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.     

HPV Infection in Women: Psychosexual Impact of Genital Warts and Intraepithelial Lesions

IntroductionGenital Human Papillomavirus (HPV) infection is the most commonly occurring sexually transmitted viral infection in humans. HPV is a wide family of DNA viruses, which may cause benign skin and mucosal tumors (genital, anal, or oral warts), intraepithelial neoplasias, and/or malignant cancers in different organs. Women are more susceptible to the oncogenic effect of HPVs, mostly at the genital site on the uterine cervix.AimsThis review analyzes the impact of: (i) genital warts (GWs) and their treatment; (ii) HPV-related genital, oral, and anal precancerous lesions on women's sexual function.MethodsA Medline search was carried out. Search terms were HPV, GWs, intraepithelial neoplasia, cervical cancer, anal cancer, oral cancer, epidemiology, HPV risk factors, sexual dysfunctions, desire disorders, arousal disorders, dyspareunia, vulvar vestibulitis, vulvodynia, orgasmic difficulties, sexual repertoire, couple sexual problems, depression, anxiety, pap smear, screening program, therapy, and vaccines.Main Outcome MeasuresSexual consequences of HPV infection in women, specifically GWs and intraepithelial HPV-related neoplasia.ResultsPsychosexual vulnerability increases with number of recurrences of HPV infections. Depression, anxiety, and anger are the emotions most frequently reported. However, to date, there is no conclusive evidence of a specific correlation between HPV infection and a specific female sexual disorder. The relationship between HPV and vulvar vestibulitis/vulvodynia-related dyspareunia seems not to be direct. Counseling problems, the role of anti-HPV vaccine, and the concept of the high-risk partner are discussed. The reader is offered a practical approach with clinically relevant recommendations that may prove useful in his/her daily practice when dealing with HPV-infected women and couples.ConclusionThe evidence of psychosexual consequences of HPV-related GWs and intraepithelial lesions is limited. Specific research on the sexual impact of GWs and intraepithelial HPV-related lesion in women is urgently needed. Graziottin A, and Serafini A. HPV infection in women: Psychosexual impact of genital warts and intraepithelial lesions. J Sex Med 2009;6:633–645.     

Clinical implications of the interaction between HPV and HIV infections

HIV-related immunodeficiency has complex effects on female genital HPV, which include increased risks of infection, multiple types, persistence, reactivation and the risk to develop pre-invasive and invasive disease.Reconstitution of immunity with anti-viral drugs improves cellular immunity, but the risk of HPV-related malignancy remains higher than background incidences and presents at younger ages. Early initiation of antiretroviral therapy (ART) allows improved retention of immune memory through existing antibodies and T-cell clones and improves long-term outcomes.Suggestions of a higher risk to contract HIV if there is existing genital HPV infection are supported and explained by pathophysiological cervical changes, including inflammation.HIV–HPV interactions should influence public health decisions towards prioritising large-scale prepubertal HPV-vaccine roll-out, secondary cervical cancer prevention and early detection programmes for HIV-infected women and early initiation of ART.This chapter will also focus on special considerations for the management of women with co-infection with these two viruses and genital HPV-related diseases.     

TLR3在宫颈抗病毒免疫及宫颈病变中的作用

Toll样受体3（toll-like receptor 3,TLR3）是天然免疫中重要的模式识别受体（PRRs）家族成员之一,可以特异性地识别病毒双链RNA,激活宿主保护性免疫反应,清除病毒.TLR3主要表达于免疫细胞,也可在上皮细胞及上皮细胞来源的肿瘤细胞中表达,在机体抗感染、炎症反应、肿瘤进展等病理生理过程中发挥重要作用.女性生殖道黏膜是抵抗病原微生物感染的重要屏障,TLR3参与女性生殖道生理、病理改变.对TLR3在宫颈人乳头瘤病毒（HPV）持续性感染、宫颈癌前病变及宫颈癌发生中的作用进行综述.     

女性肾移植患者合并下生殖道癌前期病变的临床分析

目的:了解女性肾移植患者发生下生殖道癌前期病变的临床特征。方法:回顾分析阴道镜门诊应用宫颈细胞学、阴道镜与组织病理学,检查评估12例肾移植患者是否合并宫颈、阴道、外阴、肛周等部位的癌前期病变;用凯普核酸分子导流杂交基因芯片技术检测其中8例患者宫颈阴道分泌物中人乳头瘤病毒(HPV)基因分型。结果:(1)宫颈细胞学检测结果异常11例;(2)阴道镜检查宫颈转化区异常10例,同时合并阴道或外阴、肛周多部位病变8例;(3)组织病理学诊断结果:宫颈上皮内瘤变(CIN)2～3级5例,CIN1级及(或)宫颈HPV感染6例;同时合并阴道或外阴、肛周多部位病变8例;(4)HPV基因分型的检测结果:高危型HPV感染5例,低危型HPV感染1例;(5)失访1例。获得随访的11例(6～66个月)均持续存在宫颈细胞学及(或)阴道镜检查结果异常,无1例进展为浸润癌。结论:女性肾移植患者发生高危型HPV感染与下生殖道多部位的癌前期病变相当常见。高等级的CIN、外阴上皮内瘤变(VIN)与肛周上皮内瘤变(AIN)的发生率高且消退缓慢。     

Human Papillomavirus Infections: Current Concepts,New Developments

New epidemiologic and biologic knowledge of the natural history genital human papillomavirus (HPV) infections is rapidly being accumulated. There is overwhelming evidence that most HPV infections are transient particularly in the adolescent, and are not clinically important. There is a small proportion of adult women however, who harbour persistent HPV infections. These women are at considerable risk of developing high grade intra-epithelial neoplasia, and, if undetected and untreated invasive carcinoma.Screening, diagnostic, and management strategies should be tailored according to the HPV-related carcinoma risk potential of a specific area in the lower genital tract. The cervix is undoubtedly the site which carries the highest carcinoma risk among the areas along the lower genital tract. Molecular technology is now available or detecting and typing efficiently HPV DNA. This HPV testing has been shown to be useful in guiding management of women with minor grade cytologic atypia. The HPV DNA triage approach considerably reduces unnecessary colposcopies and the cost of managing this category o women.Several alternatives are available for treating patients with genital HPV infections. The most attractive advances made in the treatment of infra-epithelial cervical lesions and external genital warts are the loop electrosurgical excision procedure and the topical application of an immuno-enhancer agent respectively. The ultimate goal for the prevention and treatment of HPV infections is centred on the development of HPV vaccines.     

Human papillomavirus DNA in situ hybridization may be used for the quality control of genital tract biopsies

Biopsies of human papillomavirus (HPV)-related lesions of the lower female genital tract were studied using in situ hybridization for HPV DNA. The probes included HPV types 6, 11, 16, 18, 31, 33, 35, 41, 43, 44, 45, 51, 52, and 56. In cervical intraepithelial neoplasia (CIN) 1 lesions, 64 of 70 (91%) of formalin-fixed tissues were HPV DNA-positive; in vulvar condylomata, 34 of 36 (94%) were positive. Only two of 52 (4%) of the lesions diagnosed as equivocal for CIN 1 or condyloma were positive. Higher-grade CIN and vulvar intraepithelial neoplasia lesions had a lower rate of HPV DNA positivity. It is suggested that in situ hybridization may be used as a quality control procedure for the histologic diagnosis of HPV-related lesions.     

Human papillomavirus infection and cervical neoplasia: new perspectives

This review addresses several problems associated with human papillomavirus (HPV) infection of the cervix and lower female genital tract. These include the definition of HPV infection and its distinction from HPV-associated neoplasia, the distinction of HPV infection from reactive epithelial changes induced by other infections, and the transmission of HPV infection via the male partner. The available evidence indicates that there are two distinct intraepithelial processes in the cervix associated with HPV. One is the classical condyloma and its counterpart in immature epithelium, atypical immature metaplasia. The other is intraepithelial neoplasia, which, like classical infection, may be mature [cervical intraepithelial neoplasia (CIN) with koilocytosis] or immature (high grade CIN or carcinoma in situ). Molecular hybridization studies indicate that HPVs 6 and 11 are most commonly detected in the former, whereas HPVs 16 and 18 DNA are most common in the latter and in invasive cancer. From the clinical standpoint the most important distinction is between HPV-related disease (condyloma or CIN) and reactive changes associated with other pathogens, such as Chlamydia. The former should be removed from the cervix, whereas the latter should be treated medically or followed. It is stressed that therapy should not hinge upon the histological distinction of HPV infection from neoplasia and that all lesions should be removed, by conservative means if possible. This is underscored by the fact that a high proportion of CIN lesions contain areas identical to condyloma and that lesions with deep endocervical canal involvement, including those with features suggesting condyloma, should be treated by cone biopsy to exclude the presence of invasive cancer. Histological classifications for nonneoplastic, HPV-infected, and neoplastic epithelium are proposed. The management of the male partner is still unsettled. However, a large proportion of male partners of these patients have penile lesions and should be included in diagnostic and therapeutic protocols of women with genital HPV infections or neoplasms.     

Anti human papillomavirus vaccine: the checkmate to human papillomavirus?

Cervical cancer is the second most frequently found neoplasia in women worldwide. At least 95% of cervical cancers contain viral DNA which, in 80% of cases, belongs to one of the human papillomavirus (HPV) viral types at high oncogenic risk: 16, 18, 31 and 45. HPV is, at this point, considered the first "necessary cause" of cervical cancer, against which primary prevention with a reduction in the risk of infection can be carried out. Numerous molecular biological studies have been conducted to identify the biological markers of this infection and to refine an effective and well tolerated vaccine capable of preventing HPV infection as well as possibly treating those cases in which the infection has already caused an HPV-related disease of the genital tract. In the near future, the real primary prevention of this disease will be conducted, similar to what occurred for Hepatitis B, using immunoprophylaxis with an anti-cancer vaccine.     

Human papillomavirus types 6 and 16 in multifocal intraepithelial neoplasias of the female lower genital tract

Five women with multifocal intraepithelial neoplasia of the lower genital tract were investigated for the presence of human papillomavirus (HPV) infection by the method of DNA-DNA hybridization which detects the viral DNA. The DNA sequences of HPV types 6 and 16 were detected in each of the five patients and in each of the areas biopsied: cervix, vagina and vulva. DNA sequences of both viral types were also found in vulval intraepithelial neoplasia grades I-III and in cervical intraepithelial neoplasia grades I and III. The detection of HPV DNAs in multifocal lesions suggests a possible common aetiology for the lower genital tract intraepithelial neoplasias.     

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.     

Strategies for the prevention of cervical cancer by human papillomavirus vaccination

As cervical cancer is causally associated with 14 high-risk types of human papillomavirus (HPV), a successful HPV vaccine will have a major impact on this disease. Although some persistent HPV infections progress to cervical cancer, host immunity is generally able to clear most HPV infections. Both cell-mediated and antibody responses have been implicated in influencing the susceptibility, persistence or clearance of genital HPV infection. There have been two clinical trials that show that vaccines based on virus-like particles (VLPs) made from the major capsid protein, L1, are able to type specifically protect against cervical intra-epithelial neoplasia and infection. However, there is no evidence that even a mixed VLP vaccine will protect against types not included in the vaccine, and a major challenge that remains is how to engineer protection across a broader spectrum of viruses. Strategies for production of HPV vaccines using different vaccine vectors and different production systems are also reviewed.     

Chlamydia trachomatis infection: implications for HPV status and cervical cancer

Genital Chlamydia trachomatis (CT) infections have been identified as a major health problem concern. CT is associated with adverse effect on women reproduction and also associated with cervical hypertrophy and induction of squamous metaplasia, providing a possible relationship with human papillomavirus (HPV) infection. Infection by high-risk HPV types is crucial to the pathogenesis of invasive cervical cancer (ICC), but other co-variants/cofactors must be present for the development of malignancy. CT biological effect may damage the mucosal barrier, improving HPV infection, or may interfere in immune response and viral clearance supporting the persistence of HPV infection. Moreover, CT-related chronic cervical inflammation, decrease of lower genital tract antigen-presenting cells, inhibition of cell-mediated immunity, and anti-apoptotic capacity may influence the natural history of HPV infection, namely persistence progression or resolution. Although several epidemiological studies have stated a positive association involving CT and HPV-related cervical neoplastic lesions and/or cervical cancer (CC), the specific role of this bacterium in the pathogenesis of cervical neoplasia has not been completely clarified. The present review summarizes several studies on CT role in cervical cancer and suggests future research directions on HPV and CT interaction.     

Human papillomavirus types 6 and 16 in multifocal intraepithelial neoplasias of the female lower genital tract

Summary. Five women with multifocal intraepithelial neoplasia of the lower genital tract were investigated for the presence of human papillomavirus (HPV) infection by the method of DNA-DNA hybridization which detects the viral DNA. The DNA sequences of HPV types 6 and 16 were detected in each of the five patients and in each of the areas biopsied: cervix, vagina and vulva. DNA sequences of both viral types were also found in vulval intraepithelial neoplasia grades I-III and in cervical intraepithelial neoplasia grades I and III. The detection of HPV DNAs in multifocal letions suggests a possible common aetiology for the lower genital tract intraepithelial neoplasias.     

Epidemiology and Burden of Disease Associated with HPV Infection

Infection with certain types of human papillomavirus is associated with approximately 660,000 cancers and over 350 million cases of genital warts annually. This ubiquitous virus is transmitted by skin-to-skin contact, including through sexual contact. Of the 40 types infecting the anogenital tract, approximately 15 are considered carcinogenic, particularly types 16 and 18 which are the commonest types found in women diagnosed with invasive cervical cancer. HPV has oncogenic potential at the cervix, vagina, vulva, penis, anus, and certain head and neck cancers. Benign disease is expressed as genital warts and the very rare condition of laryngeal papillomatosis. Infection with oncogenic types of HPV is considered essential in nearly all invasive cervical cancers and a varying percentage of the other HPV-related cancers. Recently, two HPV vaccines, the bivalent and quadrivalent vaccines, have become commercially available and both have shown high immunogenicity and efficacy. The vaccine is prophylactic, and current recommendations are to administer the vaccines to girls 9–12 years of old and, in settings with increasing resources, to extend the target group to boys and to older girls up to 26 years. The combination of vaccine and screening has the potential to significantly reduce the burden of HPV-related disease.     

Immunity of the female genital tract mucosa and mechanisms of papillomavirus evasion

Human papillomaviruses (HPV) are responsible for many cutaneous and mucosal lesions. Some viral genotypes are considered to be the causal agents of cervical cancer. Natural genital HPV infection seems to be poorly immunogenic because of its nonproductive and noninflammatory characteristics and also because of the different mechanisms developed by the virus to counteract the immune response. Knowledge of the immune system organization and its regulation in the human female genital tract needs to be clarified. It is mostly "programmed" to ensure a humoral response. Nevertheless, secretory IgA, that are particularly efficient for anti-infectious mucosal immunity are poorly present in physiological vaginal secretions. These distinctive features could explain part of the relative immune deficiency against HPV. Moreover, reduction or loss of MCH1 molecules and a defect in antigen presentation to cytotoxic lymphocytes could in part explain the cytotoxicity deficiency. There is however clear evidence that cellular immune response plays a major role in the control and course of HPV infection. This response varies according to the grade of the lesion and to the oncogenic potential of the infecting HPV. A deficiency in induction of cellular cytotoxicity mechanisms seems to be involved in the persistence of HPV infection and so in carcinogenesis. Finally, worldwide cervical cancer incidence (5000000 new cases per year) warrants effective vaccine developments. Two strategies, one preventive and one therapeutic, are now under study. Vaccine adjustments are based first on humoral immunity induction with production of neutralizing antibodies for prophylaxis and second on cellular immunity induction to kill cells with viral oncoprotein expression for therapy.     

Human papilloma virus: diagnostic, treatment and preventive issues

Human Papilloma Virus (HPV), a sexually transmitted virus, is usually found in the genital tract and causes various lesions at the mucosae of both men and women. It is considered as a causative factor of cervical cancer even if all women infected by HPV will not develop the disease. This article reviews diagnostic aspects and therapeutic alternatives for the treatment of HPV infected females, as well as aspects concerning the prophylactic HPV vaccines.     

Screening for human papillomavirus infections of the lower genital tract

Human papillomavirus (HPV) infections are the etiologic agents in the development of lower genital tract neoplasia. Risk factors for the development of cervical cancer include high risk HPV subtype, persistent infection, high viral load, immunosuppression, tobacco use, and absence of cytologic screening. Strategies to increase the yield on screening for cervical neoplasia have included the use of HPV subtyping. This review summarizes the studies of HPV testing as a primary screening test, an adjunct for screening low and high risk populations, and for follow-up in women with persistent squamous intraepithelial lesions. Use of HPV screening is not yet applicable to populations with successful screening programs in place. Molecular markers for progression to cancer in women with persistent high risk HPV infections need to be discovered.     

Increased frequency of genital human papillomavirus infection in human immunodeficiency virus-seropositive Taiwanese women.

BACKGROUND AND PURPOSE: Human papillomavirus (HPV) infection is associated with increased incidence and severity of HPV-related cervical dysplasia and cervical cancer in women with human immunodeficiency virus (HIV) infection. This study examined the incidence of genital HPV infection in HIV-infected Taiwanese women and its relationship with cervical neoplasia. METHODS: This hospital-based, case-control study enrolled 31 consecutive HIV-seropositive women and 124 age-matched women who were free from HIV infection. Polymerase chain reaction (PCR) was used to distinguish high-risk (types 16, 18, 31, 33, 52 and 58) and low-risk HPV (types 6 and 11). The occurrence of genital HPV infection was compared between women with and without HIV infection. In addition, CD4 lymphocyte counts were determined by flow cytometry and Papanicolaou test was done in women with HIV infection. RESULTS: HPV and Papanicolaou test were done soon after the diagnosis of HIV infection. HIV seropositive women had a significantly greater high-risk HPV infection rate (48.4%; 15/31) than women without HIV infection (20.2%; 25/124; odds ratio, 3.71; p = 0.001). However, the prevalence of cervical intraepithelial neoplasia was similar between women with and without HIV infection. The CD4 lymphocyte counts in HIV-seropositive women were similar between those with and without genital HPV infection. CONCLUSIONS: The risk of genital HPV infection was significantly increased in HIV-infected women. Due to the association between high-risk HPV infection and the development of cervical dysplasia and cervical cancer, regular follow-up of Papanicolaou test is necessary in these women.     

Human Papilloma Virus Infection and Associated Intraepithelial Neoplasia of the Cervix, Vagina and Vulva

A prospective colposcopic and histological study was performed on 333 patients with cytologically detected human papilloma virus infection (HPV) without cytological evidence of associated intraepithelial neoplasia. The colposcopic changes seen in the cervix, vagina and vulva were documented and target biopsies were taken from abnormal areas in these 3 sites. Colposcopic and histological evidence of HPV infection was found in the cervix of 314 patients (94%), vagina in 274 patients (82%) and vulva in 146 patients (44%). Histologically proven cervical intraepithelial neoplasia was found in 94 of 333 patients biopsied (28%), vaginal intraepithelial neoplasia in 3 of 333 patients biopsied (0.9%) and vulval intraepithelial neoplasia in 9 of 146 patients biopsied (6.2%). This study identified the colposcopic changes of HPV infection to be widespread throughout the lower female genital tract. The diagnosis of intraepithelial neoplasia undetected by cytology in 28% of patients with HPV infection indicates that such patients require colposcopy and target biopsy according to the colposcopic findings.