Asia oceania guidelines for the implementation of programs for cervical cancer prevention and control.

This paper aims to provide evidence-based recommendations for health professionals, to develop a comprehensive cervical cancer program for a clinic, a community, or a country. Ensuring access to healthcare is the responsibility of all societies, and the Asia Oceania Research Organisation in Genital Infections and Neoplasia (AOGIN) is committed to working collaboratively with governments and health professionals to facilitate prevention programs, to protect girls and women from cervical cancer, a disease that globally affects 500,000 and kills nearly 300,000 women annually, just over half of whom are in the Asia Oceania region. We share the vision that a comprehensive program of vaccination, screening, and treatment should be made accessible to all girls and women in the world. The primary purpose of these guidelines is to provide information on scientific evidence on the different modalities and approaches of cervical cancer prevention programs, for high resource and low resource settings. The secondary purpose is to provide an overview of the current situation of cervical cancer control and prevention in various Asian Oceania countries: their views of an ideal program, identified obstacles, and suggestions to overcome them are discussed.

Establishment of the 1st World Health Organization international standards for human papillomavirus type 16 DNA and type 18 DNA.

A World Health Organization collaborative study was conducted to evaluate candidate international standards for human papillomavirus (HPV) Type 16 DNA (NIBSC code 06/202) and HPV Type 18 DNA (NIBSC code 06/206) for use in the amplification and detection steps of nucleic acid-based assays. The freeze-dried candidate international standards were prepared from bulk preparations of cloned plasmid containing full-length HPV-16 or HPV-18 genomic DNA. Nineteen laboratories from 13 countries participated in the study using a variety of commercial and in-house quantitative and qualitative assays. The data presented here indicate that, upon freeze-drying, there is no significant loss in potency for the candidate HPV-18 DNA and a slight loss in potency for the candidate HPV-16 DNA; although this is likely not scientifically relevant when assay precision is considered. In general, the individual laboratory mean estimates for each study sample were grouped +/- approximately 2 log(10) around the theoretical HPV DNA concentration of the reconstituted ampoule (1 x 10(7) HPV genome equivalents/mL). The agreement between laboratories is improved when potencies are made relative to the candidate international standards, demonstrating their utility in harmonizing amplification and detection steps of HPV-16 and -18 DNA assays. Degradation studies indicate that the candidate international standards are extremely stable and suitable for long-term use. Based on these findings, the candidate standards were established as the 1st WHO international standards for HPV-16 DNA and HPV-18 DNA, each with a potency of 5 x 10(6) international units (IU) per ampoule or 1 x 10(7) IU mL(-1) when reconstituted as directed.

International standard reagents for HPV detection.

Human papillomavirus is the commonest genital viral infection in healthy sexually active subjects, and the presence of chronic or persistent HPV types in genital cells may constitute a prognostic marker of underlying, or predict future HPV-associated diseases. A variety of novel tests for detecting the presence of oncogenic HPV types in biological specimens have been reported. These are based on the various stages of infection and viral life cycle. HPV infects squamous epithelium with expression of various gene products intimately linked to epithelial cell differentiation. Hence, there are basically three classes of detectable markers directly derived from HPVs: molecular markers based on detection of nucleic acid sequences, serological markers based on detection of antibodies against viral proteins, and cellular markers based on detection of proteins expressed intracellularly, upon either infection or carcinogenesis. The nature of various assays and the development of international standard reagents for qualitative and quantitative assessment of assay performance are outlined. There is an increasing demand to develop standard tools to assess the quality of HPV detection systems, for regulatory and clinical management purposes. International standard reagents for HPV will help defining the analytical sensitivity and specificity of various detection methods, and will allow assuring that laboratory services used to evaluate disease burden, HPV vaccines, and cancer prevention strategies are accurate and comparable worldwide. The advancement of prophylactic vaccine candidates against HPV infections and related diseases stresses the increasing importance of HPV assays in monitoring the impact of HPV vaccination on disease burden.

HPV technologies advancing public health: discussion of recent evidence.

Effective primary and secondary cancer prevention programmes are key to improve public health. Cervical cancer is preventable if high quality screening programmes, diagnosis and treatment are offered to female populations at high coverage. Nevertheless, it continues to be a public health problem, and screening programmes need improvements. Human papillomavirus (HPV) has been firmely established as the necessary cause of virtually all cervical cancer cases. To date we count two clinically validated and approved HPV technologies, available to prevent cervical cancer, and other diseases caused by these carcinogenic viruses: Prophylactic vaccines for primary prevention, and HPV DNA tests for secondary prevention, to detect life threatening infections by carcinogenic HPV types, allowing timely diagnosis and clinical management of precancerous lesions. The new technologies will help improve the health of the public if made widely accessible. Similar to vaccination programmes, systematic and well organized cervical screening programmes, with high quality validated HPV tests, can save more lives than ever and improve women's health, in an effective manner.

Chapter 23: International Standard reagents for harmonization of HPV serology and DNA assays--an update.

International reference materials such as International Standard reagents facilitate quality assurance of essential biopharmaceutical products and related in vitro diagnostic tests. Standardization of antibody and DNA measurements and harmonization of laboratory procedures are key to the success of cancer prevention strategies through screening methods as well as for development and implementation of vaccination against the human papillomavirus (HPV). The WHO supported the preparation and initial analysis of a panel of candidate serological and DNA reference reagents aimed at facilitating inter-laboratory comparisons and detection of HPV worldwide. Two international collaborative studies assessed the performance of various HPV antibody and HPV-DNA detection assays and examined the feasibility of generating HPV antibody and DNA standard reagents. These studies showed that improvement in performance and comparability of assays is urgently needed and that the use of the same International Standard reference reagent could significantly improve performance and comparability. It is hoped that the establishment of International Units and International Standards for HPV antibody and DNA analysis will be pursued with high priority.

Results of the first World Health Organization international collaborative study of detection of human papillomavirus DNA.

Twenty-nine laboratories in 12 countries participated in a study to assess the performance of various human papillomavirus (HPV) detection assays through the use of a recombinant HPV DNA standard reagent panel. The panel was designed by a group of HPV experts, and samples were prepared and distributed by the World Health Organization International Laboratory for Standards and Biologicals in The Netherlands. Each panel consisted of 24 coded samples including a dilution series for HPV types 16 and 18, alone or in combination with five other high-risk (HR) HPV types including HPV types 31, 33, 35, 45, and 52, the low-risk HPV type 6, and a negative control. Qualitative assays were generally consistent across laboratories, and most invalid results reflected a lack of HPV test sensitivity. The combined data sets had a proficiency for HPV 16 of 62.5% (15/24) and for HPV 18 of 73.9% (17/23). HPV 31 was the least accurately detected by participating laboratories. Approximately half of participating laboratories failed to detect high concentrations of HPV 31 and, to a lesser extent, to detect HPV types 35, 52, and 6. The panel sample materials offer a source of renewable and reproducible material that could be used in the future development of international standard reagents for calibration of HPV DNA assays and kits.

Efficacy and other milestones for human papillomavirus vaccine introduction.

Last year, the World Health Organization (WHO) convened a gathering of experts, including scientists, national regulatory authorities, industry representatives, epidemiologists and government officials from both developed and developing countries to discuss appropriate endpoint measurements for HPV vaccine efficacy and effectiveness trials. The consultation also considered the regulatory requirements and public health issues that vaccine candidates should address before deployment, particularly in developing countries. This report summarizes the discussions and the conclusions reached over the course of the consultation. The general consensus of the consultation was that it would be desirable to have a globally-agreed, measurable efficacy endpoint for considering deployment of HPV vaccines in public health settings. After hearing from experts about virological and clinical endpoints to be considered, requirements of regulatory authorities of various countries and endpoints used to measure efficacy and effectiveness for another known cancer vaccine (hepatitis B), the experts agreed that ethical and time considerations make it necessary to use a surrogate endpoint, and not invasive cervical cancer, to define efficacy of HPV vaccines. While regulatory authorities of each country ultimately will determine the endpoints required for licensure, the consultation recommended that the endpoint for efficacy in population-based studies be, based on current knowledge, histologically-classified cervical intraepithelial neoplasias (CIN) of moderate or high-grade, as well as cancer. Since persistent infection with the same high-risk type is considered a predictor for moderate or high-grade cervical dysplasias and cancer, they might represent a useful endpoint in future vaccine efficacy studies. Indeed, if vaccines prove to be effective against transient or persistent HPV infections, it is likely that they will protect women against cervical cancer. The consultation recognized that in the context of many developing countries, efficacy alone might not provide enough information for countries to decide whether or not to adopt HPV vaccines as a public health prevention tool against cervical cancer. The consultation unanimously agreed that additional clinical bridging studies as well as studies to clarify local epidemiology should be conducted in certain developing countries to determine the potential impact of vaccination. Such countries should also undertake targeted interventions to ensure acceptability and programmatic feasibility of the vaccination. Recognizing that upon vaccine introduction it will be some years before a reduction in cervical cancer is detectable at the population level, the consultation stressed the importance of maintaining existing cervical screening programmes while such long-term studies are conducted. The following paper explains the background and rationale behind these conclusions and elaborates on specific considerations for vaccine study and introduction in developing countries.