Guide Prophylaxis and Early Detection of HPV-Related Neoplasia (Monographs in Virology)

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These rates are comparable to rates of cervical cancer before the introduction of Papanicolaou smear screening around the world [ 13 ]. Other high-risk groups compared with the general population include women who are positive for HIV, women with cervical or vulvar cancer [ 18 , 19 ], and people in chronic immunosuppressive states not due to HIV [ 20 ]. Earlier studies looking at the increased incidence of anal cancer in MSM suggested a correlation between anal intercourse and anal cancer [ 11 , 22 ], with subsequent studies confirming this association, which exposes the anal mucosa to HPV infection [ 23 , 24 ].

The long-held perception that receptive anal intercourse is limited to homosexual practices is rapidly becoming obsolete as increasing global rates of heterosexual anal intercourse have been reported [ 25 , 26 ]. In terms of absolute numbers, women in the U. In a population-based case-control study in Denmark and Sweden, Frisch et al. However, the majority of men and women in the study with anal cancer reported that they did not practice anal intercourse [ 28 ]. The implication is that either modes of anal transmission for HPV other than anal intercourse exist, or there needs to be a critical look at the role stigmatization plays in participant responses regarding anal intercourse.

Regardless, it is evident that heterosexual anal intercourse can no longer be ignored when it comes to HPV and anal cancer. The role of HIV in the development of HPV-associated preinvasive and invasive anal lesions, whether direct or interdependent, is not clearly understood. It is apparent that the higher incidence of AIN in people seropositive for HIV cannot be explained by sexual practices alone [ 29 , 30 ].

The rate of progression was further increased in HIV seropositive men with CD4 counts of less than relative risk, 3. According to a global systematic literature review conducted by Hoots et al. HPV is a capsid-enclosed, double-stranded DNA virus with a genome that encodes for eight genes identified as E or L early or late depending on the timing of their expression during epithelial differentiation.

Early proteins include E1—E7; L1 and L2 are the late proteins [ 35 ] and are present on the capsid shell. E6 and E7 are the main HPV oncoproteins [ 36 ]. E6 prevents apoptosis by binding to host p53, and E7 causes cell cycle arrest by binding to host retinoblastoma protein [ 35 ]. Independently, both E6 and E7 can prevent or defer senescence, but when they are expressed at the same time, they can lead to cell immortalization [ 37 ]. E6 and E7 oncoproteins are imperative, but insufficient, for malignant transformation on their own.

In most cases, after HPV transmission, infection is cleared in 1—2 years. In a few cases, there is persistent infection, premalignant changes, and then malignancy, all of which may take place over as few as 1—5 years [ 35 ]. A cell-mediated immune CMI response usually follows HPV infection with resultant lesion regression and future protection against infection with the same type of HPV [ 38 ]. The type of T cells involved in lesion regression is currently unknown [ 39 ], as are the mechanisms behind persistent infection or reinfection with the same HPV type.

Despite being inconsistently generated following natural HPV infection, humoral immunity depends on the recognition of distinct conformational epitopes and, even with activation, antibody peak levels are relatively low. The possible factors involved in this phenomenon include the intraepithelial replication of HPV, absence of viremia needed to invoke high-level antibody production and local antigen-presenting cells, as well as paucity of macrophages to generate a more rugged response [ 38 ]. Demonstration in animal models that minimal levels of neutralizing antibody against HPV are protective for long periods is the driving focus of the development of a prophylactic and potentially therapeutic vaccine that will be dependent on the more efficient antibody-mediated immunity [ 38 ].

AIN or anal squamous intraepithelial lesions usually precede anal cancer. AIN may follow one of two paths: It may regress on its own, or become a high-grade lesion [ 41 ]. Regression of high-grade anal lesions is very rare [ 42 ]. The squamocolumnar junction of the anal canal transition zone where the columnar epithelium of the rectum transitions to squamous epithelium of the anus is the vulnerable region within the anal canal where the histologic manifestations of HPV are most evident [ 43 ].

Anal-canal HPV infection can be latent normal tissue appearance detected through HPV DNA testing , subclinical abnormal tissues detected with cytology or high-resolution anoscopy , or clinically overt changes such as condylomata or anal cancer [ 44 ]. The vaccines are made up of DNA-free, virus-like particles, both produced by expression of the major structural L1 gene of the HPV types [ 45 — 47 ]. The high cost of the vaccine sparked interest in considering a two-dose schedule.

This was supported by a post-trial analysis of participants who received fewer than three doses [ 49 ]. Dobson et al. The results of this study played a role in the recent switch to the 2-dose schedule in the European Union, Switzerland, The Netherlands, and Mexico for girls aged 9—14 years [ 50 ]. However, the study created several questions of immunity, especially in girls aged 11—12 years and the need to study efficacy in girls older than 13 years [ 51 ].

In the U. In December , the advisory committee on immunization practices ACIP recommended the routine use of the quadrivalent vaccine for prevention of AIN in women and men [ 52 ]. Emerging studies appear to show that vaccination may be the most realistic long-term approach to prevention [ 53 ] and possibly treatment of AIN and anal cancer [ 54 ]. Whereas the efficacy of the vaccine in prevention of anogenital precursor malignant lesions has been adequately proven in trials [ 45 , 46 ], there is a paucity of data looking directly at efficacy of the vaccine against anal HPV infection and anal cancer.

The lack of screening makes the need for a preventive vaccine even more imperative. Given that persistent infection with high-risk HPV types is associated with increased risk of developing dysplasia or cancer, prevention is especially important in patients who are seropositive for HIV, who are particularly susceptible to persistent HPV infection [ 55 , 56 ]. Clinical trials evaluating preventive role of HPV vaccine in HPV-related anal intraepithelial neoplasia and anal cancer.

Given that persistent infection with high-risk HPV types is associated with increased risk of developing dysplasia or cancer, prevention is especially important in patients who are seropositive for HIV, who are particularly susceptible to persistent HPV infection. In a substudy of a phase III, efficacy, multicenter, double-blind study, Palefsky et al. Participants who were seronegative for HPV, completed all 3 vaccine doses, and were followed for 2.

This group had a vaccine efficacy rate of The risk of persistent anal infection with covered types was reduced by In the intention-to-treat group only 1 dose required with follow-up , the efficacy was Although it was recognized that targeted vaccination programs toward a specific group based on sexual practices i. In addition, based on the biological similarity between anal cancer in heterosexual men and women [ 34 ], they projected similar per-protocol group results.

In the Costa Rica vaccine trial, a randomized double-blind controlled trial, Kreimer et al. A substantial vaccination efficiency of In the full cohort, vaccination efficiency was noted to be higher in women who reported anal intercourse Wilkin et al. The overall outcome was that the qHPV appeared to be safe and highly immunogenic in this group. The implication is that a significant proportion of men will likely benefit from qHPV despite being older than the current age limit for which the vaccine is approved, and having significant prior anal HPV exposure may not be an exclusion criterion [ 58 ].

Twelve vaccinated patients This study was unique in several aspects. There is a need to conduct randomized control trials to answer two other major questions: Is the vaccine beneficial in older patients who practice receptive anal intercourse? Should it be used as adjuvant therapy in HG-AIN, given the high recurrence rate after treatment with surgery, topical, and pharmacologic therapy [ 60 — 62 ]?

Currently, the treatment recommendation for HPV-related squamous cell carcinoma of the anus involves screening at-risk patients and observing precancerous lesions with the intention of early detection and eradication. Treatment options include laser ablation, surgical resection, or chemoradiation therapy. Successful eradication has been difficult and recurrence is high, particularly among patients seropositive for HIV [ 63 , 64 ]. Current cancer treatment consensus is that a multimodality treatment approach that combines immunotherapy with radiation and chemotherapy is clearly needed to have the best effect on tumor cell reduction and eradication [ 65 ].

While the full extent and potential of prophylactic vaccination is a work in progress, there is a rapidly evolving interest in the prospect of therapeutic vaccinations. The oncogenic pathophysiology of HPV-related anal squamous cell carcinoma makes this approach a reasonable one. Several early trials have shown immense promise, but there have been inconsistent clinical responses [ 67 , 68 ] Table 2. In a nonrandomized, phase II, prime-boost vaccine trial using heterologous HPV vaccines to determine their clinical effectiveness in the management of noncervical anogenital intraepithelial neoplasia AGIN , Fiander et al.

The study was not designed to evaluate clearance of infection or to measure changes in disease severity, because no biopsies were taken. Hence, inferences cannot be made on clinical response. Garcia-Hernandez et al. Kenter et al. Several encouraging conclusions and inferences can be made from these studies. The qHPV is effective in reducing persistent anal infection with HPV-6, , , or [ 53 ], and this is supported by findings in the Costa Rica vaccine trials, albeit with some limitations of the latter [ 57 ].

The study by Palefsky et al. With the increasing rates of heterosexual anal intercourse [ 25 — 27 ] and increased risk of anal cancer with receptive anal intercourse [ 28 ], the benefits of the vaccine observed by Palefsky et al. Individuals older than 26 years may benefit from the qHPV vaccine. The significant number of older participants who were seronegative and anal-canal HPV-DNA negative and yet showed a high immunogenic response and safety profile in the trial conducted by Wilkin et al.

The trial by Swedish et al. Randomized trials are required to confirm this and also determine, if possible, predictors for responders and nonresponders. The results obtained by Baldwin et al. The incidences of AIN and anal cancer are on the rise in the U. Although it has a female preponderance [ 7 ], the incidence is rapidly increasing in men [ 4 ]. Compared with the general population, the rate is disproportionately higher in certain high-risk groups, namely, MSM [ 11 , 12 ]; people seropositive for HIV, especially in the era of ART [ 14 — 17 ]; women with cervical or vulvar cancer [ 18 , 19 ]; and people with chronic immunosuppressive states other than HIV [ 20 ].

The perception that receptive anal intercourse is limited to MSM is obsolete because data are emerging of increasing heterosexual receptive anal intercourse globally [ 25 — 28 ], and this is very significant from the public health perspective. The best approach for addressing the rising rate of anal cancer [ 4 , 8 — 10 ] will be the institution of primary and secondary prevention strategies.

Primary preventive strategies should begin with improvement in the vaccination coverage rates, which are, at best, average for the current targeted population [ 75 ].


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National statistics on U. The rates among U. In comparison, other developed countries such as Australia and the U. Australia boasts a Currently, the U. In developing countries, programs are being created to improve HPV vaccine uptake. Through low-cost vaccine programs, countries in Sub-Saharan Africa have seen success in providing coverage.

South Africa recently introduced a vaccination program in , and several other countries are conducting school-based pilot programs [ 79 ]. South Africa recently introduced a vaccination program in , and several other countries are conducting school-based pilot programs. The success rates in these countries are from implementation of school-based programs and national health coverage of the vaccine Table 3. Currently, in the U. However, only three states have implemented HPV vaccination requirements, which may be due to the political social controversy surrounding the HPV vaccine [ 76 ].

Summary of vaccination programs and uptake rates in select countries. Education of policy makers, health care professionals, and targeted populations should be pursued diligently to improve vaccination coverage in the U. Research should be conducted to evaluate the benefits of vaccination for older individuals, especially if they are identified as being at risk. The value of the vaccine in decreasing persistent anal HPV infection [ 53 ] should be evaluated further. This calls for standardized screening recommendation for high-risk groups, taking into consideration changing sexual practices and other risk factors.

The search for a therapeutic HPV vaccine is underway and improvements in our knowledge of viral tumorigenesis and immunology will hasten discovery. Mensah, James S. Lewis Jr. Craig Lockhart. Manuscript writing: Felix A. Mensah, Mudresh R. Mehta, A. Felix A. User Name Password Sign In. Mensah a , b , Mudresh R. Mehta b , James S. Mensah, M. Accepted January 6, Published online before print March 9, Implications for Practice: The incidences of human papillomavirus HPV -related anal cancer and its precursor lesion, anal intraepithelial neoplasia, are on the rise in the U.

Previous Section Next Section. Epidemiology and Risk Factors for Anal Cancer Anal carcinoma is a rare malignancy with global age-standardized incidences ranging from 0. Sexual Practices Earlier studies looking at the increased incidence of anal cancer in MSM suggested a correlation between anal intercourse and anal cancer [ 11 , 22 ], with subsequent studies confirming this association, which exposes the anal mucosa to HPV infection [ 23 , 24 ]. HPV Virology and Immunology HPV is a capsid-enclosed, double-stranded DNA virus with a genome that encodes for eight genes identified as E or L early or late depending on the timing of their expression during epithelial differentiation.

View this table: In this window In a new window. Table 1. Prospects of Therapeutic Vaccines Currently, the treatment recommendation for HPV-related squamous cell carcinoma of the anus involves screening at-risk patients and observing precancerous lesions with the intention of early detection and eradication.

Table 2. Table 3.

Previous Section. International Agency for Research on Cancer. Monographs on the Evalaution of carcinogenic risks to Humans : Human Papillomaviruses. Google Scholar. Centers for Disease Control and Prevention. Genital HPV infection - fact sheet. Accessed May 12, Human papillomavirus HPV -associated cancers. National Cancer Institute.

Accessed May 9, Management of anal cancer in Part 1: Overview, screening, and diagnosis. Oncology Williston Park ; 24 : - Medline Google Scholar. Part 2: Current treatment standards and future directions. Cancer incidence in five continents vol IX. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, Cancer ; : - CrossRef Medline Google Scholar.

Cancer statistics, CA Cancer J Clin ; 64 : 9 - Accessed May 5, Correlates of homosexual behavior and the incidence of anal cancer. JAMA ; : - High incidence of anal cancer among AIDS patients. Other viral proteins E1, E2 and E6 do not elicit antibody responses. The IgM response occurs first and decays. The IgG1 response appears later and is more persistent. There is disagreement over the protective role of antibodies after natural infection, perhaps because of differences in assays used for detection, cut-off definitions, study design, and data analysis.

Molecular mechanisms of the preventable causes of cancer in the United States

Antibody titers in blood reach peaks 2—3 log higher than in natural infections, wane to levels several-fold lower than peak and then remain stable for years. Antibody titers are thus not a correlate of immune protection; affinity and avidity is likely to be important. Antibodies in the cervix are detectable at lower concentrations and vary with the menstrual cycle.

Partial cross-protection against HPV31, HPV33 and HPV45 have been described, but although cross-neutralizing antibody concentrations are the same for both vaccines, data for the two vaccines regarding cross-protection vary. HPV-associated lesion regression is most often associated with cell-mediated immune responses to E2 and E6. Effector T-cell responses to E6 and E7 are weak and do not match the clinical progress of the infection. Our knowledge of cervical T cell populations is still scarce, but experimental data suggest that tissue-specific immune parameters may be highly informative and that local activation of cell responses could be a therapeutic target in high-grade precancers of the cervix, vagina and anus.

Our knowledge on the cervicovaginal commensal flora, as well as virus-mediated changes in the immune milieu, is limited. Reproduced with permission from Schiller JT et al [ 13 ]. The clinical trials were primarily designed to demonstrate efficacy in preventing incident vaccine-related HPV infection and the preneoplastic lesions caused by incident persistent infections related to vaccine HPV types. All of the trials were relatively large 5,—18, vaccinees , blinded, randomized and controlled trials of young women mean age 20, range 15—26 Table 9.

Reproduced with permission from Schiller JT et al. The vaccines had no therapeutic effects against established infection or CIN. Both vaccines showed some degree of cross-protection for both HPV infection and lesions related to non-vaccine types. Both vaccines exhibited excellent safety profiles in the clinical trials. These solicited symptoms were transient, resolved spontaneously and did not increase with number of doses. Table 15 summarizes the assessment of serious adverse events for both vaccines. Both vaccines exhibited excellent immunogenicity profiles.

For practical reasons, efficacy studies have not been conducted in the primary target populations of current vaccination programs, adolescent girls and boys. However, immunogenicity bridging studies demonstrating excellent safety and strong immune responses in adolescence, coupled with the documentation of durable antibody responses and protection in young adults, lead to an optimistic projection of the effectiveness of the vaccines in adolescent vaccination programs.

Taken together, the excellent clinical trial results strongly support the potential of the vaccines as high value public health interventions and justify their widespread implementation to prevent anogenital HPV infections and their associated neoplasia. The primary focus must now be on implementation issues to maximize the rapid, effective, and cost-efficient delivery of the vaccines to those individuals that are most likely to benefit from them.

By mediation of the Global Alliance for Vaccines and Immunization GAVI the price of the vaccines in developing countries is now significantly decreased, making them more affordable. The availability of prophylactic HPV vaccines has provided a powerful tool for primary prevention of cervical cancer and other HPV-associated diseases. Since , the quadrivalent and bivalent vaccines have each been licensed in over countries. By the beginning of , HPV vaccine has been introduced into national immunization programs in at least 40 countries Table In Europe, the number of countries having introduced vaccine increased from 3 in to 22 at the beginning of Countries that have included HPV vaccine in their national immunization programs, date, target age groups and coverage, — a.

Reproduced with permission from Markowitz LE et al. While all country programs target young adolescent girls, specific target age groups vary, as do catch-up recommendations. Different health care systems and infrastructure have resulted in varied implementation strategies, with some countries delivering vaccine in schools and others through health centers or primary care providers.

Within the first 5 years after vaccines became available, few low- or middle-income countries had introduced HPV vaccine. The main reason was budgetary constraints due to the high vaccine cost. Bhutan and Rwanda implemented national immunization after receiving vaccine through donation programs in and , respectively. To address questions about delivery of vaccine to adolescents in low-resource countries, demonstration projects with systematic evaluation were conducted in India, Peru, Uganda, and Vietnam beginning in These projects found that high coverage could be achieved using a variety of delivery strategies, including school-, and health center-based strategies, as well as those coupling HPV vaccination with other health interventions Table Demonstration projects and strategy refinements after evaluation of pilot programs in three low-resource countries.

In general, countries with school-based delivery and publicly financed vaccine have achieved higher coverage than those with opportunistic, clinic-based or primary care-based programs. However, school-based programs are not without challenges and may be more costly. Furthermore, in low-income countries there are concerns about reaching out-of-school children. Nevertheless, there are some clear advantages of school-based delivery for this hard to reach age group. Factors other than delivery can contribute to levels of coverage achieved, including public financing, public health promotion of vaccine and good communication strategies, organized outreach to parents, and medical profession and public acceptance.

The cause of low coverage achieved in some countries is likely multifactorial. Evaluation of vaccination programs includes monitoring of coverage, safety, and impact. Vaccine safety monitoring is part of routine activities in many countries Table These passive monitoring systems have limitations, including reporting of events that may have occurred coincidentally following vaccination, as well as incomplete reporting.

A formal evaluation of the passive surveillance system in the US, the Vaccine Adverse Event Reporting System, was conducted after over 23 million doses of quadrivalent HPV vaccine were distributed June through December In Australia, a review of data after 6 million doses of quadrivalent vaccine were distributed did not reveal unusual patterns of reports. Similarly, in the UK, no pattern of adverse events or reason for concern was found after 4.

In the US, evaluation of specific events that might be associated with vaccination is done through the Vaccine Safety Datalink VSD , a system that evaluates adverse events in those vaccinated compared to a control group. Data were analyzed in VSD after more than , doses of quadrivalent HPV vaccine had been administered to females and raised no concerns. Post-licensure studies by the manufacturers comparing rates of adverse events in vaccinated with unvaccinated groups are ongoing or have been completed.

All reviews show that the accumulating evidence on the safety of HPV vaccines is reassuring. Safety evaluations are important and communication about vaccine safety is critical, as events temporally associated with vaccination can be falsely attributed to vaccination. Anti-vaccination efforts, in part related to concerns about safety, have been mounted in several countries. Biologic outcomes ranging from HPV prevalence to cancer are being monitored by public health efforts in some countries.

In Australia, where high coverage with quadrivalent vaccine was achieved soon after introduction, impact on genital warts was observed in the age group of women targeted for vaccination. Decreases were also observed among men suggesting impact of herd immunity. According to the IMB model, individuals who are well-informed about HPV vaccination, motivated to act on what they know about it, and who possess the behavioral skills required to act effectively to seek out, fund, initiate, and complete the multi-injection HPV vaccination series, are likely to successfully navigate obstacles to vaccination and achieve immune protection.

HPV vaccine uptake motivation, based on attitudes towards undergoing HPV vaccination and perceptions of social support for undergoing HPV vaccination, are a second, fundamental determinant of whether or not an individual who is well-informed about HPV vaccination will be inclined to act on what they know to receive HPV vaccination. HPV vaccination behavioral skills— skills for bringing up HPV vaccination with providers, parents, or partners, and skills for funding vaccination and adhering to a multi-injection vaccine schedule—are required to successfully navigate the potentially complex HPV vaccination process from start to finish.

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HPV vaccination information and HPV vaccination motivation are expected to influence HPV vaccination uptake both directly and by triggering application of complex behavioral skills that are required to initiate and complete the HPV vaccination series. The IMB analysis also specifies macro level factors may affect HPV vaccine uptake indirectly, via their impact on HPV vaccine information, motivation, and behavioral skills, or directly, via unmediated impact on HPV vaccine uptake Fig.

Reproduced with permission from Fisher WA [ 15 ]. The HPV vaccination behavior sequence.

Introduction

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.

First, formative research is conducted to assess HPV vaccine related information, motivation, and behavioral skills assets and deficits in a target population. Second, targeted interventions are created on the basis of formative research to capitalize on assets in HPV vaccine related information, motivation, and behavioral skills, and to address deficits in HPV vaccine related information, motivation, and behavioral skills, in efforts to promote HPV vaccine uptake. Third, evaluation research is conducted to determine whether the targeted intervention has had intended effects on HPV vaccine related information, motivation, behavioral skills, and HPV vaccine uptake.

Research support for the IMB model analysis of factors that influence HPV vaccine uptake in developed countries, and for an IMB model approach to strengthening vaccine uptake, are discussed.

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A comprehensive approach to the evaluation of HPV prevention raises a number of technical challenges. These include accurate modeling of HPV transmission within a population, the natural history of progression to cervical preneoplastic and neoplastic disease and other HPV-associated cancers, the efficacy of vaccination against different HPV types, cervical Screening test performance for various screening and triage test technologies, diagnostic and treatment processes, and screening and vaccination uptake.

Models of HPV-related disease prevention can be conceptually categorized into several interacting components, as follows: i HPV infection, transmission and vaccination; ii natural history of cervical precancerous disease, invasive cervical cancer, GW and other HPV-related conditions; and iii cervical screening. Model of HPV transmission and vaccination, the natural history of disease, disease outcomes and cervical screening: Schematic diagram to inform future implementations.

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.

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. Reproduced with permission from Canfell K et al.

In recent years, there have been numerous economic evaluations of the vaccination of pre-adolescent females against HPV in developed countries, and if long duration vaccine protection is assured, these have almost universally found this intervention to be cost-effective, even in the context of existing screening programs. For female only vaccination, cost-effectiveness ratios are sensitive to the duration of vaccine-conferred protection and the associated need to consider booster injection, but appear remarkably insensitive to the type of model used static or dynamic , the outcomes included, or the assumed cost per vaccinated individual within a feasible range.

Studies evaluating the cost-effectiveness of catch-up vaccination to older ages consistently find that this intervention is associated with a lower cost-effectiveness, because catch-up cohorts are more likely to have prior exposure to HPV infection. However, studies differ in their conclusions about the optimal age for catch-up vaccination some found the cost-effectiveness ratio became unfavorable over the age of 15 years, others over the age of 18—21 years and still others over the age of 26 years.

The inclusion of males in population-based HPV vaccination programs has potential benefits, including direct benefits to vaccinated males for protection against male HPV-related cancers and GW, indirect benefits to both non-vaccinated females and males via increased herd immunity, and also protection of men who have sex with men. However, the return on investment of including males in existing vaccination programs will generally be lower than that of female vaccination for two reasons; firstly because the HPV-related burden of disease in males is lower than in females, and secondly, because heterosexual males derive benefits from female-only vaccination via herd immunity, particularly if coverage in females is high.

In countries choosing to adopt only one vaccine, an important category of evaluation is the comparison of the relative cost-effectiveness of bivalent and quadrivalent vaccines. Policy decision-makers need to consider, firstly, whether protection against GW, as well as cancer prevention is the goal of the intervention. In cost-effectiveness terms, the comparison depends upon a complex trade-off between assumptions for the duration of direct protection, the extent and duration of cross-protection, and protection against GW and RRP. A major focus for future modeling research will be evaluating the effects of vaccination on screening programs.

It is expected to be several decades before HPV vaccination has a direct impact on rates of cervical cancer, but in some countries, a relatively rapid impact on rates of detected high-grade precancerous abnormalities in young women is expected. The timing of this effect will depend on several factors, including the age at which screening is initiated, the oldest age to which vaccination catch-up was conducted, and vaccination coverage in the catch-up phase.

Over time, the vaccination of successive cohorts of girls will continually reduce the average lifetime risk of developing invasive cervical cancer in the population, and therefore existing screening practices will eventually become less cost-effective. Finding cost-effective screening approaches in vaccinated populations will require consideration of new strategies. Delaying the age at which screening is initiated, increasing the screening interval, and switching to primary HPV screening are important strategies for increasing the cost-effectiveness of screening in vaccinated women.

New automated platforms for primary HPV testing should drive down test costs, which will be an important consideration in maintaining the cost-effectiveness of screening in vaccinated populations. Most of these future screening options have not yet been comprehensively evaluated for cost-effectiveness in the context of HPV vaccination. The introduction of screening at longer intervals will pose substantial challenges to screening programs.

The cost-effectiveness of HPV-based screening will be adversely affected if women attend more frequently than at the recommended interval, but conversely, loss to follow-up may worsen over longer re-screening intervals. The differing compliance associated with alternative methods of organizing screening has been shown to influence the effectiveness and cost-effectiveness of longer-interval approaches in modeled evaluations. Therefore, the robustness of conclusions about the cost-effectiveness of HPV screening will need to be tested against various assumptions about the degree of over- and under-screening that will occur in different circumstances.

The majority of cost-effectiveness evaluations of HPV vaccination have assumed that vaccine uptake will be homogenous across different subgroups in the population. However, vaccine uptake is likely to be associated with factors such as socio-economic status and sexual behavior, both of which also have been associated with participation in cervical screening. It has been demonstrated that the cost-effectiveness of combined strategies is less attractive if high-risk groups are less likely to participate in both the screening and vaccination programs.

Conversely, concerns have been raised about a potential decrease in screening participation among vaccinated women. The impact of all of these effects on the cost-effectiveness of both vaccination and screening require evaluation, using the most comprehensive emerging data available. In addition, it has been observed that immunocompromised individuals, such as those with HIV, are also resistant to treatment of HPV-related diseases and prone to accelerated development of HPV-associated cancers.

The interaction between the two sexually transmitted infections appears to be related to the alteration in cell-mediated immunity in HIV infected persons, increased susceptibility, and possibly reactivation of latent HPV infection. It is, however, unknown whether the converse relationship is also true. Some of the common sexually transmitted infections have been postulated to increase the risk of HIV acquisition, including syphilis and herpes simplex virus. Anal cancer incidence is greatly increased in HIV-positive individuals, particularly in HIV-positive men who have sex with men.

Anal cancer has a well known precursor stage that can be detected in a variety of ways, including anal cytology and high-resolution anoscopy. Screening for anal cancer precursors is feasible; however, the impact on reduction of anal cancer remains to be demonstrated and no randomized trials have been performed.

There are ongoing studies on the safety, immunogenicity, and efficacy of current HPV vaccines in HIV positive-individuals and mature data are awaited. Male circumcision may be another approach to prevention of HPV transmission, which also requires further study. The recognition that HPV infection is the central, necessary cause of cervical cancer paved the way to new fronts of prevention via improved screening methods and HPV vaccination.

Much has been learned in all fronts, from the molecular basis of our understanding of how HPV causes disease to the health economics of preventive strategies at the individual and population levels. Progress in other areas of cancer control has yet to show the same multi- and trans-disciplinary gains seen in research on HPV-associated malignancies, which is one of the unequivocal success stories in disease prevention.

Yet, as an embarrassment of riches, much more research is needed to fill the gaps in knowledge that remain before we are able to reap the benefits through translation of knowledge from all fronts. Public health research on setting-specific implementation of HPV-based preventive strategies and more concerted advocacy to counter barriers facing the adoption of these strategies are likely to yield major dividends in reducing the burden of HPV-associated diseases.

The wealth of data that have been generated by the clinical trials of the two available HPV vaccines has left many questions unanswered. Table 20 lists these questions, the associated research issues, and the underlying hypotheses that would benefit from further research and epidemiologic surveillance.

Some of these questions could be addressed by post hoc exploration of completed phase III clinical trials. Partnership with industry should be sought to provide valuable insights that would aid our understanding of the role of cross-protection, the extent of protection with incomplete vaccination regimens, pan-mucosal protection against vaccine-targeted types, and anamnestic response from subsequent exposure to HPV.

Likewise, the establishment of surveillance systems linking HPV vaccination registries with data from periodic HPV surveys, screening registries, and population-based cancer registries could provide valuable information concerning duration of protection, possible type replacement, protection against other cancers, and safety.

Gaps in knowledge and pertinent research issues and hypotheses regarding the role of HPV vaccination as a primary prevention strategy. Reproduced with permission from Franco EL et al. Secondary prevention via screening has been successfully deployed in high-resource countries. Pap cytology is credited with having achieved substantial reductions in morbidity and mortality from this disease over the last 50 years. Yet, Pap cytology is seen as inefficient because it requires complex and costly infrastructure to ensure consistent quality, coverage, and treatment of precancerous lesions.

Because of the high false-negative rate of cytology, medical guidelines have historically required annual or at most triennial intervals between screen visits, which overburdens the health care system of most countries. The emergence of liquid-based thin smear cytology has mitigated some of these problems and improved the efficiency for laboratories in processing cytology caseloads; in essence, however, the problems of low sensitivity, subjective interpretation of cellular morphology, and sampling errors have not been resolved.

Over the last 15 years, a wealth of evidence from randomized clinical trials has demonstrated that these tests have much greater sensitivity and somewhat lower specificity than cytology, which would permit the lengthening of screening intervals with adequate safety. HPV testing has high reproducibility, a lower requirement for personnel training, and is amenable to using self-collected cervical samples, all attributes that would permit its deployment in large scale screening programs and in remote areas.

Automation permits high-volume testing and requires minimal training for operation. On the other hand, although several commercially available assays exist, HPV testing is still costly relative to cytology. However, lengthening of screening intervals, economies of scale post-implementation in screening programs and use of multi-analyte platforms that serve a range of clinical laboratory services would largely alleviate the costs associated with HPV testing.

The lack of specialized personnel and resource infrastructure in low-resource settings has prompted the emergence of low-technology screening methods, such as VIA. This test has been extensively field-tested in low-resource regions in Africa, Asia, and Latin America, with variable results in terms of screening accuracy. VIA may be a suitable starting point to assist the establishment of screening programs in low-resource countries in connection with immediate treatment, such as cryotherapy.

In such settings, it may also be used to triage women testing positive with a low-cost HPV DNA assay WHO is currently evaluating an HPV assay system in the field that does not require running water and relies on battery power. Research on how to combine HPV testing and VIA under screen-and-treat conditions in low-resource countries is urgently needed.

In addition to HPV testing, with its different modalities for high- and low-resource settings, and VIA, other techniques show promise as screening enhancements and are the subject of intensive research. These screening enhancements include the use of immunocytochemical markers to improve the accuracy of cytology and computer-assisted pre-selection of abnormal areas in liquid-based smears. Because of their complexity, cost, and requirement for trained personnel and laboratory infrastructure, these technological enhancements can be implemented exclusively in high-resource areas. Table 21 summarizes the existing gaps in knowledge and areas of research interest related to the secondary prevention strategies, as well as the issues pertaining to their implementation in different settings.

Gaps in knowledge and pertinent research issues and hypotheses regarding the role of screening technologies in secondary cervical cancer prevention. Cancer is an important cause of premature death in low- and middle-income countries LMIC. Two preventive tools are available that have the potential together to sharply decrease the impact of cervical cancer in LMIC. The combination of HPV vaccination and cervical cancer screening within existing programs is possible. Although there is a great deal of concern about introducing and strengthening HPV prevention efforts in LMIC, recent projects have demonstrated feasibility.

Thus, with appropriate prioritization and resources, HPV prevention can be introduced and scaled up. The integration of both screening and vaccination will save the most lives and such strategies are endorsed by many international organizations. However, some vaccine and screening programs are financed almost entirely by special externally-based programs.

These more closely resemble demonstration exercises than sustainable national programs. In order for successful demonstration projects to have a broad impact on prevention, sustainable national funding based on strong commitments is essential. There may be challenges to implementing HPV prevention programs, but none should be considered insurmountable. Failure to act on this issue can perpetuate inequity in sexually transmitted infection and cancer prevention. Table 22 presents a summary of tips on mobilization to boost screening activities, vaccine introduction, research and evaluation and activities on health promotion and education.

Reproduced with permission from Steben M et al. Age-standardized incidence rates in these countries are almost three-fold higher than in more developed regions and 1. Cervical cancer peak incidence in GAVI-eligible countries is observed in women aged 60—64 years, with estimated rates of 90 cases per , women 60—64 years, five-fold higher than in more developed regions estimates for this age group Fig.

Reproduced with permission from Kane MA et al. HPV vaccines are routinely used in the National Immunization Programs in most industrial countries, and the decision by the GAVI Alliance to accept applications from eligible developing countries for HPV vaccine support is the single most important opportunity for children in these countries to be protected against HPV-related diseases. As it has done for other vaccines, such as Haemophilus influenzae type b, rotavirus and pneumococcal conjugate vaccines, GAVI should strongly consider developing and funding a group dedicated to working on all aspects of HPV vaccine introduction in the developing world.

Immunization coverage of infants has reached high levels in many of the poorest developing countries where complementary strategies for HPV control, such as adult screening and treatment, are poorly developed. It is important to consider that there still exists wide variation between countries and that girls may have lower completion rates than boys in some countries. Experience in both industrialised and developing countries shows that school-based immunization programs have often proven to be the best strategy for reaching young adolescent populations with HPV vaccine. Immunizing young adolescents will require expansion of immunization infrastructure to reach cohorts that currently are largely unreached, but the success of school-based strategies in industrial countries and developing country demonstration projects provides hope that relatively high coverage may be achieved in many countries.

Age ranges for HPV vaccination are wider and more flexible than for infant immunization, although it is advisable to vaccinate before sexual debut. Country planners must clearly define what cohort they intend to target in order to focus their strategies, resources and messaging.

After deciding on the range of ages for vaccination, planners must determine whether birth date or some other indicator such as school grade works best for identifying eligible girls. In cultures in which birth dates are not recorded and people do not keep track of their ages, implementing vaccination by age may not work well, as PATH found in Uganda. Because HPV vaccine requires three doses over a 6-month period, timing is crucial in school-based programs to ensure that girls are fully immunized within one school year.

Program planners also must consider vacation and examination schedules, and find ways to vaccinate girls who happen to not be in school on immunization days. School-based programs also require coordination between immunization and school teams—this may be new to some EPI staff. Communication and advocacy strategies for HPV control need to carefully consider local cultural attitudes toward HPV-related issues. Strategies and materials must be tailored to the culture where they are delivered, and local providers and health officials must be prepared to discuss and defend the vaccine as appropriate in each culture.

Audience research prior to vaccine rollout often is recommended to test messages and develop new, culture-specific information. Anti-immunization groups spreading unfounded rumors and misinformation about vaccine safety have damaged many immunization programs, including HPV immunization efforts. Most misinformation about HPV involves rumors that HPV vaccines have caused deaths among vaccine recipients, but responsible investigation of these incidents show that no deaths have been related to the vaccine. It is critical that WHO and other groups develop messages and materials for health officials to handle anti-vaccine attacks and to provide them with the facts necessary to respond and the skills necessary to effectively deal with media.

Several important factors are considered by countries when they decide whether or not to introduce a new vaccine, and how that vaccine will be used Table Recommendations from WHO at global, regional and country levels are critical, as is the affordability of the new vaccine and not just in the short term. Economic models of cost-effectiveness and impact are increasingly important, but many ministries do not have the ability to construct these models. While some countries are comfortable relying on analyses from neighboring countries or generic models from the literature, other countries like to see data from their own country in the models before they accept them.

Although some authors believe that economic models are the most important factor to consider in making these decisions, in practice the decision is influenced by a wide variety of factors. Current strategies supported by health economic analyses call for female only immunization, but concerns have been expressed as to whether this is the optimal strategy for the developing world. The consensus among most health economists who have modeled the cost-effectiveness and impact of male HPV immunization in the developing world is that male immunization may not be cost-effective if high coverage of females can be achieved.

However, it is likely that a number of developing country immunization programs may not reach sufficiently high coverage of females. Immunization of both genders could result in further protection due to herd immunity, which could reduce transmission and protect the non-immunized. The issue here is that a strategy to immunize only females will leave high levels of circulating virus in the community and unprotected females, which in the case of rubella led to an outbreak of congenital rubella syndrome, and in the case of HPV would lead to continued numbers of cervical cancer cases.

At this time, it is unclear whether female-only versus both-gender vaccinations for HPV will behave similarly to that of vaccination against rubella. That said, immunizing boys would effectively double the cohort of vaccines and significantly increase costs. Decision makers in developing countries will need to take all of these issues into consideration before deciding if male immunization is a good policy for their country. So far, WHO has recommended female-only immunization, as the major burden of the consequences of HPV infection affects women, but those recommendations were made before the efficacy studies on male immunization against anal precancers and external genital lesions were completed, and before much data on HPV and oropharyngeal cancer were available.

The incidence of oropharyngeal cancer and extra-genital lesions in the developing world is not well documented and further study of these issues is needed. When closing the ICO monograph Vaccine Volume 30, Supplement 5, the International HPV Expert Group of editors and authors reached a consensus statement that aimed to summarize the evidence and the ways to move forward in relation to prevention of the HPV related diseases.

The declaration serves us as a concluding remark of this article:. All countries are encouraged to introduce routine HPV vaccination into their health programs and to create the conditions necessary for successful implementation. A range of screening and treatment protocols prevent cervical cancer in women already infected with HPV. All countries are encouraged to invest in these programs and to reduce premature death from cervical cancer in women. Data from clinical trials indicate that HPV based screening in women above the age of 30 is the most effective alternative.

Countries are strongly encouraged to offer well organized and coordinated vaccination and screening programs suitable to their national needs. Comprehensive efforts in cervical cancer prevention can be cost effective in a wide range of national economies. Xavier Bosch Spain , Ignacio G. Franco Canada , Suzanne M. Garland Australia , Maura L. Kitchener UK , Susanne K. Lacey UK , D. Thomas R. Lynette A. The work of Chris J. Jane J. Kim is supported in part by grants from the U. We acknowledge editorial assistance received from Amy Yellen-Shaw Elsevier in the preparation of this review.

Disclosed potential conflicts of interest. ABM: serves as an advisory board member for Merck and receives support for sexually transmitted disease testing from Gen-Probe. She has also received travel funds and an honorarium for speaking at a symposium supported by Becton Dickinson. MLG: Has had scientific collaborations and has received research funding from Merck.

She has acted as a consultant for Merck and GlaxoSmithKline. JTS: Named inventor on U. He has received an unrestricted grant from Merck. He has also received free specimen testing from Roche for epidemiologic projects. MD: Has disclosed no potential conflicts of interest. Europe PMC requires Javascript to function effectively.

Recent Activity. 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. The snippet could not be located in the article text.

This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Author manuscript; available in PMC Nov PMID: Gillison , e John Doorbar , f Peter L. Castle , m John T. Schiller , n Lauri E. Markowitz , o William A. Fisher , p Karen Canfell , q Lynette A. Denny , r Eduardo L. Franco , s Marc Steben , t Mark A. Kane , u Mark Schiffman , v Chris J. Xavier Bosch. Maura L. Peter L. Philip E. John T. Lauri E. William A. Eduardo L. Mark A. Chris J. Copyright notice. The publisher's final edited version of this article is available at Vaccine.

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Human papillomavirus and HPV vaccines: a review

This article has been republished " Comprehensive control of human papillomavirus infections and related diseases. See other articles in PMC that cite the published article. 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. Global prevention and management of HPV related diseases: the pressing challenges and the compelling opportunities [ 1 ] 1. Introduction The scientific community has gained tremendous knowledge about human papillomaviruses HPVs and their interactions with host cells, tissues and immune systems; has validated and implemented strategies for prophylactic vaccination against HPV infections; has developed increasingly sensitive and specific molecular diagnostic tools; and has substantially increased global awareness of HPV and the many associated diseases of women, men, and children.

Appreciation of disease causality and need for management There is inadequate recognition of the social impact of the successive stages of HPV infections: the infants who acquire low-risk HPV types 6 and 11 and develop recurrent respiratory papillomatosis RRP ; the adolescents with benign but highly contagious infections; the middle aged with consequences on reproductive capabilities and well being of the mother; the older persons with an increasing risk of cancer.

The success and promise of prophylactic vaccines The quadrivalent and bivalent HPV vaccines have proven to be very safe, with long-term durability of protection against primary infection with vaccine types and a moderate degree of cross-protection against some non-vaccine types.

A range of diagnostic methods Diagnostic screening for HPV lesions is generally available in the developed world but scarce everywhere else for lack of public health policy, professional and general education, media awareness, clinical settings, financial resources and, most crucially, insufficient capacity for effective follow-up treatment of identified lesions. The potential for therapeutic inhibition of persistent infections As the essential follow-up to disease diagnosis, new therapies are needed and they must be effective, minimally impactful on normal tissues and organs, affordable, and available everywhere.

The time for universal response is now HPV is an equal opportunity pathogen. Reframing cervical cancer prevention. Expanding the field towards prevention of HPV infections and related diseases [ 2 ] 2. HPV and cervical cancer: natural history and prevention opportunities Cervical cancer is the rare end stage of an unresolved HPV infection, currently defined as a persistent presence of the HPV DNA in repeated testing of cervical specimens.

HPV and other cancers and conditions: expanding the spectrum of disease prevention In cancers of the vagina, and their precursor lesions, HPV DNA is detected in the majority of cases. Open in a separate window. Figure 1. Elements of paradigm change in HPV-related cancer prevention Table 1 summarizes the elements in research that are prompting a paradigm change for prevention of HPV infection and related disease.

Table 1 Summary of the major elements of paradigm change for prevention of HPV infection and related disease. Burden of disease in both genders The HPV viral etiology has been established for significant fractions of cancers of the vulva, vagina, anus in both genders and penile cancer.

A significant fraction of oropharyngeal cancer in both genders is highly associated with HPV infection. In several industrialised countries with ongoing screening programs, data suggests that the actual number of cases of anal and oropharyngeal cancers are on the increase and may have already or will soon exceed that of cervical cancer.

There has been an increased understanding of the HPV co-morbidity that occurs with HIV as well as the realization that the highest mortality from both diseases tends to occur in the same countries, often in sub-Saharan Africa. Data on the high rates of anal cancer in men who have sex with men, and the very high rates in HIV-positive individuals. Early data from Australia are already showing high efficacy in prevention of genital warts in immunized cohorts of females and significant but lower efficacy in unimmunized males from the same population, a significant example of the impact of herd immunity.

Data from male efficacy studies of HPV vaccines are showing high efficacy against HPV-related anal precancerous lesions and anal cancer as well as high efficacy in preventing genital warts. The GAVI Alliance has included HPV in the list of vaccines to be supported financially in eligible countries opening the possibility of affordable immunization in the developing world. Many other multinational organizations i.

Economic analyses are being redone to reflect this level of vaccine price, since the developing countries themselves will initially have to co-pay a fraction of this price. Even if a booster dose were needed in pre-adolescence, the strategy might be highly successful. There is a need to do the appropriate bridging studies, which can be done on a relatively small number of children.

If successful, these vaccines are likely to dramatically modify preventive strategies, target populations and the screening protocols for vaccinated women. Routine introduction of HPV vaccines to women in all countries and in the widest possible age ranges. Extension of coverage and simplification of the algorithms of existing screening programs using HPV based technology. Consideration of the broader spectrum of cancers and other diseases preventable by HPV vaccination in women and evaluation of the importance of HPV vaccination in men. Global burden of HPV and related diseases [ 3 ] 3.

Figure 2. Table 2 Results from meta-analysis showing number of women tested for HPV and HPV16, number and percent positive by cervical disease grade. Cancers attributable to HPV infection: global and regional burden of cervical cancer in Infection with high-risk HPV types is recognized as one of the major causes of infection-related cancer worldwide.

Table 3 Estimated number of new cancer cases occurring in attributable to HPV infection by geographic region. Figure 3. Figure 4. Updating the natural history of HPV and anogenital cancers [ 4 ] 4. Figure 5. Heterosexual transmission and autoinoculation Data on transmission of HPV are finally emerging, demonstrating that transmission between heterosexual couples is extremely common, although rates vary widely among studies.

Natural history of HPV infections in the anus in men and women Studies show that anal HPV infections in women and in men who have sex with men are quite common, particularly in HIV-infected individuals. Natural history of penile and external genital HPV Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia PeIN is poorly understood. HPV and diseases of the upper airway: head and neck cancer and respiratory papillomatosis [ 5 ] HPV infection is causally associated with benign and malignant diseases of the upper airway, including RRP and oropharyngeal cancer.

Head and neck cancers HPV16 definitively satisfies both molecular and epidemiologic causal criteria as a carcinogenic or high-risk type in the upper airway Table 4. Table 4 Epidemiologic assessment of causality for HPV16 in oropharyngeal cancer. Specificity Across head and neck cancer anatomic subsites, the association of HPV seems specific for cancers arising in the oropharynx, including the base of tongue, lingual and palatine tonsil, and other parts of the oropharynx.

Temporality Only one nested case-control study generated within a serum cohort study has evaluated the association of HPV with prospective oropharyngeal cancer risk. Biologic gradient Risk of oropharyngeal cancer increased significantly with increasing HPV16 L1 antibody titers indicating a dose-response effect. Plausibility E6 and E7 proteins of HPV bind to and inactivate tumor suppressor proteins p53 and pRB, respectively, leading to malignant transformation of infected cells.

Coherence HPV-positive oropharyngeal cancers have evidence of integrated, high copy number HPV genomes in tumor cells as well as expression of E6 and E7 gene products. Consistent with HPVs being predominantly transmitted sexually, markers of sexual activity, including oral sex and number of lifetime oral sex partners have also been associated with increased oropharyngeal cancer risk in several studies. Experiment Downregulation of E6 and E7 oncoproteins in HPV-positive cell lines resulted in increased apoptosis and reversal of malignant phenotype as evidenced by increase in p53 and pRb levels.

Analogy HPV-induced oropharyngeal carcinogenesis is analogous to HPV-induced cervical, anal, penile, vaginal, and vulvar carcinogenesis. Molecular genetic alterations differ between HPV-positive and -negative oropharyngeal carcinomas. HPV E6 and E7 oncoproteins bind to and inactivate tumor suppressor proteins p53 and pRb, respectively, leading to malignant transformation of infected cells. Since pRb is degraded, p16 expression levels in proliferating cells are high.

Regions of high head and neck cancer incidence include countries in Asia, where prevalence of chewing tobacco use is high, as well as parts of Central and Eastern Europe, and South America. Despite overall declines in head and neck cancer incidence in most parts of the world, recent studies from several countries—mostly developed countries e. The same trend has been observed for specifically HPV-positive oropharyngeal cancers. By contrast, in most but not all of these countries, incidence of non-oropharyngeal head and neck cancer sites has significantly declined.

Differences in sexual behavior, as well as in patterns of tobacco use, likely contribute to these geographic differences. Thus, HPV status determination is now part of the routine diagnostic evaluation for prognostication. However, consensus standards for specific laboratory methods and interpretation have yet to be established. It is important to highlight that the use of HPV for therapeutic decision-making outside the context of clinical trials is not yet recommended. Clinical trials for the HPV-positive patient population, the majority of whom are expected to survive, are now designed to evaluate whether the intensity of treatment and associated morbidity can be reduced without compromising survival.

Primary and secondary prevention of HPV-associated diseases of the upper airway Although detection of oral HPV DNA is associated with oropharyngeal cancer, its utility as a mechanism for secondary cancer prevention through screening is still unknown. The biology and life-cycle of HPVs [ 6 ] 6. Biology and life cycle of HPVs The interaction between papillomaviruses and their hosts is very ancient. Normal productive life cycle Our knowledge of the viral life cycle refers mainly to high-risk mucosotropic HPVs and is commonly extrapolated to all HPVs.

Figure 6. Lesion regression, latency and clearance Most cervical HPV infections are cleared, at least to the point where the viral genomes do not persist at levels that can be consistently detected by sensitive PCR assays. Therapy of HPV-related disease [ 7 ] 7. Current treatment of HPV-related disease Standard treatment for HPV-associated anogenital lesions has primarily been by surgical excision.

The current treatment of chronic and neoplastic HPV-associated conditions is summarized below: High-grade CIN Treatment strategies focus on eliminating the abnormal HPV-infected precancerous cells while minimizing harm to the cervical integrity. Cervical cancer Early cancers International Federation of Gynecology and Obstetrics stage la can be treated by conisation or radical hysterectomy with excellent survival. Vulvar intraepithelial neoplasia VIN and vulvar cancer The standard of care for treating VIN remains surgical excision for unifocal disease and lesions suspicious for possible invasion.

AIN and anal cancer Treatments are usually ablative, using electrofulgaration, infrared coagulation, or laser ablation. PeIN and penile cancer For local disease, surgical treatment remains the best option. Head and neck cancers Inoperable oropharyngeal squamous cell carcinomas are treated by regimens using fractionated radiotherapy combined with cisplatin. GW Provider-administered treatments of GW include cryotherapy, trichloracetic acid, or surgical removal, which has the highest primary clearance rate.

RRP Treatment is by surgical debridement, but many adjuvant therapies have been used with varying claims as to their effectiveness. Development of novel treatments The immune system plays an important role in controlling the development of HPV-associated cancer through specific immunity to the E6 and E7 oncogenes. Evidence regarding HPV testing in secondary prevention of cervical cancer [ 8 ] Regularly updated reviews of the full validity of screening tests have been a major benefit to clinicians as they facilitate the understanding of the continuously increasing amounts of new information regarding innovative cervical cancer prevention methods.

Follow-up after treatment of high-grade CIN After conservative treatment of cervical precancer, HPV testing picks up residual or recurrent high-grade CIN more quickly than follow-up cytology, with higher sensitivity and without any decrease in specificity Fig. Figure 7. Figure 8. Figure 9. Figure Nucleic acid tests for the detection of alpha HPVs [ 9 ] A comprehensive inventory of commercial tests for detection of alpha-HPV has identified at least distinct HPV tests and at least 84 variants of the original tests Table 6.