Cervical cancer prevention: the impact of HPV vaccination

Cervical cancer remains a critical public health problem that is second only to breast cancer in overall disease burden for women throughout the world. In spite of the success of cervical cancer screening, Pap cytology screening is yet to be effectively implemented or has failed to reduce cervical cancer rates to an appreciable extent. Screening appears to benefit only a small fraction of women although a much larger percentage endures the inconvenience of the Pap test in order to avoid cervical cancer. The establishment of Human Papillomavirus (HPV) infection as the necessary cause of cervical precancers and cancers provides a tremendous opportunity for cervical cancer prevention through vaccination. HPV 16 and 18 which cause 70% of cervical cancers worldwide. Thus a prophylactic vaccine to prevent HPV related precancerous lesions and cancers would save lives, reduce the need for costly medical procedures and provide both women and communities throughout the world with substantial benefits. Based on the induction of neutralizing antibodies by non infectious Virus Like Particles (VLP) of L1 capside protein, prophylactic HPV vaccines have consistently induced high titter of neutralizing antibodies with minimal side effects and induce more than 90% protection from persistent HPV 16-18 infection and HPV 16 and 18 associated high-grade Cervical Intraepithelial Neoplasia (CIN) in proof of concept efficacy trials. HPV 16-18 vaccination will prevent HPV16-18 incident infection, and subsequently decrease in 90% the frequency of abnormal Pap attributable to these types and in about 50% overall abnormal Pap. HPV vaccination will reduce the number of women who require colposcopy, biopsy and cervical treatment for precancerous cervical lesions. The level of protection from death due to cervical cancer could exceed 95%. Three large phases prophylactic HPV VLP trials are now in progress and will form the basis for licensing of candidate vaccines in 2006. HPV vaccination targeting young female adolescents, aged 11 to 16 years, with a catch-up of those aged 17-25 years, would be a strategy to be addressed. Cervical cancer screening strategies, that will be cost-effective for the proper surveillance of women protected by HPV vaccination, are under analysis.     

人乳头瘤病毒疫苗的研究与临床应用

人乳头瘤病毒(HPV)感染是宫颈癌发生的必要原因之一,而全世界近70%的宫颈癌是由HPV16和18亚型导致,针对HPV16,18的预防性疫苗已经上市,针对HPV感染及宫颈癌的治疗性疫苗正在研究中。     

Human papillomavirus update (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, around one every two minutes. In the not so distant future cervical cancer may cause more deaths globally per year, (275,000 in 2008), than maternal deaths, (358,000 in 2008). Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persistent infection may cause intraepithelial neoplasia and invasive disease.Prophylactic HPV vaccines prevent disease caused by the included HPV types and potentially prevent 70–75% cases of cervical cancer. The UK added HPV vaccination to the national immunization programme in 2008. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period.Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice.Research is ongoing regarding therapeutic HPV vaccination and second generation prophylactic vaccines to prevent more cases of cancer.     

Epidemiology and natural history of genital infection by human papillomavirus

Human papillomavirus genital infection is a very common sexual transmitted disease, probably the most common of them. On one hand, this infection is more often than not transient and asymptomatic and induces an effective immunity which allows the infection cure; on the other hand it can be responsible for an intraepithelial lesion which can progress to an invasive cancer. In spite of the decrease of cervical cancer incidence thanks to Pap smear screening, it remains a real preoccupation for clinicians. If HPV is not sufficient for cervical carcinogenesis, it represents however a necessary factor. Near 100% of cervical cancers are indeed positive in HPV DNA. HPV infection is very frequent in young people aged less than 25 years and viral clearance average is 8 months. This clearance is the consequence of host immunity intervention which leads to spontaneous regression of infection and of the overwhelming majority of low grade squamous intraepithelial lesions (more than 80% within a period of two years). The major factor which permits the progression to high grade squamous intraepithelial lesions is the persistent feature of HPV infection. Cervical cancer is clearly the first viral-induced solid tumor discovered in human species. Furthermore it represents a woman death cause that can be avoided.     

Human papillomavirus prophylactic vaccines: stakes and perspectives

Human Papillomavirus (HPV) infection is established as the necessary cause of cervical precancers and cancers. To date, more than 120 genotypes are known, but only high risk oncogen genotypes could induce a cancer. HPV 16 and 18 are implied in nearly 70% of cervical cancer around the world. Although some persistent HPV infections progress to cervical cancer, host immunity is generally able to clear most HPV infections providing an opportunity for cervical cancer prevention through vaccination. Candidate prophylactic vaccines based on papillomavirus L1 virus-like particles (VLPs) are currently on human clinical trials: one targeting cervical cancer with a bivalent VLP L1 vaccine containing the two genotypes most frequently involved in cervical cancer (type 16 and 18) and the other, protecting against warts as well as cervical cancer, with a quadrivalent HPV VLP L1 vaccine containing genotypes 6, 11, 16 and 18. The first clinical trials revealed the satisfactory tolerance and excellent immunogenicity of these vaccines inducing high serum antibody titers with minimal side effects. After more than three years, both clinical trials on women 15 to 25 years old have shown that vaccines are able to type specifically protect against nearly 90% of infection and all cervical intra-epithelial neoplasia. The vaccinal strategy defined to date targets preadolescents and adolescent young females (11-13 years) before the first sexual course but some questions are still not resolved concerning the prescriber, the actors of the vaccination and the duration of the protection. Nevertheless cervical cancer screening should be carried on for many years, even if a large vaccinal strategy is decided. Such a vaccine would save lives and reduce the need for costly medical procedures and the psychological stress induced by this cancer.     

Human papillomavirus (including vaccination)

Human papillomavirus (HPV) is responsible for 99.7% of cervical cancer. Worldwide, cervical cancer causes more deaths than any other cancer, almost two per minute. Over 200 types of HPV have been identified. HPV is transmitted by skin-to-skin contact. Most HPV infections are cleared by the immune system; persisting infections can cause intra-epithelial neoplasia and invasive disease. Prophylactic HPV vaccines have been developed and prevent disease caused by the included HPV types. Current vaccines could prevent 70–75% cases of cervical cancer. The UK, in 2008 added HPV vaccination to the national immunization programme. The vaccines are safe and well tolerated. It is likely that the benefits will be seen over a 15–20 year period. Tests for HPV have been developed and are being evaluated as to their possible role in clinical practice. Research is ongoing regarding therapeutic HPV vaccination and improving prophylactic vaccines to prevent more cases of cancer.     

Prophylactic and therapeutic vaccination against human papillomavirus

Human papillomavirus is a necessary cause for the development of cervical cancer. Cervical cancer is attributed to 15 high-risk oncogenic HPV among the 120 genotypes present in human. The infection affects about 3 out of 4 women and is often transient thanks to immunological modulators leading to viral clearance. This characteristic made it possible to develop vaccines. Prophylactic vaccines are made of virus-like particles L1, non infectious, well tolerated and highly immunogenic. They prevent from viral infection by producing antibodies, which are secreted throughout the genital mucosa (humoral immunity). High-risk oncogenic HPV-16 and 18, responsible for 70% of cervical cancer, are included in Gardasil and Cervarix. Both vaccines prevent from HPV infection and related cervical and perineal lesions in more than 90% of the cases. Therapeutic vaccines are made of epitope peptides, recombinant proteins and bacteria, plasmid DNA or dendritic cells. All sensitize immunocompetent cells (cellular immunity). Ineffective in cervical cancers, they induce the regression of cervical dysplasia in about 50% of the cases. They are still under research and development, in opposition to prophylactic vaccines, which are available.     

Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix

Human papillomavirus (HPV) infection is the most common sexually transmitted disease, with more than 80% of the population infected at some time in their life. In rare cases, this infection may lead to cervical cancer. Virtually all squamous cell carcinomas and the overwhelming majority of adenocarcinomas of the cervix are HPV positive. HPV integration in the genome will lead to inactivation of the p53 pathway and the Rb pathway. Integration is essential for the onset of cervical carcinogenesis, but is probably not sufficient for progression to invasive cervical cancers. It is likely that several cofactors, such as environmental, viral and host-related factors, are necessary for the development of cervical cancer. There are several similarities and differences between the two major histological types. This article will address the role of HPV in cervical carcinogenesis as well as the molecular biology involved in the process.     

Human papillomavirus vaccines and adolescents

PURPOSE OF REVIEW: This review will describe human papillomavirus (HPV) vaccines in development, summarize data regarding safety and efficacy of these vaccines, and discuss key issues related to HPV vaccine implementation. RECENT FINDINGS: Evidence from epidemiologic and genetic studies has confirmed that HPV infection is a necessary cause of cervical cancer and contributes to the development of other cancers. HPV infection also may cause nonmalignant conditions such as external genital warts and recurrent respiratory papillomatosis. Over the past decade, several vaccines that target common HPV types have entered clinical trials. These vaccines are classified as prophylactic or therapeutic. The goal of prophylactic vaccines is to prevent primary or persistent HPV infections, and thus prevent cervical cancer and/or genital warts. Recent evidence indicates that prophylactic vaccines are well tolerated, highly immunogenic and effective in preventing persistent HPV infection and cervical intraepithelial neoplasia (CIN). Questions remain, however, concerning vaccine efficacy against HPV-related diseases other than cervical cancer, the duration of protection, vaccine acceptability and feasibility of vaccine delivery in the developing world. The goal of therapeutic vaccines is to prevent progression of HPV infection, induce regression of CIN or condylomata, or eradicate residual cervical cancer. Although therapeutic vaccines appear to induce both humoral and cell-mediated immunity, they have not consistently demonstrated clinical efficacy. SUMMARY: HPV vaccines in development have the potential to reduce the substantial morbidity and mortality associated with cervical cancer and other HPV-associated diseases. Large-scale efficacy studies that are planned or underway will provide additional information about vaccine tolerance and efficacy.     

Human papillomavirus type 18 and other risk factors for cervical cancer in Jakarta, Indonesia

Infection with human papillomavirus (HPV) has now been established as a necessary cause of cervical cancer. Indonesia is a country with a high cervical cancer incidence and with the world's highest prevalence of HPV 18 in cervical cancer. No information exists about the prevalence of HPV 18 or other HPV types in the Indonesian population. We conducted a hospital-based case-control study in Jakarta, Indonesia. A total of 74 cervical carcinoma cases and 209 control women, recruited from the gynecological outpatient clinic of the same hospital, were included. All women were HPV typed by the line probe assay, and interviews were obtained regarding possible risk factors for cervical cancer. HPV was detected in 95.9% of the cases and in 25.4% of the controls. In the control group, 13.4% was infected with a high-risk HPV type. HPV 16 was detected in 35% of the case group and in 1.9% of the control group and HPV 18 was identified in 28% of the case group and in 2.4% of the control group, suggesting that the oncogenic potentials of HPV 16 and HPV 18 in Indonesia are similar. In addition to HPV infection, young age at first intercourse, having a history of more than one sexual partner, and high parity were significant risk factors for cervical cancer. Within the control group, we did not identify determinants of HPV infection. We hypothesize that the high prevalence of HPV 18 in cervical cancer in Indonesia is caused by the high prevalence of HPV 18 in the Indonesian population.     

Management of precursor lesions of cervical carcinoma: history,host defense,and a survey of modalities

Before the initiation of screening and treatment for cervical cancer precursors, approximately 3% to 4% of women were destined to eventually develop cervical cancer. During the last 50 years the rate of cervical cancer incidence and mortality has decreased by more than 75% primarily because of the widespread availability of cervical cytologic screening and of treatment for documented cervical precancer. Successful screening of the entire population and appropriate treatment of lesions could theoretically reduce this risk to one tenth of the risk of an unscreened population [7,28]. The relatively recent understanding of the etiology of cervical cancer precursor lesions and of the immune response to them has given new direction to management options that incorporate healthy habits and dietary measures as part of traditional ablative or excisional treatment options. As we look to the future we can expect that new markers that more specifically identify individuals at-risk for cervical precancer and cancer will be developed and take precedence in cervical screening. At the same time, treating the cause of these lesions, rather than the result, should provide less traumatic and more successful therapies. To this end, harnessing the immune system through immune response modifiers and HPV vaccines seems to be on the horizon, as do new chemopreventative approaches. Of all human cancers, only cervical cancer, once the second most common cancer among women, stands on the threshold of being virtually eliminated.     

Comparative analysis of characteristics of women with cervical cancer in high- versus low-incidence regions

OBJECTIVE: To identify particular characteristics that might help explain the markedly higher rate of invasive cervical cancer in southern China as compared with Australia. METHODS: One hundred eighty-five women with cervical cancer were recruited between 1999 and 2001: 106 from Guangzhou and Changsha (southern China), and 79 from Sydney (southeast Australia). Demographic and risk factor information was obtained by questionnaire; clinicopathologic data were extracted from hospital records. The human papillomavirus (HPV) status of cancer biopsies was ascertained by consensus PCR assays, direct sequencing and/or Amplicor trade mark hybridisation. RESULTS: The mean age of the Chinese was significantly lower than the Australians (44 versus 53 years), although mean age at first sexual intercourse was similar. Australian women were more likely to smoke, to report multiple sexual partners and to have a history of sexually transmitted diseases (but not of genital warts). However, they were better educated, were more frequent users of barrier contraception and were far more likely to report regular Pap smears before diagnosis. The HPV positivity rate of Chinese cancers (83%) was less than Australian tumours (90%); but HPV 16 and 18 were the most common genotypes in both populations (59% and 77%), and predominated in cancers from younger women. HPV types 58 or 59 were amplified from 12 (14%) of the Chinese but from only one Australian cancer. CONCLUSIONS: Cervical cancer is not only more common in China but also develops at a younger age than in Australia. While significant differences in some risk factors were observed, the much lower participation in cervical screening in southern China is likely to be of greatest consequence.     

The impact of anti HPV vaccination on cervical cancer incidence and HPV induced cervical lesions: consequences for clinical management

Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to prevent persistent infection with the virus are high and may be implemented in the near future. The consequences for clinical management may include a significant reduction in the frequency of Pap smear screening in the case of prophylactic vaccines, and the availability of less invasive and disfiguring treatment options for women with pre-existing HPV associated lesions in the case of therapeutic vaccines. Implementation of both prophylactic and therapeutic vaccine regimens could result in a significant reduction of health care costs and reduction of worldwide cervical cancer incidence.     

Human papillomavirus and vaccination in cervical cancer

Cervical cancer is not only the most frequently reported cancer among women, but also the most common female genital tract neoplasm in Taiwan. Early detection is effective, because the development, maintenance and progression of precursor lesions (cervical intraepithelial neoplasia [CIN]) evolve slowly into invasive cancer, typically over a period of more than 10 years. It is now recognized that human papillomavirus (HPV) infection is a necessary cause for over 99% of cervical cancer cases. Advances in the understanding of the causative role of HPV in the etiology of high-grade cervical lesions (CIN 2/3) and cervical cancer have led to the development, evaluation and recommendation of HPV-based technologies for cervical cancer prevention and control. The prevention of HPV infection before the onset of CIN is now possible with recently available prophylactic HPV vaccines, e.g. the quadrivalent Gardasil (Merck & Co., NJ, USA) and bivalent Cervarix (GlaxoSmithKline, London, UK). This review article provides an up-to-date summary of recent studies and available information concerning HPV and vaccination in cervical cancer.     

Acceptability and Preferences of Dry HR HPV Self-Sampling Mailed Kits Among Canadian Women: A Cross-Sectional Study

Human papillomavirus (HPV), a sexually transmitted disease, is identified as the source of 99.7% of cervical cancers. Screening for cervical cancer using oncogenic HPV (high-risk [HR] HPV) detection is more sensitive than traditional cytology. However, few Canadian data exist on HR HPV self-sampling.ObjectiveTo evaluate the acceptability of HR HPV self-sampling by patients, the percentage of correctly collected samples, the return rate of mailed kits, and the HPV positivity rate in a population sample based on different cervical cancer risk factors.MethodsWe conducted an observational cross-sectional study on HPV primary cervical cancer screening with self-collected cervicovaginal samples through mail service.ResultsA total of 400 kits were mailed and 310 kits were returned, making a return rate of 77.5%. Of these, 84.2% of patients were very satisfied with this method and 95.8% (297/310) of patients would choose self-sampling over cytology as their primary screening method. All patients would recommend this screening method to their friends or family members. Of the samples, 93.8% could be analyzed correctly and the HPV positivity rate was 11.7%.ConclusionIn this large and random sample, there was a strong interest in self-testing. Offering HR HPV self-sampling could increase access to cervical cancer screening. The self-screening method could also be a part of the solution to reaching under-screened populations, in particular, those who do not have a family doctor or avoid gynaecologic exams because of pain or anxiety.     

Diagnosis of papilloma viruses in cervical cancer in 414 women from Wielkopolska region by the immunohistochemical assessment

OBJECTIVES: Cervical cancer in Poland is second most common type of cancer, after breast cancer. There are known risk factors of cervical cancer development and the most serious one is human papilloma virus infection (HPV). DESIGN: The aim of our paper is present the result study 414 cervical cancer of women from Wielkopolska region treated at the Department of Gynecology and Obstetrics, Karol Marcinkowski University of Medical Sciences in Poznań. MATERIALS AND METHODS: In morphological study grading, staging and vascular invasion were estimated. In cervical cancer tissue papillomaviruses PCR method were used. In immunohistochemical study, expression of proteins checking the cell cycle, share in signal transduction to nucleus, cell receptors for steroid hormones and viruses oncogenic proteins were investigated. In the part of cancer gene mutation of p53 (60 cancers) i k-RAS (40 cancers) were searched. RESULTS: In cancers HPV 16/18 infected vascular invasion were more frequently (p < 0.013). No statistically significant difference in cellular proteins expression in the HPV16/18 positive cancers, HPV16/18 negative and cancers without HPV was observed. However significant difference were demonstrated in proteins expression depending from degree of cancer stage. CONCLUSIONS: The result of these studies suggest that super expression for EGFr is poor prognostic factor in the early stage of cancers (I-II0).     

Human papillomavirus genotype as a prognostic indicator in carcinoma of the uterine cervix

The clinical implications of specific human papillomavirus (HPV) types in invasive cervical carcinomas are only beginning to be appreciated. In this series of 100 women with cervical cancers analyzed for the presence of HPVs 6, 11, 16, 18, and 31 by Southern blot hybridization, a more aggressive clinical behavior was demonstrated for tumors containing HPV 18 than for those with HPV 16 or those in which no HPV was identified. Among 69 stage Ib tumors, no significant differences were found in the size of tumor, presence of parametrial involvement, or lymph node metastasis among patients whose tumor contained HPV 16, HPV 18, or no HPV DNA; however, 45% of the women with HPV 18-containing tumors (five of 11) had recurrence, as compared with only 16% of those with HPV 16 (five of 31) during the 20-month mean follow-up period. This tendency for HPV 18-containing tumors to recur was seen with all histologic subtypes of cervical cancers and with all grades of tumor. In addition, patients with HPV 18-containing tumors were more likely to give a history of recent normal Papanicolaou smears than were those whose tumors contained HPV 16. Forty-four percent of women with HPV 18 in their tumors had a history of three class I Papanicolaou smears in the 3 years before the diagnosis of cancer, whereas a similar history was elicited in only 16% of those with HPV 16 in their tumors, suggesting that HPV 18-containing tumors might progress to invasion without a prolonged preinvasive period.     

Epidemiology and burden of HPV-related disease

Human papillomavirus (HPV) infection is recognized as one of the major causes of infection-related cancer in both men and women. High-risk HPV types are not only responsible for virtually all cervical cancer cases but also for a fraction of cancers of the vulva, vagina, penis, anus, and head and neck cancers. Furthermore, HPV is also the cause of anogenital warts and recurrent respiratory papillomatosis. Despite the availability of multiple preventative strategies, HPV-related cancer remains a leading cause of morbi-mortality in many parts of the world, particularly in less developed countries. Thus, in this review, we summarize the latest estimates of the global burden of HPV-related diseases, trends, the attributable fraction by HPV types, and the potential preventative fraction.     

Molecular variants of human papillomavirus type 16 and risk for cervical neoplasia in South Africa

Non-European variants of human papillomavirus (HPV) type 16 are generally associated with a greater risk of cervical neoplasia than European prototype variants. We investigated whether this association would persist in a population in which non-European HPV 16 variants were more common. We sequenced HPV 16 isolates in cervical samples collected from 93 Black South African women enrolled in a cervical cancer screening study and examined associations between cervical neoplasia identified though colposcopy with cervical biopsy and the specific HPV 16 variant identified. The European prototype variant (EP) was the most commonly identified variant in this population (47% of all isolates), but African variants (Af-1 and Af-2) were also quite common (41% of all isolates). In contrast to previous studies, we found no evidence that non-European variants were associated with an increased risk of neoplasia. Rather, most of the HPV 16-associated cancers were found in association with EP (71% of 14 cases). In this setting where African HPV 16 variants were common, no increased risk for cervical neoplasia was found among women with these variants compared with other HPV 16 variants.     

Invasive cervical cancer following cryotherapy for cervical intraepithelial neoplasia or human papillomavirus infection.

OBJECTIVE: To determine the following: 1) the causes for the failure of cervical cryotherapy to prevent cervical cancer, and 2) whether cervical cryotherapy is associated with the development of cervical adenocarcinoma rather than squamous carcinoma. METHODS: We reviewed the medical charts of 327 women with cervical cancer. One hundred forty-seven for whom pertinent history was missing were contacted by telephone or at clinic visits. History obtained verbally was confirmed by outside medical records. Cervical biopsies (N = 16) and endocervical curettages (ECCs) (N = 15) performed before cryotherapy and biopsies at the diagnosis of cancer (N = 21) were reviewed. RESULTS: Twenty-one women with cervical cancer had a history of cryotherapy for cervical intraepithelial neoplasia (CIN) or human papillomavirus infection (HPV). The interval between cryotherapy and cancer was more than 2 years in 19 and more than 5 years in ten. Several categories of pre-treatment errors were identified. Evaluation before cryotherapy was appropriate in only nine cases. Interpretive errors were noted in three of 16 cervical biopsies and ten of 15 ECCs. After cryotherapy, 12% of women had appropriate follow-up. Of the invasive cancers that developed, 24% in the cryotherapy group and 21% in the non-cryotherapy group were adenocarcinomas. CONCLUSIONS: Careful evaluation before cryotherapy, accurate pathology reports, and consistent long-term follow-up are necessary if cryotherapy is to be used to treat CIN or HPV. We found no evidence that cryotherapy is associated with the development of cervical adenocarcinoma.