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.

     

Facile, comprehensive, high-throughput genotyping of human genital papillomaviruses using spectrally addressable liquid bead microarrays

Human papillomavirus (HPV) is the worldwide cause of carcinoma of the uterine cervix, a cancer that is the second most common neoplasm in women, resulting in nearly 250,000 deaths a year. The magnitude of the risk of cancer after HPV infection, however, is virus type-specific. Over 40 HPV types can infect the genital tract. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. Blending multiplex PCR and multiplex hybridization using spectrally addressable liquid bead microarrays we have developed a high-throughput, fast, single-tube-typing assay capable of simultaneously typing 45 HPV. The overall incidence of HPV in 429 women tested using this new assay was 72.2% for those with squamous intraepithelial lesions, 51.5% for those with atypical squamous cells of undetermined significance and 15.4% for women with normal cytology, respectively. This compared well with the incidence of HPV detected by a parallel non-typing generic high-risk assay. The new assay detected a wide spectrum of HPV types and a high incidence of mixed infections. We believe our assay may find widespread applications in areas requiring virus type-specific information, such as in epidemiological studies, cancer screening programs, monitoring therapeutic interventions, and evaluating the efficacy of HPV vaccine trials.     

Screening for cervical cancer and human papilloma virus: Indian context

Cervical cancer remains the most common fatal cancer in Indian women. The primary underlying cause of cervical cancer is persistent infection with human papilloma virus (HPV); HPV 16 and 18 account for nearly 70% of all cervical cancers worldwide. Cytology-based cervical screening programs have been very effective, but require establishing an infrastructure and quality control mechanisms, which can be a challenge. Cervical screening by visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI) are acceptable alternatives for low-resource settings. Primary screening for cervical cancer with HPV testing is attractive but cost could be the limiting factor. A less expensive HPV test holds promise.     

Detection of human papillomavirus infection in women attending a colposcopy clinic

Background

Infection by human papillomavirus (HPV) is the main cause of and a necessary factor for cervical cancer. There are more than 100 known HPV genotypes, although HPV genotypes do not all have the same risk of inducing cervical cancer. The main aim of this study is to know the distribution of different types of HPV in women attending a colposcopy clinic for cervical dysplasia.

Methods

We prospectively identified and enrolled a cohort of women followed for cervical dysplasia who were referred to the colposcopy clinic of University Hospital Sant Joan de Déu in Barcelona, Spain, from April 2003 to April 2007. Two cervical scrape samples from each patient were collected for routine cytology and for identification of HPV DNA. During the study period, 2 techniques (Line Probe assay and microarray assay) were used consecutively.

Findings

HPV DNA was detected in 68% of patients (338 of 496 women) with statistically significant differences in positive results according to the cytologic category. Overall, the type distribution showed a predominance of genotype HPV-16 (27% of the total patients) followed by HPV-53 (9.4%), HPV-51 (8%), and HPV-51 (8%). Multiple genotype detection was observed in 35.5% of the patients with HPV infection. HPV-16 was mainly associated with the probable high-risk genotypes: HPV-53 and HPV-66.

Conclusion

The higher prevalence of high-risk nonvaccine genotypes should be considered to increase vaccine efficiency.     

HPV testing in the evaluation of the minimally abnormal Papanicolaou smear.

Minor cytologic abnormalities of the cervix, such as atypical squamous cells of undetermined significance (ASCUS), are vastly more common than high-grade squamous intraepithelial lesions or invasive cancer. Current guidelines for the management of ASCUS include repeating the Papanicolaou (Pap) smear at specific intervals, referring all patients for colposcopy or using an adjunctive test such as hybrid capture human papillomavirus (HPV) testing or cervicography. The usefulness of the Pap smear is limited by its considerable false-negative rate and its dependence on clinician and laboratory performance. Colposcopy is a highly sensitive procedure, but many patients with ASCUS have normal colposcopic findings. The hybrid capture test not only measures quantitative HPV load but also detects both oncogenic and nononcogenic HPV types, thereby increasing the probability that serious cervical disease is not missed. Hybrid capture sampling is simple to perform, and positive results are strongly associated with cervical dysplasia. HPV testing in women with ASCUS can be used as an adjunctive test to identify those with HPV-associated disease; it can also serve as a quality assurance measure. Together, repeat Pap smears and HPV testing should identify most patients with underlying cervical dysplasia. Combined testing may also minimize the number of unnecessary colposcopic examinations in women who have no disease.     

Assessment and management of cervical intraepithelial neoplasia

Although cervical intraepithelial neoplasia (CIN) once was thought to be a clinical problem primarily for older women, data reveal an alarming rise of this condition among younger women. The gains made in decreasing the incidence of cervical cancer have been tempered by the steadily increasing incidence of its precursor state, CIN. Because of increasing evidence of the association of the human papillomavirus (HPV) with cervical cancer and CIN, this virus is of particular concern. Colposcopy is a valuable method for evaluating CIN that has been indicated on Pap, as well as for identifying HPV. Since having an abnormal Pap and undergoing colposcopic examination may be stressful, the clinician can play a significant role in helping the client cope with the process of evaluation and treatment of abnormal Paps in addition to controlling cervical cancer.     

p16,E6/E7蛋白与宫颈癌及癌前病变相关性的研究进展

宫颈癌是女性最常见的、发病率较高、但完全可以通过筛查早期发现并进行有效防治的恶性肿瘤。在宫颈病变中,高危型HPV病毒的持续感染是导致其发生发展的明确病因,近年来,p16,HPV E6/E7蛋白在明确宫颈病变的发病机制、诊断、临床分流等方面的作用备受关注。     

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.     

What school nurses need to know about cervical cancer, HPV, and the new vaccine.

At least 12,000 women are diagnosed with cervical cancer each year in the United States, accounting for at least 4,000 deaths. Worldwide, cervical cancer is the second most common type of cancer among women. The human papilloma virus (HPV) has been linked to at least 70% of all cervical cancer. HPV can be divided into 2 categories: (a) low risk, which is responsible for genital warts, and (b) high risk, which is responsible for cervical cancer. An effective new vaccine has been approved that will decrease the spread of infection caused by HPV, therefore decreasing the future incidence of cervical cancer and genital warts. Understanding the risks of acquiring HPV and the increased risk for cervical cancer may lead to enhanced vaccine acceptance.     

人乳头瘤病毒疫苗临床应用中国专家共识

人乳头瘤病毒(human papilloma virus,HPV)疫苗接种是预防HPV感染及相关疾病的有效方法,是防控HPV感染相关疾病的一级预防措施。低龄人群接种效果优于高龄人群,性暴露前接种免疫效果最佳。HPV疫苗不仅适用于普通人群,同样推荐用于高危、特殊人群。对于具有遗传易感、高危生活方式和HIV感染的适龄女性优先推荐接种HPV疫苗。适龄女性无论是否存在HPV感染、细胞学是否异常均可接种HPV疫苗。近期有妊娠计划、妊娠期或哺乳期女性不宜接种HPV疫苗。接种HPV疫苗后仍应进行子宫颈癌筛查。     

Update on Vaccination Clinical Trials for HPV-Related Disease

Background

Cervical cancer remains a major cause of cancer death in women worldwide. Moreover, human papillomavirus (HPV)-related disease of the urogenital tract (including preinvasive and invasive cervical, vaginal, vulvar, penile, and anal disease) remains a major cause of morbidity and mortality in the United States and internationally.

Objective

The goal of this article was to review the vaccines available as well as the major Phase III trials of the quadrivalent and bivalent vaccines for the prevention of HPV-related genital tract disease.

Methods

A literature search was performed through PubMed using the terms “HPV vaccination” and limited to clinical trials over the last 6 years. The most relevant and largest scale trials were included in this report.

Results

Prophylactic vaccination has emerged as an important tool that holds promise in decreasing the burden of HPV disease. However, HPV vaccination is known to be largely type-specific. Vaccination is most effective when administered at a younger age and before sexual activity and exposure to HPV. Large trials have been conducted and show efficacy of both the bivalent (HPV types 16 and 18) and quadrivalent (HPV types 6, 11, 16, and 18) vaccine in the prevention of preinvasive lesions and infection with these HPV types.

Conclusions

Future directions include development of more affordable vaccines with extended HPV-type coverage as well as implementation of feasible worldwide vaccination programs.     

A Culturally Sensitive Approach to Cervical Cancer Prevention in the Latina Population Using the Promotora Model

Latina women of low socioeconomic status are particularly vulnerable to morbidity and mortality from cervical cancer. Lower rates of screening are associated with increased mortality rates in this population. Community health workers known as promotoras de salud can be an effective part of the health care team to help improve health care access in this population. Promotoras using a cervical cancer education curriculum known as AMIGAS can help promote access to services, provide education, and possibly save lives in an underserved population. Nurses and advanced practice nurses who care for underserved Latina women can collaborate with promotoras to increase women’s knowledge of cervical cancer screening and of community-based resources available to increase their access to Pap testing and human papillomavirus vaccination.     

Detection of human papillomavirus and human cytomegalovirus in cervical lesions by in situ hybridization using biotinylated probes.

Infections with specific types of human papillomavirus (HPV) have emerged as necessary but not sufficient factors in the development of the majority of cervical cancers. The infection by human cytomegalovirus (HCMV) has also been implicated in both cervical intraepithelial neoplasia (CIN) and cancer. In order to test prevalence of these viral pathogens in genital lesions with suspect cytopathic changes after observation of smears, cervical biopsies from 131 patients were obtained under colposcopic guidance. The biopsies were tested for the presence of HPV and HCMV by the in situ hybridization technique using biotinylated DNA probes on paraffin-embedded sections. Presence of HCMV is twice more frequent in women with HPV-induced cervical lesions (40%) than in women with any detectable HPV (20%). It may be concluded that HCMV might contribute as one synergistic factor in the development of cervical dysplasia.     

Arguments in favor of HPV testing for cervical screening and post-treatment CIN2+ monitoring

Several studies have shown that the human papilloma virus (HPV) test is a more sensitive and objective primary cervical cancer screening tool than cytology. Therefore, conversion of cytology into HPV screening (as is planned in The Netherlands and some other European regions) will result in a better protection against cervical cancer and high-grade precursor lesions. Moreover, offering self-sampling for HPV testing will increase screening attendance by re-attracting former non-attendees. However, triage of HPV positive women is necessary because the specificity of HPV testing is 2–4% lower than of cytology. Several triage strategies have been evaluated, of which two, with cytology testing included, are feasible and were recently recommended. As an alternative for cytology triage, objective, non-morphological disease markers are upcoming and so far have shown promising results. Finally, HPV testing can also contribute to a more efficient monitoring of women treated for high-grade cervical precursor lesions, permitting fewer follow-up visits.     

湖州市门诊妇女HPV感染亚型的基因芯片检测及分析

目的了解湖州市门诊妇女人乳头瘤病毒（HPV）感染状况和感染型别,为宫颈癌的防治提供理论依据。方法对414例湖州市门诊妇女宫颈分泌物应用基因芯片技术进行18种高危型和5种低危型HPV亚型检测。结果414例妇女中共检出HPV阳性97例,占23.43%,其中单一感染76例,占18.35%;双重感染17例,占4.11%;三重及以上感染4例,占0.97%。97例阳性患者中有高危型HPV感染的为80例,占HPV总阳性人数的82.47%。阳性患者中高危型以16、18、33为主,检出率分别为4.35%、2.17%、2.17%;低危型以6、11型为主,检出率分别为1.69%和1.45%。结论湖州市门诊妇女HPV感染有相当比例,且高危型HPV感染率在总阳性患者中所占比例较高。因此,对门诊妇女有必要进行HPV感染筛查,及早发现高危人群,并进行随访和相应治疗,以降低宫颈癌的发病风险。     

The role of human papillomavirus in screening for cervical cancer

PURPOSE: To review the options for effectively screening for cervical cancer, including human papilloma virus (HPV) identification, cytologic screening, colposcopy, or a combination approach. Current pathophysiology, diagnostic criteria, treatment approaches, and patient preparation and education related to cervical cancer screening and prevention are also included. DATA SOURCES: Comprehensive review of current literature, including research and review articles. CONCLUSION: Because the Papanicolau (Pap) smear is a screening tool, not a diagnostic tool, further studies must be done to identify the actual nature of discovered abnormalities. Of particular concern is the classification of atypical squamous cells of undetermined significance (ASCUS), which may simply indicate inflammation, or may be the first indicator of serious pathology. Following ASCUS Pap smears with HPV screening will allow for a clarification of the best approach to treatment. A screening algorithm supported by a review of the literature is proposed. IMPLICATIONS FOR PRACTICE: Cervical cancer is a preventable disease caused by certain forms of HPV. Current screening protocols are based on the use of the Pap smear; and in areas where this test is routine and available, morbidity and mortality rates have dropped dramatically. Many women throughout the world and in underserved regions of the U. S. do not have adequate access to routine screening with Pap smear technology. As long as women continue to die needlessly of cervical cancer, more comprehensive and accessible screening methods must be explored. (Cutting the unnecessary worldwide and in the U. S.).     

Detection of human papillomavirus type 52b in cervical dysplastic tissue

We examined infection in the tissue of cervical dysplasia of human papillomavirus (HPV) 52b, which we recently isolated from cervical cancer. To screen a lot of samples, we used an assay system with an HPV DNA typing kit containing an HPV 33 probe that cross-hybridizes with HPV 52b DNA. DNA samples from 123 patients with cervical dysplasia were first screened with this kit. Sixteen of these appeared to be positive, and they were subjected to Southern blot hybridization with the HPV 52b probe under highly stringent conditions. Of the 16 samples, two were found to have HPV 52b genome DNA. Our results, together with the fact that HPV 52b was isolated from cervical cancer, seem to support the notion that HPV 52b infection is closely associated with the onset of cervical cancer.     

A novel multiplex real-time PCR assay for the detection and quantification of HPV16/18 and HSV1/2 in cervical cancer screening

Infection with human papillomavirus (HPV), particularly HPV16 and HPV18, is the main cause of invasive cervical cancer, although other factors such as herpes simplex virus (HSV) may act in conjunction with HPV in this context. To explore the possibility of developing a system for rapid diagnosis and clinical screening of cervical cancer, we developed a multiplex real-time PCR assay that can simultaneously detect and quantify HPV16/18 and HSV1/2. To evaluate its possibilities and practical uses, 177 samples collected from patients with suspected HPV and HSV infection in exfoliated cervical cells, genital herpes or labial herpes were tested by multiplex real-time PCR and compared with results obtained by DNA sequencing. Each virus was detected over a range from 1.0 × 10¹ to 1.0 × 10⁷ copies/reaction. The clinical sensitivity was 100% for HPV16/18 and HSV1/2. The clinical specificity was 97.1% for HPV16, 98.1% for HPV18, 97.0% for HSV1 and 96.0% for HSV2. The kappa value was 0.96 for HPV16, 0.92 for HPV18, 0.94 for HSV1 and 0.93 for HSV2, when DNA sequencing was used as the reference standard. In summary, this novel multiplex real-time PCR allows the rapid and specific detection of HPV16/18 and HSV1/2, as well as coinfection with HPV and HSV, in clinical samples. In the future, this multiplex real-time PCR assay will assist in cervical cancer screening, viral treatment evaluation and epidemiological studies in which high throughput analysis is required.     

Anal Pap smears: Should we be doing them?

Purpose: To identify the need to perform anal Papanicolau (Pap) smears for diagnosing histologic changes associated with human papilloma virus (HPV) infection in order to provide early intervention for the prevention of anal cancer. To offer the primary care provider information, based on evidence-based research, about identifying the high-risk patient using risk factors, instructions on performing the anal Pap smear, interpreting the results, and initiating treatment interventions and/or referrals for care. Additionally, the possibility of an HPV vaccine for men will be discussed.
Data Sources: Evidence-based literature, theoretical framework, and peer-reviewed articles.
Conclusions: Performing anal Pap smears is a valuable tool to detect cytologic changes associated with some strains of HPV infection. For persons participating in receptive anal intercourse, this diagnostic procedure provides the opportunity for early detection to guide appropriate follow-up and interventions.
Implications for practice: Appropriate screening can be incorporated easily into a primary care practice. High-risk groups that would benefit from this screening include men who have sex with men, HIV-infected men and women, immunocompromised men and women, women with a history of cervical or vulvar cancer (or high-grade cervical lesions), and women participating in receptive anal intercourse.     

Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer

Human papillomavirus (HPV) is the most important etiological factor for cervical cancer. A recent study demonstrated that more than 20 HPV types were thought to be oncogenic for uterine cervical cancer. Notably, more than one-half of women show cervical HPV infections soon after their sexual debut, and about 90 % of such infections are cleared within 3 years. Immunity against HPV might be important for elimination of the virus. The innate immune responses involving macrophages, natural killer cells, and natural killer T cells may play a role in the first line of defense against HPV infection. In the second line of defense, adaptive immunity via cytotoxic T lymphocytes (CTLs) targeting HPV16 E2 and E6 proteins appears to eliminate cells infected with HPV16. However, HPV can evade host immune responses. First, HPV does not kill host cells during viral replication and therefore neither presents viral antigen nor induces inflammation. HPV16 E6 and E7 proteins downregulate the expression of type-1 interferons (IFNs) in host cells. The lack of co-stimulatory signals by inflammatory cytokines including IFNs during antigen recognition may induce immune tolerance rather than the appropriate responses. Moreover, HPV16 E5 protein downregulates the expression of HLA-class 1, and it facilitates evasion of CTL attack. These mechanisms of immune evasion may eventually support the establishment of persistent HPV infection, leading to the induction of cervical cancer. Considering such immunological events, prophylactic HPV16 and 18 vaccine appears to be the best way to prevent cervical cancer in women who are immunized in adolescence.