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Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of existing screening programs using HPV-based technology, 3) extension of adapted screening programs to developing populations, and 4) consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women, as well as in men. Despite the huge advances already achieved, there must be ongoing efforts including international advocacy to achieve widespread-optimally universal-implementation of HPV prevention strategies in both developed and developing countries. This article summarizes information from the chapters presented in a special ICO Monograph 'Comprehensive Control of HPV Infections and Related Diseases' Vaccine Volume 30, Supplement 5, 2012. Additional details on each subtopic and full information regarding the supporting literature references may be found in the original chapters. (C) 2013 Elsevier Ltd. All rights reserved.

A model representing carcinogenic HPV infection transmission dynamics and cervical cancer natural history was adapted to assess the consequences of introducing vaccination against HPV-16 infection. Alternative scenarios either allowing repeated infections with the HPV-16 (i.e. SIS scenario) or assuming that clearance of infection occurs through the development of a long lasting, specific immune response which protects against re-infection (i.e. SIR scenario) were investigated. The difference in reduction in lifetime cervical cancer achieved through vaccination of 12-year-old girls, between SIS and SIR scenarios, was up to 25% of expected cases in an unscreened population. This difference increased to 30% when vaccination of 12-year-old boys was also included as an intervention. The role of SIS or SIR dynamics should be accounted for in the assessment of model-based projections of the effectiveness of vaccination programmes, until available data about the transmission dynamics support the accuracy of model predictions.

Human papillomavirus (HPV) testing has clearly demonstrated a higher sensitivity but somewhat lower specificity than cytology. However, there are still issues regarding how best to use it in primary screening. In countries where cytology is of good quality, the most interesting possibility for primary screening is to use HPV testing as the sole screening modality with cytology reserved for triage of HPV-positive women. In countries with a less established infrastructure, however, use of HPV alone would also be attractive, although rapid, simple tests followed by immediate treatment are needed to minimize the number of visits and make best use of limited resources. Several approaches to deal with the lower specificity of HPV testing are also examined. These include HPV typing with a different management strategy for HPV-16 and -18/45, use of viral load to exclude infections unlikely to be associated with > or =CIN-2, and markers of proliferative lesions such as p16 and mRNA or cell-cycle markers such as cdc6 or the mcm5 proteins. Micro-array studies offer the prospect of discovering new, better DNA- or RNA-based diagnostics. The fact that HPV is a sexually transmitted infection may lead to anxiety and concerns about sexual relationships and these issues are also discussed. Ongoing HPV studies are identified and briefly reviewed.

More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Consistent evidence is available indicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. Several other tests show at least similar accuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2. In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology. The APTIMA(®) test is more specific than HC2 without showing a loss in sensitivity. Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing. After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology. Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific. Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only. Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative. The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small. HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®) 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening. The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18. There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older. However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Screening for cervical cancer precursors by cytology has been very successful in countries where adequate resources exist to ensure high quality and good coverage of the population at risk. Mortality reductions in excess of 50% have been achieved in many developed countries; however the procedure is generally inefficient and unworkable in many parts of the world where the appropriate infrastructure is not achievable.A summary and update of recently published meta-analyses and systematic reviews on four possible clinical applications of human papillomavirus (HPV) DNA testing is provided in this article: (1) triage of women with equivocal or low-grade cytological abnormalities; (2) follow-up of women with abnormal screening results who are negative at colposcopy/biopsy; (3) prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN), and most importantly (4) primary screening HPV DNA test, solely or in combination with Pap smear to detect cervical cancer precursors. There are clear benefits for the use of HPV DNA testing in the triage of equivocal smears, low-grade smears in older women and in the post-treatment surveillance of women after treatment for CIN. However, there are still issues regarding how best to use HPV DNA testing in primary screening. Primary screening with Hybrid Capture (R) 2 (HC2) generally detects more than 90% of all CIN2, CIN3 or cancer cases, and is 25% (95% CI): 15-36%) relatively more sensitive than cytology at a cut-off of abnormal squamous cells of undetermined significance (ASCUS) (or low-grade squamous intraepithelial lesions (LSIL) if ASC-US unavailable), but is 6% (95% CI: 4-7%) relatively less specific. Several approaches are currently under evaluation to deal with the lower specificity of HPV DNA testing as associated with transient infection. These include HPV typing for HPV-16 and -18/45, markers of proliferative lesions such as p16 and mRNA coding for the viral E6 and/or E7 proteins, with a potential clinical use recommending more aggressive management in those who are positive.In countries where cytology is of good quality, the most attractive option for primary screening is to use HPV DNA testing as the sole screening modality with cytology reserved for triage of HPV-positive women. Established cytology-based programmes should also be gradually moving towards a greater use of HPV DNA testing to improve their efficacy and safely lengthen the screening interval. The greater sensitivity of HPV DNA testing compared to cytology argues strongly for using HPV DNA testing as the primary screening test in newly implemented programmes, except where resources are extremely limited and only programmes based on visual inspection are affordable. In such countries, use of a simple HPV DNA test followed by immediate 'screen and treat' algorithms based on visual inspection in those who are HPV-positive are needed to minimise the number of visits and make best use of limited resources. A review of studies for visual inspection methods is presented.The fact that HPV is a sexually transmitted infection may lead to anxiety and concerns about sexual relationships. These psychosocial aspects and the need for more information and educational programmes about HPV are also discussed in this article. (C) 2008 Elsevier Ltd. All rights reserved.