Comprehensive control of human papillomavirus infections and related diseases

Abstract

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.

Keywords: Anal cancer; Cervical cancer; HPV; HPV testing; HPV vaccination; Oropharyngeal cancer; Penile cancer; Prevention; Screening; Vaginal cancer; Vulvar cancer.

Figure 1

Natural history and HPV-based prevention strategies according to age. VIA: Visual inspection with acetic acid. Reproduced with permission from Bosch FX et al. [2].

Figure 2

HPV prevalence among women with normal cytology: meta-analysis based on results from 1,016,719 women. ^aRegionally-adjusted HPV (see Bruni L et al. J Infect Dis 2010;202:1789–99 for adjustment methodology). Reproduced with permission from Forman D et al. [3].

Figure 3

Cervical cancer, global map showing estimated age-standardized (world standard) incidence rate per 100,000 in 2008 (all ages). Based on GLOBOCAN 2008. Reproduced with permission from Forman D et al. [3].

Figure 4

Cervical cancer, age-standardized (world standard) incidence rates per 100,000, 1978–2007, per 5-year period, in selected cancer registry populations (all ages). Based on Cancer Incidence in Five Continents, Volumes V to IX and Surveillance, Epidemiology, and End Results (SEER) Program. ASR (W): Age-standardized (world standard) rate. Reproduced with permission from Forman D et al. [3].

Figure 5

Natural history of HPV infection. CIN3: Cervical intraepithelial neoplasia grade 3. Reproduced with permission from Moscicki A–B et al. [4].

Figure 6

High-Risk HPV Infection and its Possible Consequences. (i) The detection of HPV DNA in a tissue biopsy or in exfoliated cervical cells may indicate infection (productive (CIN1) or abortive (CIN3) as shown in (ii)), the presence of virus particles at the epithelial surface without infection (e.g. from recent transmission), or a latent or silent infection (as shown in (ii)). To resolve this ambiguity, markers of viral gene expression (such as mRNA or proteins) are useful in confirming the presence of active disease when HPV is detected using DNA-based tests. Infection requires the entry of HPV virions into the mitotically active epithelial cells of the basal layer, which in stratified epithelium is thought to require a microwound. In the columnar cell layers, infection is thought to be facilitated by the proximity of the target cell to the epithelial surface, which may allow the virus to access a cell type that is unable to support the full productive life cycle (right). The significance of infection of different cell types remains to be properly assessed. (ii) Following infection (shown in (i)), expression from the viral genome can sometimes be suppressed (e.g., by genome methylation), leading to a ‘silent’ infection in which the viral genomes are retained in the basal layer without apparent disease. Infection may alternatively lead to an ordered pattern of viral gene expression leading to virus synthesis and release from the upper epithelial layers (productive infection or CIN1), or to deregulated viral gene expression and high-grade neoplasia (CIN2/CIN3). Persistent high-grade disease such as CIN2 and 3 is associated with a increasing risk of genome integration into the host cell chromosome and progression to cancer. Cells in cycle are indicated by the presence of red nuclei. Cells expressing E4 are shown in green, while those expressing L1 are shown in yellow. The brown shading on the diagrammatic representations of the epithelium identify all the cells (differentiated and un-differentiated) that contain viral genomes. (iii) In most cases, HPV infections are resolved as a result of a cell-mediated immune response (left). This may lead to viral clearance or to viral latency and the persistence of viral episomes in the epithelial basal layer without life-cycle completion. Viral gene expression patterns during latency are not well characterised (E1, E2 expression postulated here as suggested from animal models). Persistent deregulated gene expression, as occurs in CIN3 and following viral genome integration, can lead to the accumulation of secondary genetic changes in the infected host cell and development of cancer. This is facilitated by over-expression of the high-risk E6 and E7 proteins. Cells in cycle are shown by red nuclei. Brown shading in the immune latency state indicates cells harbouring viral episomes. In cervical cancer, the viral genome is often integrated with loss of expression of full-length E1, E2, E4 and E5, and the L1 and L2 capsid proteins, and with de-regulated expression of E6 and E7. Reproduced with permission from Doorbar J et al. [6].

Figure 7

Relative sensitivity (left) and specificity (right) of high-risk HPV DNA testing with HC2 or PCR compared to cytology after treatment of high-grade to predict therapeutic failure (residual of recurrent CIN2 or worse). CI: Confidence interval; HC2: Hybrid Capture® 2; I²: Percentage of total variation across studies due to heterogeneity; p: Test for inter-study heterogeneity; PCR: Polymerase chain reaction. Reproduced with permission from Arbyn M et al. [8].

Figure 8

Meta-analysis of the main outcomes from randomized trials comparing HPV- and cytology-based cervical cancer screening. Relative detection rate of CIN3+ (left panel) and cervical cancer (right panel), observed in the second screening round among women who were HPV-negative versus cytology-negative at enrolment. CI: Confidence interval; CIN: Cervical intraepithelial neoplasia; DRR: Detection rate ratio; I²: the percentage of total variation across studies due to heterogeneity; p: test for inter-study heterogeneity. Reproduced with permission from Arbyn M et al. [8].

Figure 9

Meta-analysis of the sensitivity of HC2 as a primary screening test to detect CIN2+ (left) or CIN3+ (right) in developing countries, industrialised countries, and China. It shows clearly that the sensitivity is very heterogeneous in developing countries (probably due to quality of gold standard), much less heterogeneous in industrialised countries and not heterogeneous in China (improved gold standard verification). CIN: Cervical intraepithelial neoplasia; ES: Estimate of sensitivity; HC2: Hybrid Capture® 2; I²: Percentage of total variation across studies due to heterogeneity; p: Test for inter-study heterogeneity. Reproduced with permission from Arbyn M et al. [8].

Figure 10

Meta-analysis of the sensitivity for detecting CIN3+ in primary cervical cancer screening, using other tests than HC2, by test system. CI: Confidence interval; ES: Estimate of sensitivity; I²: Percentage of total variation across studies due to heterogeneity; p: Test for inter-study heterogeneity. Reproduced with permission from Arbyn M et al. [8].

Figure 11

An Information–Motivation–Behavioral Skills (IMB) model of HPV vaccine offering and uptake. The IMB model specifies that HPV vaccine information and HPV vaccine motivation work through the application of HPV vaccine behavioral skills to influence HPV vaccine offering (on the part of health care providers) and uptake (initiation and completion of an HPV vaccination series). In situations in which the behavioral skills demands of HPV vaccination are minimal, there may be direct associations of HPV vaccine information, HPV vaccine motivation, and HPV vaccine offering and uptake. Reproduced with permission from Fisher WA [15].

Figure 12

The HPV vaccination behavior sequence. Seen from the perspective of (A) a parent who wishes to have their child vaccinated, (B) an adolescent or adult who wishes to be vaccinated, or (C) a health care provider who wishes to offer vaccination, there is a complex sequence of behaviors involved in vaccine series initiation and completion. Only selected vaccine uptake behavioral steps are portrayed in this figure for purposes of illustration. Reproduced with permission from Fisher WA [15].

Figure 13

Model of HPV transmission and vaccination, the natural history of disease, disease outcomes and cervical screening: Schematic diagram to inform future implementations. (a) Type-specific vaccination and naturally-acquired immunity can be modeled. Both vaccine-induced and naturally-acquired immunity can be modeled as waning over time. If the duration of immunity to HPV infection is modeled as lifelong, individuals do not become susceptible to re-infections with the same HPV type. Although vaccine can be delivered on a population basis, only susceptible individuals can be effectively vaccinated with current generation prophylactic vaccines. (b) Anogenital to oral HPV transmission has not generally been modeled explicitly in the evaluations conducted to date. (c) Several models to date have used the histological CIN1-3 designation to represent natural history states, but the natural history schematic depicted here is designed to inform future evaluations by reflecting the most current biological understanding of the natural history of HPV infection of the cervix. However, this does not necessarily imply that there are no transitory states between infection and CIN3 that are relevant to modeling; rather that future models should attempt to capture the best current understanding of underlying biological processes. (d) In practice, precancerous lesions should ideally be incorporated into models of HPV transmission since they are more likely to arise from persistent HPV infections. (e) In the future, male vaccination may be implemented in conjunction with anal cancer screening and intermediate states (i.e., anal intraepithelial neoplasia) and this will need to be reflected in comprehensive models. CIN: Cervical intraepithelial neoplasia; RRP: Recurrent respiratory papillomatosis. Reproduced with permission from Canfell K et al. [16].

Figure 14

Age-specific incidence rates of cervical cancer in the World, More and Less Developed regions, and GAVI-eligible countries. GAVI-eligible countries (2011): Gross national income per capita ≤ US$1,500. Reproduced with permission from Kane MA et al. [20].