Prophylaxis and Early Detection of HPV-Related Neoplasia (Monographs in Virology)

Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts

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Although the understanding of association of HPVs with cervical cancer is very well established further studies are required to analyse the relationships between HPV and certain cancers including breast, lung, bladder, some types of head and neck cancers and penile cancers. To improve the mortality and morbidity of HPV associated cancers and diseases, there is an enormous need for early detection and prevention strategies.

Although screening programs for early detection strategies have been developed for some cancers, such as cervical, there is still a big gap to be filled for other precancerous lesions, such as for some of the head and neck carcinomas.

One of the examples of these screening strategies may involve oral examination, cytology and salivary HPV DNA tests which may provide a better early diagnosis for oral and oro-pharyngeal cancers. Moreover development and spread of more cost-effective vaccines is mandatory. Availability of low cost screening may prevent the future generations to develop HPVs induced cancers. In light of this knowledge, HPV vaccines are useful in the protection against cervical, oral and oro-pharyngeal cancers.

Therefore, despite all these advances, other strategies for early detection and prevention for different HPV types are required. Near East University, Center of Excellence research fund www. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med ; Classification of weakly carcinogenic human papillomavirus types: Infect Agent Cancer ;4: Role of human papillomavirus in the development of head and neck squamous cell carcinomas.

Crit Rev Oral Biol Med ; Classification of papillomaviruses PVs based on PV types and proposal of taxonomic amendments. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci Lond ; Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine ;26 Suppl High throughput sequencing reveals diversity of Human Papillomaviruses in cutaneous lesions. Int J Cancer ; The biology and life-cycle of human papillomaviruses. Vaccine ;30 Suppl 5: Human papillomaviruses in the pathogenesis of anogenital cancer.

Comparison of real-time PCR signal-amplified in situ hybridization and conventional PCR for detection and quantification of human papillomavirus in archival cervical cancer tissue. J Clin Microbiol ; Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. Carcinogenicity of human papillomaviruses.

Human papillomaviruses and non-melanoma skin cancer: J Invest Dermatol ; The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera. J Infect Dis ; Cell Host Microbe ;8: The EVER proteins as a natural barrier against papillomaviruses: Microbiol Mol Biol Rev ; Curr Opin Allergy Clin Immunol ;3: The natural history of cervical HPV infection: Nat Rev Cancer ;7: Biology of human papillomavirus-related oropharyngeal cancer. Semin Radiat Oncol ; Human papillomaviruses and human disease. Am J Med ;5: High-risk human papillomavirus is sexually transmitted: Cancer Epidemiol Biomarkers Prev ; Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: Male sexual behavior and human papillomavirus DNA: J Natl Cancer Inst ; Perinatal acquisition of cervical cancer-associated papillomaviruses.

Br J Obstet Gynaecol ; A possible vertical transmission of human papillomavirus genotypes associated with epidermodysplasia verruciformis. The epidemiology of human papillomavirus infection and its association with cervical cancer. Int J Gynecol Obstet ; From HPV infection to oncogenesis: Curr Cancer Ther Rev Melief, Therapeutic vaccination against human papilloma virus induced malignancies. Curr Opin Immunol ; Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency.

Epidermodysplasia verruciformis and human papilloma virus. Curr Opin Infect Dis ; Viral-associated nonmelanoma skin cancers: Am J Dermatopathol ; Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients. Med Microbiol Immunol ; Mechanisms used by human papillomaviruses to escape the host immune response.

Curr Cancer Drug Targets ;7: Evasion of host immunity direct by papillomavirus-encoded proteins. Human papillomavirus genotype attribution in invasive cervical cancer: PLoS Comput Biol ; Therapy of human papillomavirus-related disease. Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. Potential overestimation of HPV vaccine impact due to unmasking of non-vaccine types: The impact of quadrivalent human papillomavirus HPV; types 6, 11, 16, and 18 L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged years.

A review of clinical trials of human papillomavirus prophylactic vaccines. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: Lancet Infect Dis ; Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: Global burden of human papillomavirus and related diseases. Human Papillomavirus and cancer. Spanish Society of Epidemiology; Papillomaviruses in the causation of human cancers - a brief historical account. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide.

Human papillomavirus genotype distribution in anal cancer in France: Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol ; J Clin Virol ; Detection of human papillomavirus in large cell neuroendocrine carcinoma of the uterine cervix: Evaluation of self-collected cervicovaginal cell samples for human papillomavirus testing by polymerase chain reaction.

Carcinogenicity of malaria and of some polyomaviruses. Do human papillomaviruses target epidermal stem cells? The primary target cells of the high-risk cottontail rabbit papillomavirus colocalize with hair follicle stem cells. E1 protein of bovine papillomavirus 1 is not required for the maintenance of viral plasmid DNA replication. Stable replication of papillomavirus genomes in Saccharomyces cerevisiae. Replication and partitioning of papillomavirus genomes.

Adv Virus Res ; Evolutionary and biophysical relationships among the papillomavirus E2 proteins. Front Biosci Landmark Ed ; Human papillomavirus in head and neck cancer: Clin Cancer Res ; Cellular transformation by human papillomaviruses: New markers for cervical dysplasia to visualise the genomic chaos created by aberrant oncogenic papillomavirus infections.

Eur J Cancer ; Nat Rev Cancer ; Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7. Mechanisms of genomic instability in human cancer: Reducing HPV-associated cancer globally. Cancer Prev Res Phila ;5: J Eur Acad Dermatol Venereol ; J Med Virol ; Cancer Metastasis Rev ; Morphological and immunohistochemical evidence suggesting human papillomavirus HPV involvement in oral squamous cell carcinogenesis.

Int J Oral Surg ; Primary strategies for HPV infection and cervical cancer prevention. Clin Obstet Gynecol ; Comprehensive control of human papillomavirus infections and related diseases. Vaccine ;31 Suppl 8: The causal relation between human papillomavirus and cervical cancer. Natural history of anogenital human papillomavirus infection and neoplasia. J Natl Cancer Inst Monogr Risk factors for the acquisition of genital warts: Sex Transm Infect ; Human papillomavirus immortalization and transformation functions. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes.

Correlation between physical status of human papilloma virus and cervical carcinogenesis. The epidemiology of human papillomavirus infections. J Clin Virol ;32 Suppl 1: Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: The role of retinoid deficiency and estrogens as cofactors in cervical cancer.

Arch Med Res ; Methylation of the long control region of HPV16 is related to the severity of cervical neoplasia. Vulvar squamous cell carcinoma development after diagnosis of VIN increases with age. Am J Obstet Gynecol ; Vulvar cancer and HPV infection: Human papillomavirus-related genital disease in the immunocompromised host: J Am Acad Dermatol ; Vaccine ;31 Suppl 7: High prevalence of human papillomaviruses in fresh frozen breast cancer samples.

Human papillomavirus detected in female breast carcinomas in Japan. Br J Cancer ; Presence of high-risk human papillomavirus sequences in breast cancer tissues and association with histopathological characteristics. Viruses and human breast cancer. Eur J Gynaecol Oncol ; CA Cancer J Clin ; Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol ; The molecular biology of head and neck cancer. Epidemiology and survival of HPV-related tonsillar carcinoma. Treatment of vulvar intraepithelial neoplasia with topical imiquimod.

Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: Oropharyngeal cancer incidence trends: Cancer Causes Control ; Association between human papillomavirus infection and laryngeal squamous cell carcinoma. Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain.

Human papillomavirus prevalence in invasive laryngeal cancer in the United States. Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: Oral Dis ;17 Suppl 1: Human papillomavirus in oral premalignant lesions. Progressive increase of human papillomavirus carriage rates in potentially malignant and malignant oral disorders with increasing malignant potential. Oral Microbiol Immunol ; Cancer Immunol Immunother ; Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine.

Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer. HPV-associated head and neck cancer: The prevalence of human papilloma virus HPV infections in oral squamous cell carcinomas: J Craniomaxillofac Surg ; Metastatic squamous cell carcinoma to the brain: The inherited nature of lung cancer: TP53 polymorphisms and lung cancer risk: Papillomavirus infections and cancer Papillomaviruses and Human Disease, ed. Epithelial lesions suggestive of a condylomatous origin found closely associated with invasive bronchial squamous cell carcinomas.

Solitary condylomatous papillomas of the bronchus. Arch Pathol Lab Med ; Human papillomavirus type 16 related DNA in an anaplastic carcinoma of the lung. Human papillomavirus DNA in a patient with chronic laryngotracheobronchial papillomatosis and metastatic squamous-cell carcinoma of the lung. Human papillomavirus HPV is possibly involved in laryngeal but not in lung carcinogenesis.

The role of human papilloma virus in lung cancer: Am J Med Sci ; Molecular analysis of human papillomavirus in never-smokers with non-small cell lung cancer. HPV and lung cancer risk: J Clin Virol ;63C: Human papillomavirus, genital warts, and vaccines. Screening is recommended to be continued at 3—5-year intervals until the age of 60— In older women, who have had three or more consecutive previous recent normal cytology results, stopping screening is considered appropriate, while special attention has to be paid to those who have never attended screening.

Referral for colposcopy is recommended for women with a high-grade cytological lesion ASC-H and HSIL or higher , a repeated low-grade lesion, or with an equivocal cytology result and a positive HPV test. Management options in case of atypical squamous cells of undetermined significance ASC-US include reflex HPV DNA testing preferred option when HPV testing is available , repeating the Pap smear after 6 to 12 months, or referral for colposcopy and cervical biopsy when poor follow-up compliance is suspected or when explicit risk factors are present.

Repeat cytology or referral for colposcopy preferred option are considered acceptable options for initial management of LSIL, while HPV testing is considered not sufficiently selective. The guidelines of the Italian Ministry of Health for the cervical cancer screening suggest performing a Pap test every three years in women aged 25—64, as first level of screening, followed by specific recommendations for women with abnormal cytology [ 59 ]. The efficacy of conventional cytological screening for cervical cancer has never been investigated in randomised clinical trials, but evidence of its effectiveness derives from observational studies.

Diagnostic performance of cervical cytology has been evaluated by several studies in the literature, whose results have been reviewed in recent meta-analyses. Moreover, sensitivity of cytology varied considerably among studies, ranging from In fact, cytology testing has been shown to have poor inter-laboratory and inter-operator reproducibility [ 64 ]. The meta-analysis also showed the sensitivity of cytology testing increases with patient's age and is significantly higher in women over the age of 50 than in younger women Liquid-based cytology has been more recently introduced and is now widely used for primary screening of cervical cancer.

It has the advantage of allowing automation, faster reading times, and to be used for adjunctive testing, including HPV testing.

Account Options

It has been suggested to be more sensitive than conventional cytology, but this feature has been rebutted by recent randomized studies, which compared the accuracy of liquid-based cytology with conventional cytology for primary screening of cervical carcinoma [ 66 , 67 ]. It showed however the advantage of a reduction of unsatisfactory smears [ 67 ]. The HC2 test is a nucleic acid hybridization assay with signal amplification for the qualitative detection of HPV DNA of 13 high-risk types in cervical specimens. These primers target the L1 gene in a conserved region amongst HPVs.

HPV genotyping is performed by type-specific PCR or by amplification of HPV DNA by using consensus or general primers, followed by sequencing, restriction fragment length polymorphism analysis, or reverse hybridization of the amplicon to multiple oligonucleotide probes corresponding to high-risk and low-risk HPVs. Reverse hybridization assays, such as the linear array by Roche Diagnostics, the line probe assay by Innogenetics NV Belgium , microchips by Biomedlab Co. HPV testing has been introduced in programs for cervical cancer prevention after numerous studies had demonstrated that detection of high-risk HPVs has a higher sensitivity than cytology testing in predicting high-grade cervical precancerous lesions or invasive cervical carcinoma.

In fact, the overall sensitivity and specificity of HPV testing were In fact, a meta-analysis of published studies demonstrated HPV triage of LSIL had no significantly higher sensitivity but lower specificity than repeat cytology in the detection of high-grade CIN [ 70 ]. So, HPV triage could be appropriate also for LSIL in women over 35 years, in order to reduce colposcopy burden and to increase the positive predictive value of the colposcopy referral.

Several studies demonstrated that HPV testing, performed at 4—6 months intervals following ablative therapy for high-grade lesions CIN2—3 , has a higher sensitivity and specificity than cytology in detecting residual disease or recurrence [ 73 - 75 ]. These findings were confirmed in an updated meta-analysis, which showed HPV testing has a significantly higher sensitivity ratio: HPV testing at 6—12 months for post treatment management of CIN2,3 is recommended by current guidelines of the American Society for Colposcopy and Cervical Pathology [ 56 ], whereas European Guidelines, while waiting for further data from clinical trials, recommend double testing with cytology and an HPV test at 6 months post treatment [ 58 ].

The potential role of HPV testing as a stand-alone test or in conjunction with cytology in cervical cancer screening has been investigated in several studies [reviewed in [ 62 , 65 , 77 ]]. Unfortunately, these studies were performed with different techniques and sometimes gave conflicting results. A meta-analysis including 25 non-randomized clinical trials, which compared the performance of cytology vs. The accuracy of cytology testing was lower than HPV testing: In women aged over 30 yr, the overall sensitivity of the HC2 assay was Likewise, the meta-analysis by Cuzick et al.

Moreover, at variance with cytology testing, sensitivity of the HPV test did not vary among the different Centres and was very high both in young women and in those over 50 years of age. Among the studies included in this meta-analysis, there was the HART HPV in Addition to Routine Testing trial, a multicentric screening protocol which enrolled over 10, women aged 30—60 years attending for routine screening. In this study, women with borderline cytology or negative cytology but positive HPV test were randomized to immediate colposcopy or follow-up with repeat HPV test, cytology testing, or colposcopy at 12 months [ 78 ].

Comparison of management strategies for borderline cytology and for positive HPV test with negative cytology results at baseline showed that surveillance at 12 months was as effective as immediate colposcopy [ 78 ]. Based on these results, it was suggested that HPV test could be used as a screening test in women over 30 years of age with cytology triage of HPV-positive results. In case of normal or borderline cytology, repeat HPV testing after 12 months was indicated [ 78 ]. Randomized longitudinal studies [ 79 ], which have been conducted more recently, were not included in the meta-analyses.

One of these studies is the NTCC study, an ongoing clinical trial in Italy nested in the routine activity of organized screening programmes, which enrolled approximately women, who were randomly assigned to conventional cytology or to an experimental arm that followed two phases depending on the period of recruitment [ 23 ].

During the phase 1 of recruitment, women were randomly assigned to the conventional arm for screening by conventional cytology or to the experimental arm, which used both HPV DNA testing with HC2 and liquid-based cytology. HPV-positive women were managed differently according to age. Among women aged 35—60 years, those who had a cytological abnormality or were HPV-positive were referred to colposcopy.

Results at recruitment showed that the screening method in the experimental arm was more sensitive than conventional cytology in women aged 35—60 years [ 80 ]. Adding liquid-based cytology improved sensitivity only marginally but increased false positives [ 80 ]. Moreover, addition of liquid-based cytology as a primary screening test to HPV testing had a negligible effect on sensitivity but strongly reduced PPV compared with HPV testing only [ 81 ].

The use of more restricted referral criteria i. So, in order to avoid overtreatment, it was suggested that HPV-positive women aged 25—34 years should be referred to colposcopy only if cytology is also abnormal or if infection persists after 1 year [ 23 ]. In older women, high-grade lesions are less likely to regress [ 78 , 80 ], therefore a more aggressive management strategy for HPV-positive results appears to be justified. Persistence of the additional lesions detected at baseline by HPV testing in older women was also suggested by the recently published results from two longitudinal randomized controlled trials, that included only women at least 30 [ 83 ] or 32 [ 84 ] years of age.

This study enrolled women aged 30—56 years and attending the regular cervical cancer screening programme in the Netherlands. Management strategies were more conservative than in the NTCC study. Women with repeat positive cytology and HPV test results were referred to colposcopy [ 83 ]. Women with a positive HPV test and a normal Pap test were offered a second HPV test at least 1 year later, and those who were found to be infected with the same high-risk HPV type were offered colposcopy with cervical biopsy.

To avoid ascertainment bias, a similar number of Pap smears and colposcopy with biopsies were performed in randomly selected women in the control group. All women were followed for a mean of 4. Likewise, in a longitudinal cohort study which enrolled over 20, women in Portland who underwent simultaneous screening with a Pap test and HPV testing with HC2, the 5-year cumulative risk of CIN3, was 4. A direct comparison between Pap test and HPV test by using the HC2 assay as stand alone tests for cervical cancer screening was evaluated in a recent randomized trial in Canada, involving 10, women aged 30—69 years [ 86 ].

Both tests were performed on all women in a randomly assigned order but, to the aim of the study, only one first test was considered for statistical evaluation. HPV test specificity was Local assess is needed to identify a good triage test for women with LSIL research need.

Women with normal Pap test result and negative HPV test have a very low risk to develop cervical cancer and should not perform the subsequent follow-up visit earlier than 5 years IA. Women who are persistently HPV-positive on repeat testing should undergo colposcopy, whereas those who are negative on both tests may be rescreened in 5 years IA. The extent of long-term protection against high-grade lesions after a negative HPV DNA test has been estimated to be longer than 5 years, but further research is need to establish the most appropriate screening interval research need.

First follow-up results from ongoing controlled randomized trials, which compare longitudinal performance of Pap test vs. Local assessment is needed before screening policies based on primary HPV testing can be recommended research need. Due to the relatively low specificity of HPV-DNA testing and the high rate of false negative results at Pap test, new molecular tests have been proposed in order to identify women with a higher risk of progression to invasive cancer.

The implementation of these new molecular tests in cervical cancer screening could be useful to identify the subpopulation of high-risk HPV-positive women who deserve a closer follow-up and appropriate treatment. Only a few women with HPV infection will develop cancer. Thus, a single positive HPV test in the absence of clinically significant lesions does not justify treatment [ 87 ].

Several longitudinal studies demonstrated that persistence of high-risk HPV is necessary for cancer initiation and progression and that the majority of high-risk HPV infections and associated low-grade lesions spontaneously regress within 6—18 months [ 1 , 88 - 93 ]. Screening strategies based on repeat HPV testing at 12 months following detection of a high-risk HPV could be useful to identify women at risk of cancer, who should undergo colposcopy, and to avoid overtreatment of lesions which will regress [ 94 , 95 ].

From a practical point of view, persistence can be defined as the detection of the same HPV type or, with a higher degree of certainty, the same intratypic variant two or more times over a certain period. There is no consensus as to the length of time that implies persistence, but at least 6 months to 1 year is the time frame that is usually chosen [ 1 ]. A prospective study of type-specific HPV natural history, with a median follow-up of 5.

Evaluation of type-specific HPV persistence was used as a management strategy for women with a positive HPV test but normal Pap test in a controlled randomized trial in Sweden, as above reported [ 84 ]. No significant difference in sensitivity and specificity was observed between the two tests for detection of HPV in high-grade squamous intraepithelial lesion HSIL. As above reported, higher cut-off values improve the specificity of the HC2 test [ 80 - 82 ] and correlate with an increased risk of HPV persistence and development of high-grade cervical lesions [ 78 ].

Contrasting results have been obtained with other high-risk HPV types, although, generally, a positive relationship between viral load and severity of cervical lesions has been reported [ - ]. Some studies demonstrated that detection of HPV and HPV types represents a risk factor for CIN2—3 [ , ], but also identification of other high-risk HPV types could be useful to select at risk patients [ , ].

In multiethnic populations, Asiatic-American and other non-European variants of HPV and HPV are associated with a higher risk of persistent infection and development of cervical precancerous lesions and invasive cancer [ - ]. The TG sequence variant of the HPV16 E6 gene is associated with increased viral persistence and oncogenicity [ , ].

The aminoacid change caused by this mutation could affect E6 degradation activity on p53, besides changing its immunogenicity. HPV sequence variants may also be associated with different oncogenic potential, even in the absence of virus integration, due to derepression of the E6 and E7 promoter [ , ]. Thus, typing, subtyping, and sequencing of HPV oncogenes and the upstream regulatory region could be useful for epidemiological purposes but also as prognostic markers.

To assess the clinical impact of such an extended test, the results from two randomized trials which used HPV test for cervical cancer screening and ASC-US triage, respectively, were analyzed [ ]. In the cancer screening protocol, addition of other high-risk HPV types, besides the 12 most common, did not ameliorate test sensitivity. Thus, at the moment, increasing the number of high-risk HPV types, besides those already present in the FDA-approved HC2 test, does not seem to be advantageous neither for screening nor for triage of an abnormal Pap smear.

On the other hand, reduction of the number of high-risk types included in the HPV test to those most common in invasive cervical cancer e. Clinical studies demonstrated HPV DNA integration is associated with a higher risk of treatment failure and with a shorter disease-free interval than cases without integration [ , ].

In spite of the high level of pINK4A synthesis, this protein remains functionally inactive, as E7 induces cyclin A and cyclin E expression, thereby functionally bypassing its interference with the cell cycle. In fact, pINK4A triage allows maintaining all the gain in sensitivity obtained by HPV testing alone with respect to conventional cytology, but with referral to colposcopy similar to that of conventional cytology [ ].

Both antibody-mediated and cell-mediated immune responses are essential for clearance of HPV and HPV-related cervical lesions. Serum levels of anti-HPV antibodies are stable, even after virus clearance, so HPV serological assays simply demonstrate previous exposure to the virus. The low sensitivity of the test is in part explained by lack of seroconversion in some individuals with documented HPV infection [ ]. On the other hand, high anti-HPV antibody titre is more common in women with persistent infection than in those who clear infection [ - ].

Unfortunately, no standardized and validated HPV serological assays are available [ , ]. These vaccines are based on the self-assembly of recombinant L1 protein into VLPs, that are non-infectious capsids that contain no genetic material. Intramuscular injection of the vaccine induces high titres of neutralising antibody in almost all subjects within a month from completion of the vaccination protocol [ , , - ].

The bivalent vaccine is advised for reduction of precancerous cervical lesions and cancer incidence. The quadrivalent vaccine, besides cervical lesions, is advised for reduction of vulvar precancerous lesions and genital condylomas. The USA and several other Countries are targeting 11—year-old girls for vaccination. In particular, the Italian HPV vaccination program is universally offered free-of-charge to all year old girls, and advised to all adolescent women before sexual debut. The choice of a target population of young girls is based on the results of immunogenicity and safety studies, which were conducted in girls and boys aged 9—15 years quadrivalent vaccine and aged 10—14 years bivalent vaccine.

These studies demonstrated that both vaccines are safe and immunogenic, and induce antibody titre which is more than 50 times the titres induced by natural infection [ , , - ].

Moreover, in prospective studies, it is not ethical to allow a woman to develop invasive disease in order to demonstrate efficacy of prevention strategies. Randomised clinical trials demonstrated that three doses vaccination is effective for the prevention of persistent infection and for precancerous lesions caused by HPV genotypes included in the vaccine. Results on efficacy reported in published studies are mainly two types: A phase II randomised trial was carried out on women randomised in the vaccine group and in the placebo group. A subset of subjects participated to a subsequent follow-up of this study.

It is to notice that the unique woman, included in the vaccine group, who developed a HPV or HPV associated lesion, had a positive CIN3 for HPV at the initial control and in all the following 5 samplings during follow-up, only one these samples resulted to be HPV positive. A pilot randomized phase II study on safety, immunogenicity, and efficacy of the vaccine for prevention of incident and persistent HPV and HPV infection enrolled and randomized 1, women aged 15—25 years to receive either the vaccine or placebo [ ].

The role of human papillomaviruses in cancer progression

In the per protocol analysis, vaccine efficacy was In the intention-to-treat analyses, vaccine efficacy was In a subsequent report from the same study, after a follow-up of 4—5 years, per protocol analysis on the results obtained from a group of women in the vaccination group and in the placebo group who received all three doses of vaccine, demonstrated vaccine efficacy against incident infection was Interim results at a mean follow-up of This finding has been demonstrated in a randomized phase III trial in women aged 18—25 years, who received the AS04 adjuvanted bivalent VLP vaccine [ ] and in two randomized trials of the quadrivalent HPV vaccine enrolling 17, women without consideration of HPV status [ ].

They demonstrated vaccination led to sustained cross-protection against incident infection with HPV and for the entire follow-up period up to 5. Furthermore, broad protection was observed against month persistent infections defined as detection of the same HPV type in all available cytology samples collected over any month period with 12 combined oncogenic HPV types, not including HPV and vaccine efficacy The final end-of study data with approximately 3.

Data on safety of the quadrivalent HPV VLP vaccine reported a higher rate of side effects in the vaccination group than in the placebo group. Side effects included local reaction at the site of injection erythema, pain, edema altogether, Also data on safety of the bivalent vaccine reported a higher rate of injection site symptoms and systemic side effects fatigue, headache, myalgia in the vaccine group than in the control group [ ]. No increased incidence of spontaneous abortion, late fetal deaths, or congenital anomalies was observed in pregnancies occurring in women receiving either type of vaccines as compared with controls [ , ].

Screening protocols could be modified only after appropriate clinical trials research need. But, there is insufficient evidence to define the best protocol to manage women with positive tests I. Further research is needed to define the best protocol to manage women with a positive test and to evaluate test efficacy in primary screening programs. LB drafted the manuscript.

All authors read and approved the final manuscript. We thank the members of SIV who reviewed the draft version of this guideline when it was posted on the SIV website and who sent a great number of comments, most of which were incorporated into the final version of the manuscript. Moreover, we thank for their helpful suggestions: Pascale, Naples, Italy; A.

Decks, specialist for GSK vaccine. National Center for Biotechnology Information , U. Journal List Infect Agent Cancer v. Published online Dec Author information Article notes Copyright and License information Disclaimer. Received Jul 22; Accepted Dec This article has been cited by other articles in PMC. Abstract Objective To provide guidelines for health-care providers on strategies for cervical cancer prevention based on HPV testing and anti-HPV vaccination.

Outcomes Overall efficacy of different preventive strategies, assessing reduction in the incidence of invasive cervical cancer and precancerous lesions. Values The quality of the evidence and ranking of recommendations for practice were rated using criteria defined by SIV, which were adapted from the Canadian Task Force on Preventive Health Care. Human papillomavirus and cervical cancer The demonstration that human papillomavirus HPV infection has a pathogenetic role on cervical cancer development and the understanding of the epidemiology of HPV infection and its relationship with the natural history of precancerous lesions and cervical cancer have been crucial in the development of diagnostic and vaccination strategies for prevention of one of the most common and lethal cancers, especially in developing countries.

Pathogenesis Several basic experimental studies have clarified the mechanisms of HPV oncogenesis [ 29 , 32 ]. Screening for cervical cancer and diagnosis of HPV infection Screening programs for cervical cancer prevention derive from knowledge on the natural history of cervical cancer and its precancerous lesions and the role of HPV infection in cancer development. Table 1 European and US guidelines on cervical cancer screening and prevention. Every 3 yr if HPV negative and cytology negative. Inconclusive evidence to establish upper age limit. Open in a separate window. Applications of HPV testing in cervical cancer screening programs Using HPV DNA test for triage of abnormal Pap test HPV testing has been introduced in programs for cervical cancer prevention after numerous studies had demonstrated that detection of high-risk HPVs has a higher sensitivity than cytology testing in predicting high-grade cervical precancerous lesions or invasive cervical carcinoma.

Using HPV DNA test for follow-up after treatment of cervical dysplasia Several studies demonstrated that HPV testing, performed at 4—6 months intervals following ablative therapy for high-grade lesions CIN2—3 , has a higher sensitivity and specificity than cytology in detecting residual disease or recurrence [ 73 - 75 ]. Using HPV DNA test for cervical cancer screening The potential role of HPV testing as a stand-alone test or in conjunction with cytology in cervical cancer screening has been investigated in several studies [reviewed in [ 62 , 65 , 77 ]].

Good evidence for efficacy and substantial clinical benefit support recommendation for use. Moderate evidence for efficacy or only limited clinical benefit supports recommendation for use. Evidence for efficacy is conflicting and does not allow supporting a recommendation for or against use, but recommendations may be made on other grounds. Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use.

Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. There is insufficient evidence in quality and quantity to make a recommendation; however, other factors may influence decision-making. Evidence from at least 1 randomized, controlled trial. Evidence from at least 1 clinical trial without randomization, from cohort or case-controlled analytic studies preferably from more than 1 centre or from multiple time-series studies or dramatic results from uncontrolled experiments.

Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees. New molecular tests for management of women with HPV infection Due to the relatively low specificity of HPV-DNA testing and the high rate of false negative results at Pap test, new molecular tests have been proposed in order to identify women with a higher risk of progression to invasive cancer.

Measurement of viral load As above reported, higher cut-off values improve the specificity of the HC2 test [ 80 - 82 ] and correlate with an increased risk of HPV persistence and development of high-grade cervical lesions [ 78 ]. Summary of recommendations and guidelines When should HPV testing be used in cervical-cancer screening programs?

Who should be vaccinated and how should vaccine efficacy be evaluated? Competing interests The authors declare that they have no competing interests. Authors' contributions LB drafted the manuscript. IARC Monographs on the evaluation of carcinogenic risks to humans. Mortality and prevalence worldwide.

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