Human papillomavirus in cervical screening and vaccination

Recent decades have witnessed a reduction in the incidence of cervical cancer in countries where screening programmes have achieved broad coverage. The recognized importance of high-risk HPV (human papillomavirus) infection in the aetiology of cervical cancer may introduce a role for HPV DNA testing in cervical screening programmes. Positive HPV DNA tests indicate women at risk of cervical cancer with greater sensitivity, but reduced specificity, compared with exfoliative cytology. Combining HPV testing with cytology may be useful in the triage of minor cytological abnormalities into those requiring referral to colposcopy (HPV positive) compared with those who can be safely managed by cytological surveillance (HPV negative). With its high sensitivity and high-negative-predictive value, HPV testing may also be useful for predicting treatment failure, since residual disease is very unlikely in the event of a negative HPV test. Ultimately, prevention is better than cure, and the advent of HPV prophylactic vaccines may obviate the need for population-based cervical screening programmes in the future. A multivalent vaccine administered to adolescents prior to the onset of sexual activity and boosted at regular intervals throughout their sexually active life may provide protection against type-specific HPV infection, malignant precursors and invasive cervical disease. Several large randomized placebo-controlled trials have been conducted with promising results. For those generations of women already exposed to high-risk HPV infection, therapeutic vaccines may offer advantages over conventional treatment, although much work still needs to be done.     

Human papillomavirus, cervical cancer, and the vaccines

How are human papillomavirus (HPV), cervical cancer, and the recently developed HPV vaccines associated with each other? Human papillomavirus is a highly prevalent infection that is easily and unknowingly transmitted because of its asymptomatic nature and long incubation period. Infection requires skin-to-skin contact and is typically sexually transmitted. More than one-half of sexually active women acquire HPV, making it the most prevalent sexually transmitted disease. Cervical cancer ranks second in deaths from cancer among women in developing countries and kills nearly 4000 women in the United States annually. Several types of HPV have been strongly linked to causing cervical cancer and genital warts. Those causing cervical cancer are considered high-risk types and those causing genital warts are considered low-risk types. Until recently, prevention strategies included abstinence, condom usage, and early detection with a Papanicolaou test (Pap smear). New developments have led to 2 vaccines aimed at preventing the viral infection. One is a quadrivalent vaccine preventing infection from 4 HPV types (HPV types 6, 11, 16, and 18) (Gardasil). It is approved in the United States and Europe for the prevention of HPV-associated cervical cancers and genital warts in females between the ages of 9 and 26 years old. The second is a bivalent vaccine preventing infection from 2 high-risk oncogenic HPV types (HPV types 16 and 18) (Cervarix). It is currently under study and not yet available in the United States. Both vaccines have proven highly effective at preventing infection from their corresponding HPV types. Of importance, neither vaccine is to be used for treatment. Vaccination does not replace routine cervical cancer screening with Pap smears, as the vaccines do not protect against all HPV types.     

Molecular basis for advances in cervical screening.

Human papillomaviruses (HPVs) cause cervical lesions, which can, in some instances, progress to high-grade neoplasia and cancer. Around half a million cases of cervical cancer occur each year, with most occurring in developing countries where cervical cancer is a major cause of cancer-related death. The reduction in cervical cancer incidence in developed countries is largely attributed to the introduction of cervical screening.Cervical screening currently depends on the identification by cytology of abnormalities in cells taken from the surface of the cervix. The standard Pap test was developed >50 years ago, and despite modifications, still forms the basis of the test currently in use in most routine screening laboratories. Advances in our understanding of the molecular mechanisms that lead to the development of cervical cancer have been slow to impact on screening, despite the relatively high false-negative rates that can be associated with the conventional Pap smear.Improvements in screening strategies fall into a number of categories. Methods that improve cell presentation and attempt to eliminate artefacts/obscuring debris can be combined with image analysis systems in order to enhance diagnostic accuracy. Such approaches still rely on cytological evaluation and do not incorporate advances in our knowledge of how HPV causes cancer. By contrast, markers of virus infection or cell cycle entry, particularly those that offer some degree of prognostic significance, may be able to highlight abnormal cells more reliably than cytology, and could be combined with cytology to improve the detection rate. Our understanding of the molecular biology of HPV infection and the organization of the HPV life-cycle during cancer progression provides a rational basis for marker selection. The general assumption that persistent active infection by high-risk HPV types is the true precursor of cervical cancer provides the rationale for HPV DNA testing in conjunction with enhanced cytology, while the development of RNA-based approaches should allow active infections to be distinguished from those that are latent. The detection in superficial cells of marker combinations at the level of RNA or protein has the potential to predict disease status more precisely than the detection of markers in isolation. There is also a need for better prognostic markers if the predictive value of screening is to be improved.The potential to control infection by vaccination should reduce the incidence of HPV-associated neoplasia in the population, and this may cause a change in the way that screening is carried out. Nevertheless, the lack of a therapeutic vaccine, and the difficulties associated with eliminating infection by multiple high-risk HPV types, means that some form of screening will still be required as a preventive measure for the control of cervical cancer for the foreseeable future.     

Cervical cancer: A comprehensive approach towards extermination

Human Papilloma Virus (HPV) is one of the most common sexually transmitted pathogen, globally. Oncogenic types of HPV are the causative agents of many neoplastic diseases, including cervical cancer, which ranks as the most common cancer affecting females in developing countries. HPV infection of the cervical epithelium and the subsequent integration of viral DNA into the host genome are the major risk factors for cervical cancer. The scientific discovery of HPV as the causal agent of cervical cancer has led to the development of HPV-based diagnostic tools. Prophylactic vaccines, based on the oncogenic HPV type virus-like particles have been introduced in several developed countries as a preliminary preventive approach. Nevertheless, it remains a continuous threat to women in developing countries, where the prophylactic vaccines are unaffordable and organized screening programmes are lacking. This warrants implementation of prevention strategies that will reduce cervical cancer-related mortality. In this review, we have discussed molecular pathogenesis of HPV infection and the risk factors associated with it. The diagnosis, treatment and prevention strategies of HPV-related cervical cancer have also been discussed.

• Key messages

• HPV-related cervical cancer: risk factors, diagnosis and prevention strategies.

• HPV pathogenesis, diagnosis, and prevention strategies of cervical cancer.

• Risk factors, diagnosis and prevention strategies of HPV-related cervical cancer.

     

Human papillomavirus testing for primary cervical cancer screening

Cervical cancer is the second most common cancer in women worldwide and the seventh most common cause of cancer deaths in women in Europe. Today, we know how to prevent almost every case of this disease; organized cervical cancer screening based on the Papanicolaou or Pap smear has been proven to prevent 80% of cervical cancer deaths, while new technologies for the detection of the human papillomavirus (HPV) or the prevention of HPV infection offer the potential to make even more progress in the battle against this disease. Testing for carcinogenic or high-risk HPV types is gaining acceptance for the triage of women with borderline cytology and for follow-up after treatment of high-grade cervical lesions. Now, a number of large-scale randomized controlled trials have shown that HPV testing as a primary screening test can detect approximately 50% more high-grade lesions than the Pap test, albeit with a lower specificity if all HPV-positive women are followed up. However, alternative screening algorithms in which HPV-positive women are triaged with cytology have been shown to have equivalent specificity to the Pap test without compromising the increased sensitivity. Further advantages of HPV testing come from the fact that it is an objective and automatable test with a dichotomous result. These attributes can yield cost savings through reductions in staff numbers and simplification of quality control procedures while reducing turnaround times. In countries seeking to improve cervical cancer prevention, the implementation of HPV testing as the primary screening test with cytology for the triage of HPV-positive women is an option that should be fully evaluated. This review summarizes the recent advances in HPV testing in cervical cancer prevention.     

cobas® 4800 HPV Test,a real-time polymerase chain reaction assay for the detection of human papillomavirus in cervical specimens

Cervical cancer screening incorporating high-risk human papillomavirus (HPV) detection has become the preferred screening strategy in some countries and is increasingly more widespread in other countries with organized or opportunistic screening programs. Given knowledge that high-risk HPV genotypes differ in their oncogenic potential, commercial HPV assays with genotyping capabilities have been developed and have garnered attention in the recent literature. The cobas^® 4800 HPV Test is a qualitative multiplex assay that provides specific genotyping information for HPV types 16 and 18, while concurrently detecting 12 other high-risk HPV genotypes as a pooled result. It is currently the only clinically validated, US FDA-approved assay with this capability. Since HPV types 16 and 18 have been designated as conferring the greatest risk for cervical disease, their detection may prove useful in guiding patient management.     

Detection of high-risk human papillomavirus type 16 and 18 using isothermal helicase-dependent amplification

Persistent infection with human papillomavirus (HPV) induces cervical cancer. Here, we describe a sensitive, specific, and rapid assay for high-risk HPV16 and 18 detection by isothermal helicase-dependent amplification. This method can be used as cost-effective diagnostic method for low-income countries, where highest incidences worldwide of cervical cancer are registered.     

HPV and Cervical Cancer: Updates on an Established Relationship

Abstract

Despite cervical cancer being considered a preventable disease, it still remains the second most common malignancy in women worldwide, with a higher incidence in underdeveloped countries. Human papillomavirus (HPV) is considered the causative agent of cervical cancer. The major mechanisms through which HPV contributes to neoplastic initiation and progression include the activity of 2 viral oncoproteins, E6 and E7, which interfere with critical cell cycle tumor suppressive proteins, p53 and retinoblastoma (Rb) protein. However, HPV infection alone is not sufficient to induce malignant transformation, and other significant cofactors contribute to the multi-step process of tumor formation, such as individual genetic variations as well as environmental factors. However, these cofactors are not important in the absence of HPV. Papanicolaou testing (Pap smear) and HPV DNA testing are tools used in the screening and diagnosis of cervical neoplastic lesions. Vaccination against HPV appears to be cost-effective in the prevention of HPV infection. A thorough understanding of the mechanisms that underline HPV carcinogenesis may result in the development of sophisticated targeted therapeutic approaches, such as antisense oligonucleotides against HPV oncoproteins.     

Human papillomavirus (HPV) vaccine policy and evidence-based medicine: Are they at odds?

Abstract

All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant's full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world's leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidence-based medicine and ethical guidelines for informed consent.     

The East Africa Consortium for human papillomavirus and cervical cancer in women living with HIV/AIDS

The East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer, and to encourage collaborations between researchers in North America and East African countries. To date, studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on the persistence of HPV, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP. It will now be determined how HPV testing fits into cervical cancer screening programs in Kenya and Uganda, how aflatoxin influences immunological control of HIV, how HPV alters certain genes involved in the growth of tumours in HIV-infected women. Although there have been challenges in performing this research, with time, this work should help to reduce the burden of cervical cancer and other cancers related to HIV infection in people living in sub-Saharan Africa, as well as optimized processes to better facilitate research as well as patient autonomy and safety.

KEY MESSAGES

• The East Africa Consortium was formed to study the epidemiology of human papillomavirus (HPV) infections and cervical cancer and the influence of human immunodeficiency virus (HIV) infection on HPV and cervical cancer.
• Collaborations have been established between researchers in North America and East African countries for these studies.
• Studies have led to a better understanding of the influence of HIV infection on the detection and persistence of oncogenic HPV, the effects of dietary aflatoxin on HPV detection, the benefits of antiretroviral therapy on HPV persistence, and the differences in HPV detections among HIV-infected and HIV-uninfected women undergoing treatment for cervical dysplasia by either cryotherapy or LEEP.

     

Human papillomavirus infections in primary care

Cervical cancer continues to be a leading cause of mortality worldwide. The incidence and mortality associated with invasive cervical cancer have declined significantly in developed countries due to widespread availability of screening with the Papanicolaou (Pap) test. However, the incidence and prevalence of non-invasive cervical intraepithelial neoplasms and genital warts related to oncogenic and nononcogenic strains of human papilloma viruses (HPV) have remained relatively stable. Recent advances in molecular diagnostics have resulted in improved characterization of various HPV types and have led to changes in terminology of Pap test findings. Changes in nomenclature may lead to confusion among primary care providers regarding how best to further evaluate abnormal cytological results. This article provides a concise overview of the approach to the treatment of genital warts and management of abnormal cervical cytology based on guidelines from the American Society of Colposcopy and Cervical Pathology. It also reviews advances in HPV vaccine development and the new recombinant vaccine recently approved for use in the United States.     

Cigarette smoking and cervical cancer: Part II: a geographic variability study.

Cigarette smoking is considered a causative factor in a variety of cancers. However, the role of smoking in cervical cancer is disputed, in part because women who smoke may have other risk factors for cervical cancer, particularly HPV infection. We reviewed cigarette smoking prevalence, cervical and lung cancer incidence, and gross domestic product (GDP) per capita in the US and 73 other countries. It appears that smoking may play a prominent role in cervical cancer in developing countries, but less of a role in other countries.     

Incidence and clinical management of oral human papillomavirus infection in men: a series of key short messages

Oral human papillomavirus (HPV) infections are less prevalent than genital and anal infections. However, the incidence of oropharyngeal squamous cell carcinomas has increased significantly over the last 2 decades in several countries. At least 90% of these cancers are associated with oncogenic type HPV16. Oral HPV infections are notably more frequent in men than in women, and the incidence of HPV-positive oropharyngeal squamous cell carcinomas has increased, predominantly among mid-adult men. Nevertheless, little is known about the progression of oral HPV infection to cancer, and it remains unclear which medical interventions should be applied to modify the natural history of the disease. This narrative review aimed at non-experts in HPV infection provides an update on oral HPV infection and its clinical management in men. Furthermore, using the cervix as a reference anatomical site, the lessons learned from investigations on cervical HPV infection are also addressed.     

HPV分型及高危八型定量检测在宫颈病变中的意义

目的分析宫颈病变中的人乳头瘤病毒的亚型分布及病毒载量的情况,以及其与宫颈疾病进展的关系。方法潮州中心医院就诊的220例液基细胞学检查异常的患者行阴道镜检查及组织病理学检查。收集宫颈脱落细胞标本,运用HybriMax导流杂交技术检测HPV的21个亚型,运用实时荧光PCR定量检测八个高危亚型的病毒载量。结果220例样本中,HPV感染率为87.3％,其中HPV16是最主要的基因型（50．91％）,随着宫颈病变程度的增高,总HPV感染率和HPV16感染率逐渐升高。HPV58,HPV33,HPV52,HPV31和HPV18是仅次于HPV16的五种基因亚型,其检出率分别为22．73％,11．82％,11．36％,5．9％和4．54％。高危HPV亚型的病毒载量与宫颈病变的严重程度呈正相关（1=0．373,P〈0．001）。结论尽管HPV52和HPV58是该地区HPV感染的主导亚型,但在宫颈病变患者中HPV感染以HPV16为主,而与宫颈癌最相关的是HPV16和HPV18。病毒载量是一个潜在的确定子宫颈癌及癌前病变的辅助指标。     

Cervical cancer in sub-Saharan Africa: a preventable noncommunicable disease

Introduction: Infections caused by high-risk human papillomavirus (HPV) are responsible for 7.7% of cancers in developing countries, mainly cervical cancer. This disease is steadily increasing in sub-Saharan Africa, with more than 75,000 new cases and 50,000 deaths yearly, further increased by HIV infection.

Areas covered: The current status of cervical cancer associated with HPV in sub-Saharan Africa has been systematically revised. The main issues discussed here are related to the public health burden of cervical cancer in sub-Saharan Africa and predictions for the coming decades, including molecular epidemiology and determinants of HPV infection in Africa, and promising prevention measures currently being evaluated in Africa.

Expert commentary: By the year 2030, cervical cancer will kill more than 443,000 women yearly worldwide, most of them in sub-Saharan Africa. The increase in the incidence of cervical cancer in Africa could counteract the progress made by African women in reducing maternal mortality and longevity. Nevertheless, cervical cancer is a potentially preventable noncommunicable disease, and intervention strategies to eliminate cervical cancer as a public health concern should be urgently implemented.     

人乳头瘤病毒基因亚型与宫颈病变的相关性及临床意义

目的探讨人乳头瘤病毒(HPV)基因亚型与宫颈病变的相关性及临床意义。方法选取2019年在济南市天桥人民医院妇科就诊患者864例作为研究对象,采集患者宫颈细胞进行HPV基因检测并实施宫颈病理活检,组织切片取样行病理学检查,比较HPV基因亚型与病理诊断结果并进行相关性分析。结果864例患者中,正常或炎症宫颈620例,宫颈上皮内瘤变(CIN)Ⅰ级58例,CINⅡ级36例,CINⅢ级88例,宫颈癌62例。HPV阳性检出率随宫颈病变程度不断加重而升高,差异均有统计学意义(P<0.05)。伴随病情不断发展,HPV 16型在不同宫颈病变中的阳性检出率逐渐升高,在宫颈癌患者中同样也是HPV 16型阳性检出优势明显,为77.4%(48/62)。HPV多重感染在不同宫颈病变中的检出情况:正常及炎症11.3%,CINⅠ级17.2%,CINⅡ级27.8%,CINⅢ级29.5%,宫颈癌9.7%;宫颈癌中HPV多重感染占比明显更少,更多的是单一HPV基因型感染,且感染类型全部为高危型。结论随着宫颈病变程度不断加重,HPV阳性检出率随之逐渐升高;宫颈癌中HPV基因亚型主要包括:HPV 16、33、52型。     

系统性红斑狼疮与人乳头瘤病毒感染及相关疫苗

人乳头瘤病毒(human papilloma virus, HPV)能引起宫颈良性病变(如尖锐湿疣)、癌前病变以及宫颈癌, 尤其是血清型16和18, 与宫颈癌的发生密切相关。系统性红斑狼疮(systemic lupus erythematosus, SLE)患者HPV感染较普通人群概率更高且多种HPV亚型感染常见, 同时异常巴氏涂片、高度宫颈上皮内病变的风险亦显著增加, 因此在SLE患者中预防HPV感染非常必要。疫苗是预防感染性疾病最有效的工具之一。已有3种HPV疫苗获批上市, 分别为2价(针对HPV 16、18型)、4价(针对HPV 6、11、16、18型)和9价(针对HPV 6、11、16、18、31、33、45、52、58型), 用以阻止宫颈癌前病变和宫颈癌, 4价和9价疫苗同时也可阻止HPV引起的良性疾病, 比如尖锐湿疣。目前多项前瞻性研究显示, HPV疫苗在SLE患者中安全有效, 可产生保护性应答。2019年欧洲抗风湿病联盟发表了成人自身炎症性风湿性疾病(autoimmune inflammatory rheumatic diseases, AⅡRD)患者疫苗应用的更新建议, 推荐AⅡRD患者, 特别是SLE患者, 应按照一般人群的建议接种HPV疫苗。此外, 特别值得注意的是, HPV疫苗接种并不能替代常规宫颈不典型增生筛查, 亦不能治疗HPV感染, SLE患者即使接种了HPV疫苗, 也应定期进行筛查。     

FQ-PCR检测宫颈癌hWAPL基因mRNA及其诊断价值分析

目的探讨荧光定量聚合酶链反应(FQ-PCR)检测宫颈癌人半翼(hWAPL)基因mRNA的诊断价值。方法使用高危型人乳头瘤病毒(HPV)检测试剂盒以及建立的FQ-PCR检测慢性宫颈炎、宫颈上皮内瘤样变(CIN)和宫颈癌共100例患者hWAPL基因mRNA和高危型HPV。结果宫颈癌组hWAPL基因mRNA表达显著高于慢性宫颈炎组和CINⅠ～Ⅲ组(P<0.05);慢性宫颈炎组与CINⅠ～Ⅲ组比较,差异无统计学意义(P>0.05)。慢性宫颈炎组和CINⅠ～Ⅲ组部分患者中查出高危型HPV,但无宫颈癌变。宫颈癌组高危型HPV检出率显著高于无宫颈癌病变各组。结论高危型HPV检出率与宫颈癌发生密切相关,但hWAPL基因mRNA表达与宫颈癌变更直接相关,更有特异性,有助于宫颈癌的早期诊断。     

Hybrid capture based human papillomavirus typing in cervical screening compared to cytology and histology

INTRODUCTION: Cervical cancer is frequently associated with infection from various types of human papillomavirus (HPV) with high a oncogenic potential (high-risk types). Commercial systems for HPV typing are available, but the question as to when HPV typing should be performed has not yet been solved. OBJECTIVES: To assess the value of HPV typing in a clinical setting in a population with opportunistic screening. STUDY DESIGN: Cytology, histology and HPV status of 593 patients from a high-risk collective were evaluated retrospectively. For HPV typing, the hybrid capture (HC) system was used. RESULTS: Infection with high-risk types of HPV was associated with more severe cervical lesions. Women with PAP III or PAP IIID who were infected with high-risk HPV were at increased risk for high-grade cervical lesions (CIN III+) (p = 0.006). Conization influenced HPV status: of 63 patients who were HPV high-risk positive before conization, 4 remained positive afterwards. CONCLUSION: HC appears to be a useful system to triage women with PAP III or IIID and to detect patients with residual HPV infection after conization. However, because of high costs and no significant increase in the sensitivity of cytology, the use of HPV typing in routine cervical screening cannot be recommended in countries with opportunistic annual cytological screening.