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.     

p53 Expression and Genetic Evidence for Viral Infection in Intraepithelial Neoplasia of the Uterine Cervix

Infections with high-risk strains of human papillomaviruses (HPVs) and with herpes simplex virus type 2 (HSV 2), as well as inactivation of the p53 tumor suppressor gene, are important cofactors in cervical carcinogenesis. We analyzed 41 paraffin-embedded cervical intraepithelial lesions, including 25 cases of low-grade cervical intraepithelia neoplasia (CIN), and 16 cases of high-grade CIN for the presence of HPV 16/18 and HSV 2 genomic sequences and for the nuclear accumulation of the p53 protein. HPV 16 DNA was detected in 24.% of low-grade CINs and in 43.7% of high-grade CINs. HPV 18 was found only in 8.% of low-grade CINs. None of the cases tested scored positive for HSV 2 DNA. Nuclear accumulation of p53 was found in 4% of low-grade CINs, and in 31.2% of high-grade CINs, including 57.1% of the lesions that were positive for HPV 16. These results indicate that HPV 16 infection was over sixfold more common than HPV 18 infection and that p53 overexpression was significantly associated with high-grade lesions.     

At what age should we be vaccinating for human papillomavirus?

Human papillomavirus (HPV) infections cause high disease burden. Primary prevention by vaccination is a major breakthrough. HPV vaccines are well tolerated and safe. Vaccines protect unexposed individuals against high-grade CIN and VIN/VaIN caused by the vaccine HPV types. Vaccines also provide protection against related oncogenic HPV types. The primary target population is young adolescents before their sexual debut. Catch-up vaccination policy up to age 26 may facilitate long-term health benefits but should not divert resources from vaccinating the primary target population or from effective cervical cancer screening programmes. Health benefits of vaccinating older age groups beyond age 26 are unknown.     

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.     

A PCR study on the coexistence of herpes simplex virus, cytomegalovirus and human papillomavirus DNAs in cervical neoplasia

There is strong epidemiological and biological evidence that the development of squamous cell carcinoma of the cervix is a multistep process in which human papillomaviruses (HPVs) play a crucial but not total role and where the synergistic effect of herpes simplex virus (HSV) and human cytomegalovirus (HCMV) has been suggested. The presence of HPV, HSV and HCMV deoxyribonucleic acids (DNAs) was assessed by a polymerase chain reaction (PCR) in cervical biopsies obtained from 41 women with cervical neoplasia (21 high-grade cervical intra-epithelial neoplasia (CIN) and 20 squamous cell cancers) and 33 controls. Human papillomavirus 16 DNA was significantly more common in high-grade CIN (57%) and cancer (50%) than in normal cervix (9%). Herpes simplex virus and HCMV DNAs were present in 12% and 21% of normal cervices, 19% and 24% of high-grade CIN, and 25% and 25% of cancers, respectively. After adjustment for patients' age, coinfection associating high-risk HPVs (HPV 16 and/or HPV 18) and herpes viruses (HCMV and/or HSV) were observed in cervical neoplasia (odds ratio (OR) = 19.11; 95% confidence interval (CI): 2.14–170.36). Conversely, the OR for infection by HPV 16 and/or HPV 18 alone did not reach statistical significance (OR = 7.22; 95% CI: 0.85–61.16). Moreover infection by HCMV and/or HSV alone (OR = 0.89; 95% CI: 0.33–2.24) was not associated with cervical neoplasia. Our results support the role of HSV and HCMV as cofactors of HPV 16 and HPV 18 in cervical neoplasia.     

Detection and Clinical Management of Cervical Pathology in the Era of HPV

While infection with high-risk (HR) human papillomavirus (HPV) is central to cervical carcinogenesis, natural history studies show that both low- and high-grade cervical intraepithelial neoplasia (CIN) lesions are very early manifestations of HR-HPV infection. Most high- and low-grade lesions are self limited, and only those HR-HPV infections capable of persisting for decades are at risk of progression. Our new understanding of the natural history of HPV associated lesions has dramatically changed cervical cancer screening, classification and management of cervical lesions. As an increasing proportion of women are vaccinated against those oncogenic-HPVs responsible for most cervical cancers, the positive predictive value of cytology and HPV testing for identification of women at risk for cancer will decrease. New biomarkers, capable of identifying those high-grade lesions which are truly at risk of progression and need treatment, will need to be developed to serve as adjuncts to morphology and patient management.     

Prophylactic HPV vaccines

Infection with human papillomavirus (HPV), in particular HPV 16 and HPV 18, is the main cause of cervical cancer. Two prophylactic vaccines against types 6, 11, 16 and 18 have shown great promise in clinical trials, with recent results demonstrating 100% efficacy against persistent HPV infection and development of CIN up to five years of follow-up. One of these (Gardasil, recently licensed) contains all four HPV types, offering protection against genital warts (types 6 and 11) as well as cervical cancer. The other (Cervarix) contains types 16 and 18, targeting cervical cancer alone. Recent data suggest a degree of cross-protection, against types 31 and 45; this could significantly increase the level of protection afforded by the vaccines. It is envisaged that girls between 11 and 12 will be the target, and this is what has been recommended in the United States. There is still debate about the issue of vaccinating boys. A fundamental issue is the lack of education of both the public and health professionals about HPV. In theory, an HPV vaccine could prevent almost all cervical cancer, eventually removing the need for cervical smears. However, there is at least one whole generation of women for whom the vaccine will come too late, and who will continue to require screening.     

Cervical biopsy specimens and human papilloma virus positivity in patients with external genital warts

Cervical biopsy specimens were taken from 16 women with external genital warts in order to diagnose concomitant cervical human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) according to pathology. Positive HPV infection was detected 56% (9/16) of the patients. Among those patients 66% (6/9) had concurrent subclinical low-grade CIN lesions. One of those patients had a high-grade CIN lesion. It is concluded that cervical HPV infection was rather common in women with external genital warts and it is valuable to examine cervical HPV infection by biopsy to detect concomitant CIN.     

Will widespread human papillomavirus prophylactic vaccination change sexual practices of adolescent and young adult women in America?

Two virus-like particle human papillomavirus (HPV) vaccines have been shown to be nearly 100% effective in preventing type-specific persistent HPV infections and associated type-specific high-grade cervical intraepithelial neoplasia (CIN). Recently, it has been hypothesized that the administration of this vaccine to young girls in the United States might increase sexual promiscuity among adolescent women and/or young adults. Thus, it has been suggested that focused vaccine strategies either based on the risk of CIN or gender might be more rational or cost-effective. However, such strategies are unlikely to completely eradicate the burden of this disease and decrease the cost of cervical cancer screening. The suggestion that widespread vaccination will alter sexual practices is refuted and the rationale for the vaccination of all girls and boys is outlined.     

A modified terminology for cervical intraepithelial neoplasia

Recent data are consistent with the concept that human papillomavirus (HPV) is etiologically important in the causation of cervical squamous cell cancer. There appear to be certain important events in the process of HPV infection and neoplasia. It is suggested that the terminology of the HPV-related precursor lesions be modified and that two terms, rather than three, would best satisfy the requirements of both science and clinical care. The "early" lesions should be referred to as "low-grade cervical intraepithelial neoplasia (CIN) with HPV-related changes" and the lesions that have the features of cancer precursors as "high-grade CIN."     

Usefulness of human papillomavirus testing in the follow-up of patients with high-grade cervical intraepithelial neoplasia after conization

OBJECTIVE: We aimed to define the adjunctive role of human papillomavirus (HPV) DNA testing in the follow-up of high-grade cervical intraepithelial neoplasia (CIN) after conization. STUDY DESIGN: We analyzed a consecutive series of 2,154 patients who received conization. Patients who had cone diagnosis of cervical cancer or CIN 1, a hysterectomy within 12 weeks after conization, and no follow-up data were excluded. The remaining 765 patients (monitored by Pap smears, colposcopy with or without high-risk HPV DNA testing) were analyzed. RESULTS: Of the 765 patients, 279 had CIN at cone margin or endocervix (group A) while 486 were both margin- and endocervix-free (group B). The 3-year cumulative rate of residual/recurrent high-grade CIN was 10.3% (95% CI, 6.9-13.7). HPV follow-up status (P=.015), margin status (P=.001), and follow-up cervical cytology (P<.0001) were significant predictors for residual/recurrent high-grade CIN by multivariate analysis. Four high-grade CINs and 1 microinvasive carcinoma of group A were detected initially by HPV testing, while 48.3% (199/410) of those without recurrent/persistent high-grade CIN still had persistent HPV infection. CONCLUSION: HPV DNA testing is useful in the follow-up and understanding of the natural history after conization for high-grade CIN.     

Immune responses against virus and tumor in cervical carcinogenesis: Treatment strategies for avoiding the HPV-induced immune escape

Despite the availability of prophylactic vaccines against human papillomavirus (HPV), cervical cancer (CC) is still a major problem globally. It is the cancer with the second highest incidence and the third highest mortality in women worldwide, but, in less developed countries, it is an even greater problem being the second most common cause of cancer death. Although HPV infection is one of the most common sexually transmitted diseases, and high-risk HPV16 is the most frequent genotype involved, only a small number of HPV-infected women develop high-grade squamous intraepithelial lesions whereas, in the remainder of the women, the virus disappears spontaneously. There is a lot of evidence to support the view that host-dependent immunologic status and HPV-induced immune evasion are responsible for persistent HPV infection and subsequent development of cervical neoplasia. Therefore, the role of the immune system, not only in viral clearance but also in tumor antigen recognition, is particularly relevant in the case of cervical carcinogenesis. A better understanding of these processes would help in the development of therapeutic vaccines. This review aims to explain which immune cells and molecules are involved in the process of viral and tumor recognition, how their failure can lead to cervical carcinoma and what are the main therapeutic strategies so far tested in preclinical models and clinical trials to stimulate the immune system in cervical carcinoma.     

Neoplasia intraepitelial vulvar: Cribado en población de riesgo

BackgroundPatients with cervical intraepithelial neoplasia (CIN) are more likely to develop lesions caused by the human papilloma virus (HPV) in other locations of the lower genital tract (including the vulva). Vulvoscopy is not included in the follow-up of women with CIN. It is proposed to study the efficiency of including vulvoscopy in follow-up. An analysis is also performed on incidence of high-grade vulvar dysplasia, as well as the influence of protective and risk factors analysed.Material and methodsThe study included 95 patients with a diagnosis of CIN in the cone biopsy piece. All the information relative to their socio-demographic and clinical characteristics was collected and included, performing of the vulvoscopy as well as the biopsy.Results and conclusionsThe mean age of the patients was 40 years. Just under two-thirds (62.1%) of them were or had been smokers (more than half of those had quit smoking at the time of the study). Only 21.1% said they were not using a barrier method. Although 78.9% of those studied were or had been users of hormonal contraception, only 8 out of the 95 continued using it. Most (88 out of the 95 women) were vaccinated against HPV. No high-grade vulvar dysplasia was diagnosed. The modification in the lifestyle after the diagnosis of the cervical disease, the transience of the HPV infection, and the greater susceptibility of the cervical epithelium to this, are indicated as the most probable causes of the discordance between the expected prevalence of vulvar disease and the effective rate found within the studied population.     

Colposcopy and cervical intraepithelial neoplasia

Cervical cancer is both preventable and curable. It has a long natural history with a prolonged pre-cancerous phase that is easily detectable and treatable. Exfoliative cytology has been the mainstay for screening of cervical intra-epithelial neoplasia (CIN). Assessment of women presenting with abnormal cervical cytology and the selection of those requiring treatment relied mainly on colposcopic impressions of the cervical transformation zone and the histological appraisal of directed punch biopsies. The need to maximise clinical resources, achieve quicker and more effective management of patients, limit postoperative complications and preserve reproductive function has led to the popularity of local excisional methods for cervical premalignancy. Although the cure rates for all local ablative and excisional methods are more than 90% after one treatment, the excisional methods provide a more reliable histopathological diagnosis and the patient can be treated at the initial visit. The recognition that persistent infection with oncogenic human papillomavirus (HPV) causes cervical cancer has led to the development of new HPV tests/biomarkers and prophylactic vaccines against HPV. The HPV DNA test that targets the viral DNA has been introduced as a test of cure after CIN treatment and as a triage tool in women presenting with borderline or low-grade findings at cytology. HPV DNA test will be introduced in primary screening in the future. The national HPV immunisation programme was initiated in the NHS in September 2008. The vaccines are safe, well tolerated and highly efficacious in HPV naive women.     

Human papillomavirus genotype prevalence in cervical biopsies from women diagnosed with cervical intraepithelial neoplasia or cervical cancer in Melbourne, Australia

Multicenter international phase III clinical trials using multivalent human papillomavirus (HPV) vaccines for cervical cancer (CC) prevention are underway. As HPV immunity is type specific, defining HPV genotype prevalence in different regions to ascertain whether predominant types differ geographically is considerably important prior to vaccine implementation. This study aimed to define HPV genotypes present in CC and high-grade dysplasia among women in Melbourne, Australia. HPV genotype analysis of a cross section of women in Melbourne with cervical dysplasia/cancer was performed. A total of 493 cervical biopsies from patients being treated for moderate (n= 122) or severe (n= 180) cervical intraepithelial neoplasia (CIN II/III) or CC (n= 191) were tested for HPV genotypes using the PGMY09/11 primer system and line blot assay. HPV detection rates were 63.9%, 72.8%, and 86.9% in CIN II, CIN III, and CC biopsies, respectively. The most prevalent HPV genotypes among CC biopsies were HPV-16 (52.9%), HPV-18 (18.3%), HPV-45 (6.3%), HPV-39 (3.1%), and HPV-73 (2.6%). Multiple HPV infections, comprising two to five types, were identified in 14.4% of biopsies, being significantly fewer (5.2%) among CC biopsies (P < 0.0001). These results indicate that the two most prevalent CC-associated HPV genotypes in Australia parallel those described internationally, with type variations thereafter.     

HPV16 and increased risk of recurrence after treatment for CIN

OBJECTIVE: Addition of high-risk human papillomavirus (hrHPV) testing to post-treatment monitoring policies of women treated for high-grade cervical intraepithelial neoplasia (CIN) may improve the effectiveness of detecting recurrent/residual disease. Recent studies have shown that HPV type 16 confers an increased risk of high-grade CIN and cervical cancer. This study aimed to find out whether the post-treatment CIN3 rate is increased in HPV16-positive women treated for CIN3. METHODS: We included 229 hrHPV-positive women treated for CIN3. HPV typing was performed by GP5+/6+-PCR followed by reverse line blotting on a cervical scrape taken before treatment. HPV typing data were related to the occurrence of post-treatment CIN3 within a median follow-up time of 20.1 months (range 3-85.4 months) following treatment. RESULTS: Twenty nine of the 151 (19%) HPV16-positive women versus 6 of the 78 (8%) women with other hrHPV types had recurrent/residual CIN3. Post-treatment CIN3 rate was significantly increased in women with HPV16 compared to those harboring other hrHPV types (p=0.03). None of the other hrHPV types were associated with higher post-treatment CIN3 rates. CONCLUSION: Women treated for HPV16 containing CIN3 should be monitored more intensively because of their increased risk of post-treatment CIN3. Thus, the HPV genotype should be considered in post-treatment monitoring policies.     

216例宫颈细胞学为ASCUS的临床意义及处理探讨

目的：探讨宫颈细胞学诊断为意义未明的不典型鳞状细胞（ASCUS）的临床意义及处理方法。方法：2008年1月—2009年12月,对天津医科大学总医院妇科门诊的216例宫颈细胞学诊断为ASCUS的患者行阴道镜评估与镜下活检,其中140例同时接受了人乳头瘤病毒（HPV）检测。结果：①ASCUS患者宫颈上皮内瘤样病变（CIN）的发生率为44.44%,高级别CIN与宫颈癌发生率为20.37%。②高级别CIN及宫颈癌发病平均年龄为（44.57±11.23）岁,明显高于湿疣和低级别CIN者（均P＜0.05）。③发生宫颈高级别CIN及宫颈癌的ASCUS患者高危HPV亚型以16型最常见,出现概率为41.67%,HPV58、18、52型感染率排在第2～4位。④HPV阳性者CIN检出率为55.56%,明显高于HPV阴性者的31.25%和直接阴道镜检的38.16%（均P＜0.05）。⑤HPV检测高度鳞状上皮内病变（HSIL）阴性预测值为93.75%。结论：ASCUS病理类型复杂,32岁以下年轻患者发生宫颈湿疣可能性大,40岁以上特别是合并HPV16、58、18、52型感染者应警惕高级别CIN及宫颈癌的可能。ASCUS患者应先行HPV检测分流,阳性者联合阴道镜检查以提高CIN检出率,阴性者可定期重复细胞学检查。     

216例宫颈细胞学为ASCUS的临床意义及处理探讨

目的：探讨宫颈细胞学诊断为意义未明的不典型鳞状细胞（ASCUS）的临床意义及处理方法。方法：2008年1月—2009年12月,对天津医科大学总医院妇科门诊的216例宫颈细胞学诊断为ASCUS的患者行阴道镜评估与镜下活检,其中140例同时接受了人乳头瘤病毒（HPV）检测。结果：①ASCUS患者宫颈上皮内瘤样病变（CIN）的发生率为44.44%,高级别CIN与宫颈癌发生率为20.37%。②高级别CIN及宫颈癌发病平均年龄为（44.57±11.23）岁,明显高于湿疣和低级别CIN者（均P〈0.05）。③发生宫颈高级别CIN及宫颈癌的ASCUS患者高危HPV亚型以16型最常见,出现概率为41.67%,HPV58、18、52型感染率排在第2～4位。④HPV阳性者CIN检出率为55.56%,明显高于HPV阴性者的31.25%和直接阴道镜检的38.16%（均P〈0.05）。⑤HPV检测高度鳞状上皮内病变（HSIL）阴性预测值为93.75%。结论：ASCUS病理类型复杂,32岁以下年轻患者发生宫颈湿疣可能性大,40岁以上特别是合并HPV16、58、18、52型感染者应警惕高级别CIN及宫颈癌的可能。ASCUS患者应先行HPV检测分流,阳性者联合阴道镜检查以提高CIN检出率,阴性者可定期重复细胞学检查。     

High-risk human papillomavirus DNA testing and high-grade cervical intraepithelial lesions

OBJECTIVE: To explore the role of high-risk human papillomavirus (HPV) DNA testing in the improvement of the recognition of cervical cancer and precancerous lesions in women with abnormal cervical cytology. METHODS: A total of 2152 women with abnormal cervical cytology were submitted to both HPV DNA testing and biopsy guided by colposcopy and the results were correlated. RESULTS: Positive rate of high-risk HPV DNA in groups of atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells, cannot exclude high-grade (ASC-H), low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions was 53.7, 53.2, 84.6 and 93.0%, respectively. In each group, the detection rate of grade 2,3 cervical intraepithelial neoplasia (CIN 2,3) or cervical cancer in patients with positive HPV DNA was significantly higher than that with negative HPV DNA (P<0.05). In ASC-US group, the negative predictive value of high-risk HPV DNA testing for detection of CIN 2,3 and cervical cancer was 99.8% and the sensitivity 98%. CONCLUSION: HPV DNA testing is a useful indicator in the management of patients with ASC-US and plays an important role in the evaluation of risk for CIN 2,3 and cervical cancer.