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.     

Role of human papilloma virus testing in cervical cancer prevention

A clear causal relationship has been established between human papilloma virus (HPV) infection and the development of cervical cancer. Genital HPV infection is currently the most common sexually transmitted disease worldwide. The recent 2001 American Society for Colposcopy and Cervical Pathology Consensus Guidelines have included HPV testing for management of women with cervical cytological abnormalities. Clinicians now face the challenge of deciding when to use HPV testing in follow-up of abnormal Pap tests. This article includes updates on HPV, cervical cancer screening, and HPV testing technology. Recommendations for integration of HPV testing into clinical practice are provided.     

A study of women's knowledge regarding human papillomavirus infection, cervical cancer and human papillomavirus vaccines

AIMS: Human papillomavirus (HPV) infection is a common sexually transmitted viral infection and is associated with the development of cervical cancer. HPV vaccines are now undergoing phase 3 clinical trials in Australia. It is likely that an HPV vaccine will become licensed for use in the near future. METHODS: Ninety women aged 18-30 years from three different groups (those attending a dysplasia clinic, a local university health service and participants currently involved in a phase 3 HPV vaccine trial) completed a questionnaire assessing their knowledge base regarding HPV infection, cervical cancer, Pap tests and HPV vaccines. RESULTS: Respondents demonstrated good understanding of the Pap test and interpretation of an abnormal result. Most respondents (89%) had heard of HPV and attributed a number of different clinical symptoms to infection. For women who had not heard of an HPV vaccine, 79% of respondents stated that the most common resource they would use to obtain further information is their general practitioner. DISCUSSION: Many women do not understand the risk factors for HPV infection, the clinical problems it may cause and the potential long-term complications of infection. Few women have heard of a HPV vaccine, but most women surveyed would approach their general practitioner for more information if one became available. CONCLUSION: This study highlights the need for further education regarding HPV infection and the potential long-term complications such as cervical cancer. It also demonstrates that education of general practitioners regarding an HPV vaccine is essential, as this is the most likely resource women will use to obtain further information in the future.     

阴道微生物与人乳头瘤病毒感染及宫颈上皮内肿瘤相关性研究进展

人乳头瘤病毒（HPV）感染是宫颈癌前病变或宫颈癌发生的必要条件,阴道微生物多样性的改变可能是造成HPV持续感染继而发生宫颈病变的伴随因素。正常女性阴道微生物多样性较低,仅由少数几种乳酸杆菌（Lactobacillus）构成主要菌群。随着对细菌16SrRNA基因高通量测序技术的应用,越来越多的研究证实阴道菌群中非乳酸杆菌属微生物的多样性增加与HPV感染及宫颈病变存在密切联系。标志性的阴道微生物可能通过多种分子机制与宿主细胞及HPV相互作用,导致阴道局部免疫抑制、慢性炎症的状态,从而造成HPV持续感染及宫颈病变。重建阴道微生态平衡状态尤其是乳酸杆菌为主的阴道菌群是未来HPV感染及相关宫颈病变治疗的新途径。本文就阴道微生物多样性改变与HPV感染及宫颈病变发生的研究观点进行总结归纳。     

妊娠合并宫颈疾病诊治进展

妊娠期宫颈可发生炎性疾病,人乳头瘤病毒(HPV)感染,宫颈上皮内瘤样病变(CIN)甚至宫颈浸润癌。近年来,对妊娠期宫颈疾病的关注度逐渐上升。妊娠合并宫颈疾病可通过细胞学检查、HPV-DNA检测、P16/Ki67双联染色、阴道镜、活检和宫颈锥切等进行诊断。治疗方面妊娠合并HPV感染没有特别治疗;CIN患者排除宫颈浸润癌后可行细胞学及阴道镜随访至分娩;妊娠合并宫颈癌的处理较为复杂,需要考虑到肿瘤治疗与胎儿安全之间的平衡,治疗需综合考虑肿瘤大小、淋巴结转移情况及患者继续妊娠的意愿。分娩时机及分娩方式方面,合并宫颈感染性疾病及CIN的妊娠患者均按照产科处理;Ⅰa1期、间质浸润深度3 mm并且切缘阴性宫颈癌患者可妊娠至足月阴道试产,对于更高期别患者建议胎儿成熟后剖宫产终止妊娠。     

The use of vaccines in treating cervical cancer: present status and future prospects

Abstract. Onon TS, Kitchener HC. The use of vaccines in treating cervical cancer: Present status and future prospects.
HPV types are carcinogenic agents in cervical cancer. This view is supported by epidemiological and biological evidence. The oncogenic products and capsid proteins of high risk HPV types are potential targets against which effective immunity may be generated by vaccination. Both therapeutic and prophlylactic immunisation are potential strategies to deal with the widespread problem of HPV infection and possibly established cervical neoplasia. Clinical trials are now underway to evaluate candidate vaccines.     

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 human papillomavirus vaccines: the beginning of the end of cervical cancer

Persistent infection with one of the oncogenic human papillomavirus (HPV) types is a necessity for the development of cervical cancer. By HPV vaccination, cervical cancer could become a very rare disease. Two types of HPV vaccines can be distinguished: (i) therapeutic vaccines which induce cellular immunity targeted against epithelial cells infected with HPV and (ii) prophylactic vaccines inducing virus-neutralizing antibodies protecting against new but not against established infections. At present, several vaccines have been developed and tested in clinical trials. The vaccines are generally well tolerated and highly immunogenic. The current clinical data indicate that prophylactic vaccines are very effective against new persistent infections and the development of cervical intraepithelial lesions. The protection is type specific. However, the follow-up of the vaccination trials is still short. The effect of HPV vaccines on future cancer incidence will only be known after decades of follow-up. This article will address the status of recently terminated phase II and currently running phase III trials with prophylactic HPV vaccines.     

宫颈癌HPV预防性疫苗的研究进展

人乳头瘤病毒（HPV）感染是常见的性传播疾病之一。高危人乳头瘤病毒（hrHPV）持续感染是宫颈癌前病变及宫颈癌的主要危险因素。HPV16和HPV18型导致全球大约70%的宫颈癌。宫颈癌普查可减少宫颈癌发生的危险,但不能阻止HPV的感染。很多报道表明,有效的HPV疫苗可以减少HPV相关的宫颈癌、生殖道疣状物的发病率和死亡率。因此,为了有效预防这类疾病,全世界开展了HPV预防性疫苗的研究。目前临床应用的HPV疫苗有HPV 2价疫苗、4价疫苗及9价疫苗,它们可以有效预防相应HPV类型的感染,从而大量减少与此相关的宫颈病变及宫颈癌的发病率和死亡率。本文就HPV、宫颈癌及这3类HPV疫苗的免疫原性、接种剂量的数量和临床应用进行综述。     

Differential viral loads of human papillomavirus 16 and 58 infections in the spectrum of cervical carcinogenesis

Human papillomavirus (HPV) load was reported to be related to the severity of cervical neoplasia but with controversy. The viral load-disease severity relationship was showed in HPV 16, but no study was made in HPV 58, the second most prevalent HPV in cervical cancer in East Asia. We studied cervical HPV loads in HPV 16- and HPV 58-infected cases of normal, low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (CC) by using quantitative polymerase chain reaction (Q-PCR) with type-specific primers in defined cell number. With the exception of HPV 16 infection in normal, viral loads varied greatly in each disease regardless of genotypes. The load of HPV 16 differed significantly among disease severities, with a dramatic increase from normal (1.14 +/- 2.25 copies/cell) to LSIL, HSIL, and CC (1599 +/- 2301, 7489 +/- 24,087 and 1878 +/- 2979 copies/cell, respectively) (P < 0.01). No significant difference was noted among different HPV 58 infections, with loads in normal, LSIL, HSIL, and CC of 503 +/- 641, 7951 +/- 27,557, 353 +/- 744, and 1139 +/- 2895 copies/cell, respectively. In comparison with HPV 16, HPV 58 subclinical infection confers a significant higher load (P < 0.01). Different HPV types behave differentially in the spectrum of cervical carcinogenesis. Unlike HPV 16, the infection load of HPV 58 does not correlate to the clinical severity. The wide variation of HPV loads among different HPV types and among squamous intraepithelial lesions and CC makes the viral load test unrealistic in differentiating different severities of cervical neoplasia.     

Human papillomavirus infection: an old disease, a new vaccine

Human papillomavirus (HPV) infection is common and causes a wide spectrum of disease. With recent advances in the development of prophylactic HPV vaccines, it is likely that these will be licensed for use in the near future. This review focuses on the science behind HPV vaccines, published clinical trial results for both prophylactic and therapeutic HPV vaccines, important issues relevant to implementation and cost-effectiveness models of HPV vaccination programs. It may be that an HPV vaccine that protects against the complications of HPV infection such as cervical cancer will be one of the most significant public health initiatives of this decade.     

The quadrivalent human papillomavirus vaccine: potential factors in effectiveness

Cervical cancer, caused by human papillomavirus (HPV) infection, is the second most common female cancer in the world, causing over a quarter of a million deaths worldwide every year. The quadrivalent HPV vaccine (Gardasil) has the potential to significantly reduce morbidity and mortality associated with cervical disease. However, a variety of factors affect the vaccine's success, including exposure to HPV prior to vaccination, duration of protection provided by the vaccine, the in vivo interaction between HPV serotypes, and variation in HPV serotype prevalence worldwide. This article describes the pathophysiology of HPV infection, efficacy and safety of the quadrivalent HPV vaccine, factors that may influence the vaccine's effectiveness in reducing cervical cancer rates, and recommendations for maximizing this effectiveness.     

肾移植术后免疫抑制剂治疗对人乳头瘤病毒感染及宫颈癌发生率的影响

目的:通过肾移植术后接受免疫抑制治疗的女性患者的人乳头瘤病毒(HPV)感染及宫颈癌发生率与同期我院妇科女性患者的对比,探讨肾移植术后免疫抑制治疗对女性高危型HPV感染及宫颈癌发生率的影响,为肾移植术后患者高危型HPV感染和宫颈癌的早期诊断和防治提供依据。方法:选取在我院行肾移植术的女性患者中,无其他器官移植,移植前无HPV感染、宫颈上皮内瘤变(CIN)及宫颈癌的患者865例作为研究组,选取我院妇科同期未进行器官移植的患者作为对照组,比较分析2组高危型HPV感染和宫颈癌发病情况。结果:研究组患者的高危型HPV感染率、CINⅢ及宫颈癌发生率均高于对照组,差异有统计学意义(均P<0.001);而研究组中高危型HPV感染、CINⅢ及宫颈癌的平均发病年龄与对照组比较差异均无统计学意义(均P>0.05)。结论:肾移植术后免疫抑制治疗不会使患者HPV感染及宫颈癌的发病年龄提前,但可能导致发生率增高。     

Association between HLA-DQB1 and cervical dysplasia in Vietnamese women

Host genetic background seems to play a key role in cervical carcinogenesis as only a small subset of women infected with high-risk human papillomaviruses (HPVs) develop cervical cancer. The rate of cervical cancer in Vietnamese women is notably high. To explore the association of human leukocyte antigen (HLA)-DQB1 alleles, HPV infection, and cervical dysplasia in this population, cervical smears were obtained from 101 women attending the obstetrics and gynecology clinic of Da Nang General Hospital in Vietnam. Besides the Papanicolaou test, HPV and HLA-DQB1 genotyping were performed using cervical smear DNA. Additionally, a subset of 30 blood samples was used as the gold standard for HLA genotyping. HLA-DQB1 alleles showed no association with HPV infection status. However, a positive association with cervical dysplasia was found for HLA-DQB1*0302 (P= 0.0229, relative risk (RR) = 4.737) and HLA-DQB1*0601 (P= 0.0370, RR = 4.038), whereas HLA-DQB1*0301 (P= 0.0152, RR = 0.221) was found negatively associated. The low diversity of HLA-DQB1 alleles, wide spectrum of HPV genotypes, and high prevalence of HPV 16 and HPV 18 observed in the study population suggest a permissive/susceptible genetic background that deserves further research. Total concordance of HLA-DQB1 genotyping results between blood and cervical cells confirms the potential value of cervical smears as an effective tool for the development of cervical cancer biomarkers.     

HPV多重感染与宫颈病变关系探讨

目的 探讨HPV多重感染与宫颈病变的关系。方法 对2004年8月-2005年5月期间在北京中日友好医院妇科门诊就诊的591位女性的宫颈细胞标本进行HPV基因型分型检测，比较不同宫颈病变类型组HPV多重感染的比例。结果本组资料中多重感染的比例为44，6％，最常见类型为HPV52、58及HPV16、18二重感染。除宫颈鳞癌组，HPV多重感染的比例随宫颈病变级别增加而增加，各组与正常组相比，差异显著（P〈0．05）。结论 HPV多重感染与宫颈病变的发生有关。     

Epidemiologic and mucosal immunologic aspects of HPV infection and HPV-related cervical neoplasia in the lower female genital tract: A review

Abstract. Tjiong MY, Out TA, ter Schegget J, Burger MPM, van der Vange N. Epidemiologic and mucosal immunologic aspects of HPV infection and HPV-related cervical neoplasia in the lower female genital tract: a review.
Human papillomavirus (HPV) infections are known to play an important role in the pathogenesis of cervical neoplasia. Considering the morbidity and mortality of cervical cancer, infection with HPV can be regarded as a worldwide problem, especially in developing countries. Currently, many studies focus on the development of both prophylactic and therapeutic HPV vaccines. Crucial for these vaccination protocols to be successful is that they will result in a long-lasting ability to generate an immune response that will eliminate the virus. HPV transmission and subsequent infection is a local event in the lower female genital tract and therefore the efficacy of vaccines against this locally transmitted infection can be best assessed by parameters of local immunity. In this review we describe both the epidemiology of HPV-related cervical neoplasia and the general aspects of mucosal immunity in the female genital tract while focusing on the local humoral immunity in HPV-related cervical neoplasia.     

宫颈癌变进展中人乳头瘤病毒甲基化的研究

高危型人乳头瘤病毒（HPV）持续感染是宫颈癌发生的直接原因,然而HPV感染后多数可被宿主免疫机制清除,只在部分病例中HPV感染持续存在并与宿主细胞DNA整合,导致宿主细胞癌变。HPV表观遗传学的改变在病毒整合及致宿主细胞癌变中起一定作用。对目前有关HPV表观遗传学特点在影响HPV自身表达和宫颈病变进展中作用的文献加以综述,了解HPV DNA甲基化状态在宫颈癌发生、发展中的作用。HPV基因表观遗传学状态有可能成为临床诊断和判断预后的分子标记物。     

宫颈病变患者配偶人乳头瘤病毒检测结果分析

目的了解宫颈病变患者配偶人乳头瘤病毒(HPV)感染情况,为宫颈病变的预防提供依据。方法对2009年12月至2011年4月在深圳市人民医院妇科门诊就诊,有宫颈病变且高危型HPV检测阳性的患者共86例及健康妇女35例(其配偶分别为研究组86例和对照组35例),采用PCR体外扩增和DNA反向点杂交相结合的DNA芯片技术,检测其配偶阴部HPV感染情况。结果研究组HPV检出阳性率为45.35%(39/86),明显高于正常对照组的17.14%(6/35)(P﹤0.01)。研究组HPV阳性者中有53.8%(21/39)的夫妻双方感染相同的HPV亚型,其中52型占首位。结论宫颈病变患者配偶HPV感染明显高于正常人群,且部分夫妻感染相同的HPV亚型,故对配偶进行HPV检测和健康宣教有利于宫颈病变的预防。     

Expression of the costimulatory molecule CD86, but not CD80, in keratinocytes of normal cervical epithelium and human papillomavirus-16 positive low squamous intraepithelial lesions

Keratinocytes have been traditionally considered as nonprofessional antigen presenting cells, since multipassaged cells from skin biopsies of healthy individuals do not constitutively express major histocompatibility complex (MHC) class II or costimulatory molecules, but can be induced to do so after exposure to interferon-gamma. In normal and human papillomavirus (HPV)-infected cervical epithelium, keratinocytes are affected by a variety of soluble mediators that could modulate the expression of molecules including costimulatory proteins; however, the presence of these molecules within the cervix has been poorly studied. Therefore, our aim was to further explore the presence of costimulatory molecules on normal cervical epithelium and HPV-16 positive low squamous intraepithelial lesions (LSIL). We found in situ CD86 (but not CD80) displayed on the surface of normal keratinocytes from the spinous layer of human cervical epithelium. The presence of the protein and its messenger RNA level (evaluated by in situ hybridization) was diminished in HPV-16 positive LSILs. Although downregulation of costimulatory molecules is frequently related to cytokines expression, we did not observe differences in the presence of interleukin-10, the main cytokine that inhibits CD86 expression. Expression of CD86 on keratinocytes from normal cervical epithelium could indicate the potentiality of these cells to activate cytotoxic T cells, while the shut-off of this molecule in HPV-16 positive lesions could be a mechanism for evading host immune surveillance, resulting in the persistent HPV infection and probable progression of cervical lesions.     

宫颈癌及癌前病变组织中Notch1及HPV16 E6/E7表达的研究

目的 探讨Notch1受体和人乳头瘤病毒16感染在宫颈癌前病变和宫颈癌发生发展中的作用。方法 采用免疫组化SP法检测18例宫颈上皮内瘤变（cervical intraepithelial neoplasia,CIN）和35例宫颈癌标本中Notch1受体及HPV16E6/E7蛋白的表达,以34例正常宫颈组织及慢性宫颈炎组织作为对照。比较各组间Notch1及HPV16E6/E7表达的差异,并分析Notch1与HPV16E6/E7表达的关系。结果 Notch1蛋白在细胞胞浆、胞核及胞膜中表达,HPV16E6/E7在细胞核中表达。从对照组到CIN组到宫颈癌组,Notch1及HPV16E6/E7的表达均逐渐增强（P〈0.01）。Notch1的阳性表达与宫颈癌不同分期、分化程度、淋巴结是否转移无关（P〉0.05）。在宫颈癌组中Notch1与HPV16E6/E7的表达均呈正相关性（P〈0.01）。结论 Notch1表达与HPV16E6/E7感染可能与CIN及宫颈癌的发生密切相关,两者在宫颈癌的发病机制中可能协同发挥作用。