus (HPV)-related cancers are a major worldwide public health concern. Virtually all cervical cancer is HPV-related, with 70% caused by HPV16 and -18. Variable proportions of certain non-cervical cancers (e.g., anal, vulvar, oropharyngeal) are HPV-related; over 90% of the HPV-related ones are related to HPV16, -18. The HPV-related cancers are dominated by cervical cancer in the developing world, where cervical cancer screening is limited. In this setting, widespread uptake of current HPV vaccines by adolescent girls could reduce this cancer's incidence and mortality by approximately two-thirds, with cost-effective screening programs of adult women having the potential to reduce mortality more rapidly. In the industrialized world, non-cervical HPV-related cancers, especially oropharyngeal, are rapidly increasing, and now rival the incidence of cervical cancer, whose rates continue to decline thanks to established cervical screening programs. Therefore, reducing HPV-associated non-cervical cancers with HPV vaccination has greater importance in the industrialized world, especially since there are no approved screening programs for these cancers. Preventing the substantial number of non-cervical HPV cancers in men will require either “herd” immunity through high vaccination rates in females or male vaccination. Current HPV vaccination can complement cervical screening in protecting against cervical cancer and may permit the safe reduction of screening intensity in industrialized countries. Second-generation HPV vaccines (active against a broader array of cervical cancer–related HPV types) could prevent an even higher proportion of cervical precancer and cancer and might permit further reductions in screening intensity.
PMCID: PMC3285475  PMID: 22219162
14.  Human Papillomavirus Prevalence in a Population of Women Living in Port-au-Prince and Leogane, Haiti 
PLoS ONE  2013;8(10):e76110.
There have been no published studies of carcinogenic human papillomavirus (HPV)--the necessary cause of cervical cancer--in Haiti, a nation that has one of the greatest burdens of cervical cancer globally.
Characterize prevalence of carcinogenic HPV and the prevalence of individual carcinogenic HPV genotypes in women with cervical precancer or cancer, cervical intraepithelial neoplasia grade 2 (CIN2) or more severe (CIN2+).
Women (n=9,769; aged 25-60 years) were screened for carcinogenic HPV by Hybrid Capture 2 (HC2; Qiagen, Gaithersburg, MD). Carcinogenic HPV positives underwent colposcopy and visible lesions were biopsied. A subset of carcinogenic HPV positives was tested for individual HPV genotypes using a GP5+/6+ assay.
The prevalence of carcinogenic HPV was 19.0% (95% confidence interval: 18.4%-19.9%) and decreased with increasing age (ptrend < 0.001). Women with 3 or more sexual partners and who started sex before the age of 18 years had twice the age-adjusted prevalence of carcinogenic HPV of women with one partner and who started sex after the age of 21 (24.3% vs. 12.9%, respectively). HPV16 and HPV35 were the most common HPV genotypes detected in CIN2+ and more common in women with CIN2+ than those without CIN2+. HPV16 and/or HPV18 were detected in 21.0% of CIN2 (n = 42), 46.2% of CIN3 (n = 52), and 80% of cancers (n = 5).
The prevalence of carcinogenic HPV in Haiti was much greater than the prevalence in other Latin American countries. High carcinogenic HPV prevalence and a lack of cervical cancer screening may explain the high burden of cervical cancer in Haiti.
PMCID: PMC3789741  PMID: 24098429
15.  Adolescent Understanding and Acceptance of the HPV Vaccination in an Underserved Population in New York City 
Journal of Oncology  2011;2012:904034.
Background. HPV vaccination may prevent thousands of cases of cervical cancer. We aimed to evaluate the understanding and acceptance of the HPV vaccine among adolescents. Methods. A questionnaire was distributed to adolescents at health clinics affiliated with a large urban hospital system to determine knowledge pertaining to sexually transmitted diseases and acceptance of the HPV vaccine. Results. 223 adolescents completed the survey. 28% were male, and 70% were female. The mean age for respondents was 16 years old. Adolescents who had received the HPV vaccine were more likely to be female and to have heard of cervical cancer and Pap testing. Of the 143 adolescents who had not yet been vaccinated, only 4% believed that they were at risk of HPV infection and 52% were willing to be vaccinated. Conclusions. Surveyed adolescents demonstrated a marginal willingness to receive the HPV vaccine and a lack of awareness of personal risk for acquiring HPV.
PMCID: PMC3236523  PMID: 22187557
16.  Incidence, clearance and predictors of human papillomavirus infection in women  
Persistent infection with carcinogenic human papillomavirus (HPV) is linked to high-grade lesions and cervical cancer. To better understand the natural history of HPV, we sought to determine the rates of incident and cleared carcinogenic HPV infection, by age, among women aged 15–49 years and to explore risk factors for incident infection.
Women enrolled in an earlier HPV prevalence survey (500 of 800 who were HPV-negative and all 121 who were HPV-positive) were invited to participate in follow-up HPV testing at their periodic health examination one year later. A cervical soft-brush specimen for HPV testing and a smear for cytologic examination were obtained, and participants completed a questionnaire on their demographic characteristics and sexual history.
Two hundred and fifty-three (50.6%) previously HPV-negative women and 54 (44.6%) previously HPV-positive women were retested. The mean interval between visits was 14.0 (standard deviation 2.0, median 13.5, range 9.0–21.3) months. Incident HPV infection occurred in 11.1% (28/253) of the women overall, with the highest rate, 25.0% (6/24), in the 15–19-year age group. In the univariate analyses, risk factors for incident HPV were the median number of sexual partners in the past year (≤ 1 v. ≥ 2: odds ratio [OR] 8.2, 95% confidence interval [CI] 3.0–22.2; p < 0.001) and the median number of sexual partners over a lifetime (> 3 v. ≤ 3: OR 3.0, 95% CI 1.2–7.2; p = 0.014). In multivariate logistic regression modelling adjusted for age, median number of sexual partners in the past year, median number of sexual partners over a lifetime, marital status, current smoking and current use of oral contraceptives, only the median number of sexual partners in the past year remained significantly associated with incidence (OR 6.2, 95% CI 1.6–24.5; p = 0.009). Of the previously HPV-positive women, 51.9% (28/54) had cleared the infection.
Incident infection with carcinogenic HPV was highest in women aged 15–19 years, and risk factors were consistent with a sexually transmitted infection. A large proportion of the women who were HPV-positive appeared to have cleared the infection after one year.
PMCID: PMC143547  PMID: 12591782
17.  Human Papillomaviruses As Therapeutic Targets in Human Cancer 
Journal of Clinical Oncology  2011;29(13):1785-1794.
Cervical carcinomas are almost universally associated with high-risk human papillomavirus (HPV) infections, and are a leading cause of cancer death in women worldwide. HPV oncoproteins contribute to cancer initiation and progression and their expression is necessary for the maintenance of the transformed state. The fact that the initiating oncogenic insult, infection with a high-risk HPV and viral oncoprotein expression, is common to almost all cervical cancers offers unique opportunities for prevention, early detection, and therapy. The potential for prevention has been realized by introduction of prophylactic vaccines that are to prevent transmission of specific high-risk HPVs. Given, however, that these vaccines have no therapeutic efficacy and HPV-associated cervical cancers arise years if not decades after the initial infection, it has been estimated that there will be no measurable decline of HPV-associated tumors before 2040. Cervical cancer alone will be diagnosed in more than 375,000 US women between now and 2040. Other HPV-associated anogenital and head and neck cancers are predicted to afflict another 700,000 men and women over this time period. Hence, therapeutic efforts to combat high-risk HPV-associated disease remain of critical importance.
PMCID: PMC3675666  PMID: 21220591
18.  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
19.  Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women 
We describe type-specific progression, regression and persistence of incident human papillomavirus (HPV)-6-11-16 and -18 infections, along with type distribution in cervical intra-epithelial neoplasia (CIN) lesions.
The study population consisted of 16–23 year-old women undergoing Pap testing and cervical swab polymerase chain reaction testing for HPV DNA at approximate 6 month intervals for up to 4 years in the placebo arm of a clinical trial of an HPV 16-vaccine. HPV types in incident infections were correlated with types in lesion biopsy specimens.
56.7% of CIN-1 and nearly one-third of CIN-2/3 lesions following incident HPV-6-11-16 or -18 infections did not correlate with the incident infection HPV type. Cumulative 36-month progression rates to CIN-2/3 testing positive for the relevant HPV type were highest for HPV-16 infections (16.5%), followed by HPV-18 (8.2%). Overall, 26.0% of CIN-1, 50.0% of CIN-2 and 70.6% of CIN-3 biopsies tested positive for HPV-6-11-16-18 infections.
Women with a given HPV type may often be co-infected or subsequently infected with other types which may lead to subsequent cervical lesions. This issue has been addressed in this study reporting data for the natural history of HPV-6-11-16 and -18 infections and is a relevant consideration in designing future studies to evaluate the incidence/risk of CIN following other type-specific HPV infections.
PMCID: PMC2034372  PMID: 17626624
20.  Towards the eradication of HPV infection through universal specific vaccination 
BMC Public Health  2013;13:642.
The Human Papillomavirus (HPV) is generally recognized to be the direct cause of cervical cancer. The development of effective anti-HPV vaccines, included in the portfolio of recommended vaccinations for any given community, led to the consolidation in many countries of immunization programs to prevent HPV-related cervical cancers. In recent years, increasing evidence in epidemiology and molecular biology have supported the oncogenic role of HPV in the development of other neoplasm including condylomas and penile, anal, vulvar, vaginal, and oro-pharyngeal cancers. Men play a key role in the paradigm of HPV infection: both as patients and as part of the mechanisms of transmission. Data show they are affected almost as often as women. Moreover, no screening procedures for HPV-related disease prevention are applied in men, who fail to undergo routine medical testing by any medical specialist at all. They also do not benefit from government prevention strategies.
A panel of experts convened to focus on scientific, medical, and economic studies, and on the achievements from health organizations’ intervention programs on the matter. One of the goals was to discuss on the critical issues emerging from the ongoing global implementation of HPV vaccination. A second goal was to identify contributions which could overcome the barriers that impede or delay effective vaccination programs whose purpose is to eradicate the HPV infection both in women and men.
The reviewed studies on the natural history of HPV infection and related diseases in women and men, the increasing experience of HPV vaccination in women, the analysis of clinical effectiveness vs economic efficacy of HPV vaccination, are even more supportive of the economic sustainability of vaccination programs both in women and men. Those achievements address increasing and needed attention to the issue of social equity in healthcare for both genders.
PMCID: PMC3751659  PMID: 23845195
HPV infection; Condylomas; Cervical cancer; Genital cancer; Oro-pharyngeal cancer; Anti-HPV vaccines; Universal vaccination; Vaccination programs; Incremental cost-effectiveness ratio
21.  The epidemiological and economic impact of a quadrivalent human papillomavirus (hpv) vaccine in Estonia 
BMC Infectious Diseases  2013;13:304.
This analysis assessed the epidemiological and economic impact of quadrivalent human papillomavirus (HPV4: 6/11/16/18) vaccination in Estonia.
A dynamic transmission model was used to assess the epidemiological and economic impact of the routine vaccination of 12-year-old girls with a HPV4 vaccine in preventing cervical cancer, cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 and genital warts.
The model projected that at year 100, HPV4 vaccination would lead to a reduction of HPV 16/18 related cervical cancer incidence and deaths by over 97% and the incidence of HPV 6/11 related genital warts among Estonian women and men by over 94% and 81%, respectively. The incremental cost-effectiveness ratio of the HPV4 vaccination strategy was € 4,889 per QALY gained over a time horizon of 100 years.
Routine vaccination of 12-year-old girls with HPV4 vaccine appears to be cost-effective in Estonia, in addition to providing both short term and long term health gains.
PMCID: PMC3706227  PMID: 23819789
HPV; Vaccine; Cost effectiveness; Screening; Cervical cancer; Genital warts; Estonia
22.  Generation and characterization of a preventive and therapeutic HPV DNA vaccine 
Vaccine  2007;26(3):351-360.
Cervical cancer is one of the most common cancers in women worldwide. Persistent infection with human papillomavirus (HPV) is considered to be the etiological factor for cervical cancer. Therefore, an effective vaccine against HPV infections may lead to the control of cervical cancer. An ideal HPV vaccine should aim to generate both humoral immune response to prevent new infections as well as cell-mediated immunity to eliminate established infection or HPV-related disease. In the current study, we have generated a potential preventive and therapeutic HPV DNA vaccine using human calreticulin (CRT) linked to HPV16 early proteins, E6 and E7 and the late protein L2 (hCRTE6E7L2). We found that vaccination with hCRTE6E7L2 DNA vaccine induced a potent E6/E7-specific CD8+ T cell immune response, resulting in a significant therapeutic effect against E6/E7 expressing tumor cells. In addition, vaccination with hCRTE6E7L2 DNA generated significant L2-specific neutralizing antibody responses, protecting against pseudovirion infection. Thus, the hCRTE6E7L2 DNA vaccines are capable of generating potent preventive and therapeutic effects in vaccinated mice. Our data has significant clinical implications.
PMCID: PMC2258233  PMID: 18096279
HPV; DNA vaccine; E6; E7; L2
23.  Therapeutic Human Papillomavirus (HPV) Vaccines: A Novel Approach 
The Open Virology Journal  2012;6():264-269.
Cervical cancer is the second largest cause of cancer-related death in women worldwide, and it occurs following persistent infection, sometimes for decades, with a specific subset of human papillomavirus (HPV) types; the approximately 13 oncogenic subtypes. Prophylactic vaccines against HPV infections hold promise for cost-effective reductions in the incidence of cervical cancer, but this may not be enough. Two prophylactic HPV vaccines are presently available and both contain L1 virus-like particles (VLPs) derived from the HPV subtypes most frequently associated with cervical cancer, HPV-16 and -18. Since the L1-VLP vaccines can only effectively prevent infection by the specific HPV subtype against which the vaccine was developed, cervical cancers caused by high-risk HPV subtypes other than HPV-16 and -18 may still occur in recipients of the current HPV vaccines. Furthermore, HPV vaccination coverage for adolescents is insufficient in most countries and therefore even HPV-16 and -18 infections are unlikely to be fully eradicated using the existing strategies. The development of HPV therapeutic vaccines remains essential. Many therapeutic vaccines aimed at clearing HPV-related cervical lesions have been developed and tested in patients with HPV16-positive cervical intraepithelial lesions (CIN) or cervical cancers. To date, definitive clinical efficacy and appropriate immunological responses have never been demonstrated for cervical neoplasia although promising results have been reported in patients with vulvar intraepithelial neoplasia. Here we discuss shortcomings of previous HPV therapeutic vaccine candidates and propose a novel vaccination strategy that leverages newly gained knowledge about mucosal immunity and the induction of mucosal immune responses.
PMCID: PMC3547358  PMID: 23341862
HPV therapeutic vaccine; mucosal vaccination; cervical mucosal immune system; E7-expressing lactobacillusbases vaccine.
24.  Current status of cervical cancer and HPV infection in Korea 
Cervical cancer is an important cause of cancer-related deaths in women in developing countries. In Korea, cervical cancer is the third leading cancer among females and is fifth highest in mortality. The persistent oncogenic human papillomavirus (HPV) infections are the greatest risk of developing cervical intraepithelial neoplasia and invasive cancer. The overall prevalence of HPV was 10.4% in Korea and strong risk factors for HPV infection included a young age at sexual debut. The National Cancer Screening Program, which includes cervical cancer screening, has the following principles: the main screening tool is the Papanicolaou test conducted by gynecologists, which targets all women age 30 and over, and which is done every 2 years. HPV DNA tests have not yet been permitted as a screening test for cervical cancer in Korea; however, these are conducted along with a Pap test for screening cervical cancer in the clinic. The use of prophylactic HPV vaccine has been accepted in Korea; The Korean Society of Gynecologic Oncology and Colposcopy's recommendation for routine vaccination is for females aged 15-17 years with a catch-up vaccination recommended for females aged 18-26 years who have not been previously vaccinated. However, many people in Korea are not familiar with the HPV vaccine. Therefore, it is necessary to improve awareness for the disease and HPV vaccination and to establish the effective strategies to obtain funding for HPV vaccination. In the future, cervical cancer is expected to disappear throughout the world, including the Asia Pacific region, through a combination of vaccination and qualified screening programs for cervical cancer.
PMCID: PMC2676497  PMID: 19471667
Cervical cancer; Human papillomavirus vaccines
25.  Prevalence of human papillomavirus in university young women 
Oncology Letters  2011;2(4):701-706.
Cervical cancer is the second most prevalent female cancer worldwide. The majority of cases appear between the age of 30 and 50. Human papillomavirus (HPV) plays a central role in cervical cancer with 99.7% of HPV DNA identified in invasive cervical carcinomas. The prevalence of the HPV infection varies substantially among countries and according to age and lifestyle. HPV is a common sexually transmitted infection among males and females with a 70% higher incidence in sexually active females. This study aimed to determine the prevalence of human papillomavirus in young university women by analyzing the correlation between Papanicolaou (PAP)-stained cervical tests and HPV detection by genotyping, as well as other risk factors. A total of 200 women aged between 18 and 25 years were enrolled in this study, which took place between September 2008 and May 2009 at the Universidad de Tarapacá, Arica, Chile. Results of the PAP smears showed that 97.5% of cells had normal characteristics, although an inflammatory pattern was noted. The prevalence of generic HPV infection was 3.5% when testing for HPV DNA using the polymerase chain reaction (PCR) method. An analysis of the genotype of infected female individuals indicated that high-risk HPV types, such as HPV 16 and 31 were present in 42.84 and 14.29% of females, respectively, and low-risk types such as HPV 6, in 14.29%. Only one sample with differentiated non-HPV (14.29%) was found. A 95% correlation between PAP-stained cervical tests and the method of testing for HPV was observed. Using the PCR method, it was found that of the 195 negative PAP smears, 5 were positive for HPV and two of the samples that were positive for ASC-US were also positive. A significantly increased (P<0.05) HPV infection risk was observed in the 18–21 age group with a higher prevalence (71.40%) when compared to the 22–25 age group (28.6%). A significant (P<0.042) difference was found between smoking and HPV infection. In conclusion, a significant (P<0.05) correlation was found between PAP and PCR methods for HPV testing in young university women. A significant correlation between smoking and HPV was detected, whereas no difference was noted with other parameters.
PMCID: PMC3406457  PMID: 22848252
human papillomavirus; prevalence

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