The Mode of Transmission of the Human Papilloma Virus - Essay Example

The Human Papilloma Virus INTRODUCTION The Centers for Disease Control and Prevention (CDCP) has identified the Human Papillomavirus (HPV) as the most common sexually transmitted viral infection of the reproductive tract. 12.7 million cases of cancer occurred in 2008 worldwide that are attributed to HPV infection.1 There are over 150 identified HPV genotypes that infect genital mucosa1. Of these, over 40 can infect the reproductive areas of both genders, and can readily spread through direct skin-to-skin contact during vaginal, anal, or oral sex.2 Furthermore, at least 13 of them can be considered as high-risk due to their neoplastic prospective. High-risk HPV 16 and 18 are most commonly associated with cervical, vulvar, vaginal, penile, oropharyngeal cancer and anal cancers.3 In females, cervical cancer is the second most frequent cancer worldwide, and the third most common cause of mortality from cancer.2 Additionally, 80% of cases occur in developing countries.3 Although low-risk HPVs (such as type 6 and 11) are not cancerous, they can still cause benign or minimal abnormalities of cervical cells, such as skin warts on or around the genitals or anus, and recurrent respiratory papillomatosis (RRP).3 These figures are a global public health concern. This report addresses why HPV is a public health problem in developed countries and evaluates the policies and strategies taken to deal with HPV infection. MODE OF TRANSMISSION HPV is an entirely mucosal infection and does not include a bloodstream phase. While HPV is sexually transmitted, penetrative sexual intercourse is not necessary for transmission to occur. Many researches indicate unprotected genital contact is a well-documented mode of infection, including genital–genital, oral–genital and manual–genital contact.4-6 For both genders, the infection rate is increased soon after becoming sexually active. HPV PREVALENCE AND INFECTION RATES Indeed, half of sexually active men and women are infected with several HPV types at any point in their lives, and some may be repeatedly infected. In 2011, Hariri et al. (2011) conducted a nationwide population-based study in the US to investigate the prevalence of both high/low-risk HPV in 14–59 year old females during 2003–2006.7 They found the overall prevalence of high- and low-risk HPV was 43% among 14-59 year old women. They also found those aged 20-24 years are more likely to be affected by high-risk HPV, and the risk decreases with age. Recent figures show almost 7% of adults are infected by oral HPV during their lifetime.8,9 Gillison et al. (2012) conducted a cross-sectional study in 2009-2010 to determine the prevalence of oral HPV infection in the US.8 They pointed out the prevalence of oral HPV infection among individuals between 14-69 years was 6.9%, and of this 1.0% were infected by a high risk type of HPV. They also confirmed oral HPV infection peaks among adults aged 30-34 years (7.3%) and 60-64 years (11.4%). Males were 2.7 times more likely to be infected by oral HPV than women. Infection in those with a history of any type of sexual contact (7.5%) had a significantly higher prevalence compared to those without (0.9%). Although about 90% of HPV infections are usually cleared within a few months to two years after acquisition without intervention, a small percentage of HPV high risk types can continue and progress into neoplastic changes.10 HPV ASSOCIATED MALIGNANCIES OR OTHER DISEASES Approximately 5% of all cancers worldwide are accounted for by high-risk HPV infection.3 In 2008, it was suggested between all cancer-related outcomes of HPV infection, cervical cancer is the most prevalent, with over half a million new cases resulting in more than 270,000 deaths worldwide.11  In the USA, an estimated 6.2 million cases of newly infected individuals are detected annually.1 Some UK studies have shown 1 in 134 persons are expected to develop cervical neoplasm at some point during their lifetime.12 Researchers believe that since a first HPV infection occurs, it can take 10-20 years for cancer to develop. Despite persistent high-risk HVP being essential for cervical cancer progression, not all females with high-risk HPV infection develop cancer.13 However, the proportion of high-degree cervical abnormalities that progress into advanced stage malignancy are expected to be under 50%.3 Although statistics on anogenital neoplasm other than cervical cancer are limited, increasing evidence-based studies have linked HPV with anus, vulva, vagina, penis and oropharyngeal tumors. On a global scale, half of penile cancers are attributed to HPV.14 A population-based study conducted in the US by Hernandez et al. (2014) indicated that HPV DNA was present in 63% of invasive penile cancer cases.14 Moreover, according to the CDC (2013), over 20,000 carcinoma cases that occur annually in females are caused by HPV infection. Around 12,000 HPV associated cancer cases tend to occur in males every year, mostly oropharyngeal cancers.1 Throughout the past 20 years, the newly diagnosed cases of HPV-associated oropharyngeal cancer have grown, particularly among men. By 2020, expected HPV related oropharyngeal cancer cases in the US will exceed the cervical cancer rate.10 However, their relationship with HPV makes them preventable by using similar cervical cancer intervention modality.10 While, non-cancerous HPV types are rarely fatal, they can still result in significant morbidity. Genital warts is one such frequent and highly transmitted condition associated with HPV infections.11 One percent of sexually active individuals in the US have clinical manifestations of genital warts during their lifetime.11 Dinh et al. (2008) conducted a national survey in which they suggested less than 6% of both genders aged 14-59 were diagnosed with genital warts at any given time.14 Furthermore, both forms of RRP (juvenile onset and adult onset forms) are rare conditions described as frequent warts or papillomas in the upper respiratory tract, typically the larynx. The juvenile onset type occurs due to HPV transmission from a mother to child during childbirth.11 GROUPS AT HIGHER RISK OF DEVELOPNING CERVICAL CANCER Cancer of the cervix is widely spread by HPV associated disease. The risk factors of malignancy growth associated with HPV infection includes early age initial sex associated with increased risk of cervical cancer development.3 A study shows women who become sexually active earlier in their lives are at greater risk of cervical cancer development than older women.2 Furthermore, it is evident that the number of cigarettes smoked daily, and the numbers of sex partners are directly related to an increased risk of oral HPV infection.8 Individuals subject to immune suppression, such as HIV-positive patients, are expected to be infected with a wider range of HPV-types.9 Former et al. (2012) suggested the prevalence of invasive cervical neoplasm increases in females with severe cervical lesions to around 90%.15 Having 3 or more full-term pregnancies is also associated with increased risk of cancer development.3 This may be attributed to the fact that women might be exposed to HPV due to unprotected sex for pregnancy reasons. A further explanation is that pregnant women might undergo some hormonal changes, which puts them at increased risk of HPV persistence and tumor development. Moreover, long-term oral contraceptive use may perhaps enhance cervical cancer growth.3 Research suggests taking oral contraceptives for more than 5 years doubled the risk of cervical cancer, but when stopped, the risk decreases 10 years later. Poverty and poor diet are also risk factors. For example, overweight women are more likely to develop adenocarcinoma of the cervix. Women with low socioeconomic status usually have inadequate access to health care services, which means they might not get screened or treated at an early stage. In addition, chronic inflammation and family history of cervical carcinoma are also risk factors.3 In men, the risk of HPV infection is increased by such factors as early age sexual activity, smoking, having many sex partners including men, or not being circumcised. Evidence indicates that circumcision in men reduces the risk of HPV infection or persistence. HPV SCREENING POLICIES AND INTERVENTION USED FOR PREVNTION PRIMARY PREVENTION (HPV VACCINATION) In 2006, the US FDA approved bivalet and quadrivalent HPV vaccine, which targets the HPV strains responsible for around 70% of cervical malignancy and 90% of genital warts.16 Vaccines against familiar HPV-types provide a successful new-approach in preventing infection that causes cervical abnormalities and cancers, particularly when given before HPV exposure. Although the prophylactic HPV vaccines have no therapeutic benefits on targeted HPV types, many clinical trials have confirmed that vaccines are very efficient in preventing cervical pre-cancerous lesions.16 These vaccines have been broadly offered in rich countries targeting 9 and 13 year-old girls before they become sexually active. Experts regard HPV vaccines as highly effective for women vaccinated at a young age, which is evident by the decreasing number of abnormal cells detected in young women. In 2007, Australia was the first country to adopt a national publicly funded vaccination program targeted at 12-13 year old school girls on a regular basis, using 3 scheduled doses of the quadrivalent vaccine.17 Then they were offered a catch-up vaccination for high-school girls and for women through age 26 in community immunization services.17 This puts Australia in an exceptional position to assess the impact of such intervention on a population. Following the introduction of the HPV school-based program in Australia, it was observed the rate of most serious precancerous abnormalities in vaccinated girls decreased to 48% compared to their unvaccinated counterparts.17 The efficacy of quadrivalent is confirmed in four large clinical trials. A total of 20,541 females aged between 16-26 years were enrolled.  The vaccine prevented 99% of HPV 16-related lesions and 100% of HPV 18-related lesions.18 Prevention against genital warts was similarly high (99%). These efficacy outcomes reflect the massive impact of vaccinating girls before sexual activity and prior to exposure to HPV.19 Recent evidence suggests the quadrivalent vaccine can help prevent various HPV related infections and cancers in males. However, the rates of vaccinated men are extremely low. Therefore, HPV vaccine is recommended by CDC only for boys aged 11-12, and for men through age 26.10 In 2013, Australia offered this vaccine for schoolboys aged 12-13.17 Research into its cost-effectiveness show in the case of humble female vaccination rates and with the specification of a wide variety of infection outcomes, anti-HPV vaccination for men can be fairly cost-effective.20 When HPV vaccination programs are needed, policy decision makers should consider the disease burden, healthcare infrastructure, and the capacity for initiating and sustaining an immunization program for young individuals.21 Further considerations include public support, political will, and cultural acceptability, as well as the cost-effectiveness and affordability of vaccination compared with other prevention programs competing for resources.21 Policymakers however, have questioned the cost-effectiveness of HPV vaccine over high coverage screening programs claiming to have reduced the cervical cancer rate by up to 80%.22 Researchers also argue it is better to educate women on safe sex than financing expensive vaccination programs.22 In contrast, advocates believe that vaccination has decreased the rate of infection and helped saved lives, especially among at risk groups or in high-risk countries where screening can be difficult.21 Although the vaccine is expensive, the cost of treatment of cervical cancer is much higher. Studies have shown that even if the vaccine is made effective against HPV type 16 and 18 only, immunity can save 15,000-25,000 US$.23 Besides, the US Health Department provides vaccination at minimum or no charge for those who cannot afford it.23 There is an ongoing debate about including HPV vaccine in the mandatory vaccination schedule. Skeptics suggest that as HPV is not a droplet infection, and needs practice not usually expected at a young age, there is no need for any immediate vaccination for pre-adolescent girls.22 However, opponents argue that HPV vaccines have certainly proven to be more efficient in preventing HPV cervical-related conditions especially among younger recipients. For a successful nationwide introduction of the vaccine, support from the public, healthcare providers, and other stakeholders is essential. Therefore, well-planned communication strategies are necessary for a successful vaccination program. SECONDARY PREVENTION (SCREENING AND TREATMENT OF PRE-CANCER LESIONS) HPV Screening 1. Cervical cancer screening: The majority of cervical malignancies are associated with HPV infections. Cervical Intraepithelial Neoplasia (CIN) is a noninvasive lesion that is graded histologically as CIN1, CIN2, or CIN3 according to the severity of cell changes.24  Lesions CIN2+ (CIN2 or CIN3) have a potential of neoplastic transformation if left untreated.24 Evidence suggests 2% of females develop CIN2+ annually.24 HPV symptoms are not always obvious, and significant signs are rarely shown in most infected people. However, well-recognized causal association among high-risk HPV types persist in the cervix and the occurrence of invasive cervical cancer has led to the development of several screening tests. Following the introduction of efficient screening programs in developed countries, the incidence of cervical cancer incidence and mortality rates has rapidly declined. Over 20 years, the death rate has declined by 34-80% worldwide.25,26 Higher reductions have been observed in large populations in the USA, Iceland, Canada and Finland.27 Also, early (pre-invasive) diagnosis has had a significant effect on disease prognosis since the 5 year survival rate of early stage is 100% compared to the 48% five year survival rate of advanced stages. Papanicolaou test (Pap test)/ Cytology This is performed to detect abnormal changes in cervical cells that might be pre-cancerous or malignant. The Pap test is recommended for every female aged 21-65 years, which should be repeated every 3 years as a regular check-up.1 Numerous observational data supports its efficacy in decreasing death from cervical neoplasm. Several studies indicate cervical cancer in unscreened females are 3 to 10 times more likely to develop than in regularly screened women, hence the importance of the test.28 The sensitivity of regular cytology testing is expected to be high because the slow growth of cervical cancer provides the opportunity for screening to successfully detect any changes through the precancerous stage. Nanda et al. (2000) evaluated the accuracy of conventional cytology in detecting cervical cancer, and its precursors through reviewing 94 studies of what had been published about the Pap test.29 They estimated Pap test sensitivity and specificity significantly differed between studies. However, twelve minimally biased studies estimated that Pap conventional test sensitivity ranged from 30-87% and specificity ranged from 86-100%.29 Eight years later, Arbyn et al. (2006) conducted a mini-meta analysis comparing the performance of liquid based cytology (LBC) with the conventional Pap-test. They concluded that LBC is neither more specific nor more sensitive for detection of CIN1 or above when compared with conventional cytology.30 WHO’s recommendations following Pap-test findings9: 1. Normal/ Negative: Regular screening every 3 years 2. Unclear/ ASC-US (Atypical Squamous Cells of Undetermined Significance): HPV DNA test is recommended. 3. Abnormal: in low-grade changes can be resolved on its own and in high-grade changes (pre-cancer) should be removed. Colposcopy with biopsy: (Golden standard) This procedure is carried out for examining and evaluating female cervix following positive cytology test results. To confirm if pre-malignant or malignant cells are present, a biopsy sample is microscopically examined by a pathologist. The sensitivity of colposcopy with two or more biopsies is significantly greater in detecting invasive cervical cancer compared to a single biopsy procedure.31 Furthermore, in HIV positive women, a colposcopy screening approach would be worthwhile.32 Colposcopy with biopsy is recommended when high-risk HPV is detected twice in 12 months or less, even if the Pap test shows normal results.31 Visual inspection acetic acid (VIA) For developing countries with limited resources, an alternative VIA cervical screening approach is VIC, which recommended due to its ease of use, affordability and reduced need for doctoral visits. Many studies have compared VIA to cytology as a screening test for cervical lesions by considering their sensitivities and specificities compared with the golden standard. Gaffkin et al (2003) reviewed fifteen studies available through PubMed, about direct VIA published between 1982 and 2002.33 These included over 34,000 females worldwide, and the subjects ranged from nurses to physicians performing the tests. The estimated value of VIA sensitivity found in these studies ranged from 66%-96%, and specificity was between 64 and 98%.33 Test qualities of cytology ranged from 11% to 99%.33 The authors noted the efficacy of VIA is higher compared to cytology in terms of cervical cancer diagnosis. In Turkey, Ardahan et al. (2011) conducted a study to investigate cervical cancer screening validity of VIA compared to colposcopy findings.34 When VIA findings were compared with colposcopy, VIA had a sensitivity of 85.29%, specificity of 68.75%, positive predictive value (PPV) of 85.3%, and a negative predictive value NPV of 68.8 %.34 When VIA was compared with the findings for cytology, the sensitivity of VIA was 82%, specificity was 50%, PPV was almost 68%, and NPV was 69%.34 Although some studies have reported lower specificity rates, a broad consensus is that VIA is a practical approach as an adjuvant or alternate to cytology, and is therefore one of the most widely accepted screening methods for cervical cancer. HPV DNA test (HC2) This test based on the DNA detection of most common oncogenic types of HPV27 is recommended for women aged above 30, and those with ASCUS results on Pap smears. Co-testing using HPV DNA and LBC testing is widely accepted. A clinical trial concluded that since the infection rate is high among women younger than 30, HPV testing is not recommended even with ASCUS.35 HPV testing is more sensitive for identifying females with CIN2+ (sensitivities ranged 84–97%) compared to the Pap test.36,37 In an RCT, both cytology and HPV testing were demonstrated in females aged 30-69, and the sensitivity of the Pap-test and HPV were 55% and 95% respectively. The co-testing sensitivity of HPV and cytology is 100% with 7.9% referral rate.38 However, the specificity of HPV testing is considerably low compared to cytology, especially among women younger than 30. In women aged above 30 years, the specificity of HPV cytology testing was 94% and 97% respectively.38 2. Other diagnostic tests used Presently, there is no regular approved screening test for HPV-warts or other cancers. However, men can have some other tests if abnormal changes are observed. Anal cytology The goal of anal cytology is to identify patients with anal canal cellular changes. Patients with atypia are then referred to undergo high-resolution anoscopy. Researchers generally recommend an anal cancer screening program similar to cervical lesion screening, using anal cytology, followed by high-resolution anoscopy when Anal Intraepithelial Neoplasia (AIN) is detected, and to undergo treatment to prevent the growth of anal cancer.39 The reported sensitivity and specificity of anal cytology relative to findings at biopsy (sensitivity, 69%-93%; specificity, 32%-59%, respectively) are similar to findings in studies comparing cervical cytology and cervical biopsy for cervical cancer prevention.39 Although the CDC does not recommend anal cytology screening, other organizations recommend annual anal cytology for MSM and any HIV-positive males with a history of anogenital warts. Among patients with HIV- or HPV-related lesions, histological signs of dysplasia are apparent in over one-fifth of those who undergo testing.39 Among HIV-positive MSM, the PPV of abnormal anal cytology to predict anal dysplasia is approximately 95%.39 Anal cytology should be offered only in areas where further diagnostic and alternative therapeutic treatments are available, including high-resolution anoscopy. High resolution anoscopy (HRA) This is regularly used for the detection of anal cancer and pre-cancerous lesions. However, the role of this diagnostic test is not well recognized. Some evidence suggests that HRA is 90% sensitive, but 19.23% specific for AIN lesion detection with PPV of 42%, and NPV of 75%.40 Penal HPV screening HPV penile screening is not recommended since its high prevalence, and the generally self-limited duration of infection in immunocompetent men.39 In contrast to AIN and anal cancer, very little data are available regarding the slow growth characteristics of penile cancer in MSM, or in HIV-positive men.39 Unlike AIN, it cannot be diagnosed by cytology, so any suspicious penile lesion requires biopsy for pathology. Aceto-whiting test A five percent acetic-acid solution is applied to the cervix or the genital skin, which can lead to whitening of the infected area. This test should be reserved as an adjunct to colposcopy to increase the visibility of subclinical lesions.24 SCREENING INTERVALS AND FOLLOW-UPS Table 1: Scenarios and ideal screening intervals Scenarios Screening intervals Negative results on VIA or Pap-test Required every 3-5 years Negative results on HPV-test Required after at least 5 years Women who have received therapy Following treatment, screening is required at 1 year to intervals to ensure treatment has successes. Women with HIV+ or unknown status in high risk HIV areas: If the screening test is negative Women who have received therapy Screening should be within three years Following treatment, screening is required at 1 year to make sure treatment has successes. Source: WHO, 201424 TREATMENT To date, there is no therapy or treatment for HPV. However, there are some ways of treating HPV related health problems. Naturally, human immunity clears HPV within 1-2 years.1 The persistence of the virus might lead to cervical cell changes, which can then be treated. Genital warts: This can be visually detected and treated with medication, and then surgically removed or frozen off.1 Warts have high recurrence rates, so various therapies may be required. Individuals receiving treatment for genital warts may still pass the virus on to their sex partner. If the wart is not treated, it may either resolve by itself, or it does not change, or else it proliferates but will not develop into cancer. TERTIARY PREVENTION (TREATMENT OF CERVICAL CANCER) Existing therapies for cervical cancer include cryotherapy, large loop excision of the transformation zone (LEEP/LLETZ), and cold knife conization (CKC).24 Cryotherapy is the first recommended treatment for “screen-and-treat” in HPV-positive females, and it has been assessed as eligible for cryotherapy. Women eligible for cryotherapy are “Screen-positive women... if the entire lesion is visible, the squamocolumnar junction is visible, and the lesion does not cover more than 75% of the ectocervix”.24 Invasive cancers are not eligible for cryotherapy and LEEP is the alternative option. Negative HPV-test in woman using a “screen- and treat” strategy, are not treated. HPV positive women will be treated prior to any therapy, VIA-tests are used to exclude large lesions or suspected cancer, and to decide the eligibility of treatment and whether cryotherapy or LEEP is suitable.24 HPV-positive women with VIA-positive results should be treated, while treatment is not required in HPV-positive women with a VIA-negative result. Anus, penis and oropharynx cancers: Often, two or more of these treatment options (surgery, radiation therapy and chemotherapy) are used.24 CONCLUSION AND FUTURE AREAS FOR FOCUS In conclusion, HPV is the most common sexually transmitted infection, and its persistence is strongly associated with the risk of development of cervical cancer. More than any other cancer, cervical cancers reflect remarkable global health inequity. It has been proven that vaccination and screening interventions bring genuine health benefits. However, in the context of wide vaccination coverage of young girls, cost-effectiveness, and securing sustainable funding can be challenging. More studies are needed to assess the precision of screening tests and to measure the outcomes in HIV-positive individuals, or those who are at higher risk of being HIV-positive. In men, before definitive guidelines on the role of anal cytology can be offered, more studies are needed to elucidate the role of early detection of AIN, and the effects of AIN treatment on disease progression to invasive carcinoma especially for HIV and MSM patients. Many uncertainties are raised regarding HPV vaccination. Since vaccination studies involving females have been followed-up for six years only, the potential for long lasting immunity offered by the vaccination, and the effectiveness of the vaccine among girls with HPV infection, remain unknown. Furthermore, in some areas, the number of schoolgirls is relatively low when compared to other girls. Thus, community-based attempts should be considered instead. More evidence will continue to emerge however, so policy adjustments may be needed in the light of new information. Vaccination is not likely to be able to prevent more than 80% of lesions with oncogenic strains other than HPV-type 16/18. Therefore, trials are required to determine the best vaccination program. Furthermore, the effectiveness of the vaccination among men also remains unknown, and the vaccination of boys has not been sufficiently investigated so there are no indications for them. Further investigations are needed to predict and develop the best prevention intervention vaccination program among men. Researchers and policymakers should assist in the planning and implementation of the new policy and in undertaking further evaluation. REFERENCES: 1. Centers for Disease Control and Prevention. Human Papillomavirus (HPV) [Internet]. National Center for Health Statistics. 2013. [Accessed on 13th Mar 2014] Available from: http://www.cdc.gov/hpv/whatishpv.html 2. Division of STD Prevention (1999). Prevention of genital HPV infection and sequelae: report of an external consultants meeting. Atlanta, GA: Centers for Disease Control and Prevention. January 4, 2012. 3. National Cancer Institution. HPV and Cancer/ fact sheet [Internet]. The National Institution of Health. 2012. [Accessed on 12th March 2014]. Available from: http://www.cancer.gov/cancertopics/factsheet/Risk/HPV 4. Winer RL, Hughes JP, Feng Q, Xi LF, Cherne S, OReilly S, et al. Detection of genital HPV types in fingertip samples from newly sexually active female university students. Cancer Epidemiol Biomarkers Prev [Research Support, N.I.H., Extramural Research Support, Non-U.S. Govt]. 2010 Jul;19(7):1682-5. 5. Fairley CK, Gay NJ, Forbes A, Abramson M, Garland SM. Hand-genital transmission of genital warts? An analysis of prevalence data [Internet]. Epidemiol Infect. 1995. [Accessed on 13th Mar 2014];115(1):196-176. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2271568/ 6. Marrazzo JM, Stine K, Koutsky LA. Genital human papillomavirus infection in women who have sex with women: a review. Am J Obstet Gynecol. 2000;183(3):770-774. 7. Hariri S, Unger ER, Sternberg M, et al. Prevalence of genital human papillomavirus among females in the United States, the National Health and Nutrition Examination Survey, 2003-2006 [Internet]. J Infect Dis. 2011. [Accessed on 13th Mar 2014]; 204(4):566-573. Availble from: http://www.ncbi.nlm.nih.gov/pubmed/21791659 8. Gillison ML, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA [Research Support, N.I.H., Intramural Research Support, Non-U.S. Govt]. 2012 Feb 15;307(7):693-703. [Accessed on 13th Mar 2014]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22282321 9. World Health Organization. Fact Sheet N*380 - Human papillomavirus (HPV) and cervical cancer. 2013. [accessed on 12th March 2014], available from: http://www.who.int/mediacentre/factsheets/fs380/en/ 10. Centers for Disease Control and Prevention. Chapter 5: Human Papillomavirus (HPV) [internt]. National Center for Health Statistics. 2011. [Accessed on 20th Mar 2014]. Available from: http://www.cdc.gov/vaccines/pubs/surv-manual/chpt05-hpv.html 11. Molano M, Posso H, Weiderpass E, van den Brule AJ, Ronderos M, Franceschi S, et al. Prevalence and determinants of HPV infection among Colombian women with normal cytology. Br J Cancer [Research Support, Non-U.S. Govt]. 2002 Jul 29;87(3):324-33. 12. Cancer Research UK Statistical Information Team, Sasieni PD, Shelton J, Ormiston-Smith N, et al. What is the lifetime risk of developing cancer?: The effect of adjusting for multiple primaries. Br J Cancer. 2011;105(3):460-5. 13. Hernandez BY, Goodman MT, ER U, al. e. Human Papillomavirus genotype prevalence in invasive penile cancers from a registry-based United States population.[Internet]. Front Oncol 2014. [Accessed on 20th Mar 2014];5(4):9 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/24551592. 14. Dinh TH, Sternberg M, Dunne EF, LE. M. Genital warts among 18- to 59-year-olds in the United States, national health and nutrition examination survey, 1999-2004. Sex Transm Dis. 2008;35:357-360. 15. Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases [Internet]. Vaccine. 2012. [Accessed on 21st Mar 2014];20;30 Suppl 5:F12-23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23199955 16. Braaten KP, Laufer MR. Human Papillomavirus (HPV), HPV-Related Disease, and the HPV Vaccine. Rev Obstet Gynecol. 2008 Winter;1(1):2-10. 17. Australian Institute of Health and Welfare. HPV vaccine reduces cervical abnormalities that are precursors to cervical cancer [Internet]. Australias health series no. 12. Cat. no. AUS 126. Canberra: AIHW. Available from: http://www.aihw.gov.au/media-release-detail/?id=60129545390. 2013. 18. Ault KA. Human papillomavirus vaccines and the potential for cross-protection between related HPV types. Gynecol Oncol [Research Support, Non-U.S. Govt Review]. 2007 Nov;107(2 Suppl 1):S31-3. 19. Cutts FT, Franceschi S, Goldie S, Castellsague X, de Sanjose S, Garnett G, et al. Human papillomavirus and HPV vaccines: a review. Bull World Health Organ [Review]. 2007 Sep;85(9):719-26. 20. Stupiansky NW, Alexander AB, Zimet GD. Human papillomavirus vaccine and men: what are the obstacles and challenges? Curr Opin Infect Dis. 2012;25 (1):86-91. 21. Raffle AE. Challenges of implementing human papillomavirus (HPV) vaccination policy. BMJ [Review]. 2007 Aug 25;335(7616):375-7. 22. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing countries--key challenges and issues. N Engl J Med. 2007 May 10;356(19):1908-10. 23. Sinka K, Kavanagh K, Gordon R, Love J, Potts A, Donaghy M, et al. Achieving high and equitable coverage of adolescent HPV vaccine in Scotland. J Epidemiol Community Health. 2014 Jan;68(1):57-63. 24. World Health Organization. Guidelines for screening and treatment of precancerous lesions for cervical cancer prevention: WHO guidelines [Internet]. Geneva World Health Organization; 2013. p. 1-58. . 25. Lăără E, Day NE, Hakama M, . . Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. 1987;Lancet1(8544 ):1247-9. 26. Christopherson WM, Lundin FE Jr, Mendez WM, et al. Cervical cancer control: a study of morbidity and mortality trends over a twenty-one-year period. Cancer. 1976;38(3):1357-66. 27. National Cancer Institution. Cervical Cancer Screening [Internet]. 2014. 28. Herrero R, Brinton LA, Reeves WC, et al. Screening for cervical cancer in Latin America: a case-control study. Int J Epidemiol. 1992;21(6):1050-6. 29. Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, et al. Accuracy of the Papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systematic review. Ann Intern Med. 2000;132(10):810-9. 30. Arbyn M, Bergeron C, Klinkhamer P, Martin-Hirsch P, Siebers AG, J. B. Liquid compared with conventional cervical cytology: a systematic review and meta-analysis. Obstet Gynecol. 2008;111(1):67-77. 31. Gage JC, Hanson VW, Abbey K, Dippery S, Gardner S, Kubota J, et al. Number of cervical biopsies and sensitivity of colposcopy [Internet]. Obstet Gynecol. 2006;108(2):264-72. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16880294. 32. Torrisi A, Del Mistro A, Onnis GL, Merlin F, Bertorelle R, Minucci D. Colposcopy, cytology and HPV-DNA testing in HIV-positive and HIV-negative women. Eur J Gynaecol Oncol [Clinical Trial Comparative Study Controlled Clinical Trial]. 2000;21(2):168-72. 33. Gaffikin, Lynne DrPH. Performance of Visual Inspection With Acetic Acid for Cervical Cancer Screening: A Qualitative Summary of Evidence to Date. Obstet Gynecol Surv. 2003;58(8). 34. Ardahan M, Temel AB. Visual inspection with acetic acid in cervical cancer screening Cancer N 2011;34(2):158-63. 35. ASCUS-LSIL Traige Study (ALTS) Group. A randomized trial on the management of low-grade squamous intraepithelial lesion cytology interpretations. Am J Obstet Gynecol. 2003;188(6):1393-400. 36. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: a summary of meta-analyses. Vaccine [Research Support, Non-U.S. Govt Review]. 2006 Aug 31;24 Suppl 3:S3/78-89. 37. Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al. A systematic review of the role of human papilloma virus (HPV) testing within a cervical screening programme: summary and conclusions. Br J Cancer [Review]. 2000 Sep;83(5):561-5. 38. Mayrand MH, Duarte-Franco E, Rodrigues I, et al. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med. 2007;357(16):1579-88. 39. McGinley K, Hey W, Sussman D, Brown G. Human Papillomavirus Teasting in Men [Internt]. J Am Osteopath Assoc. 2011;111(3 suppl 2):S26-S28. Available from: http://www.jaoa.org/content/111/3_suppl_2/S26.full.pdf. 40. Gimenez F, Costa-e-Silva IT, Daumas A, Araújo Jd, Medeiros SG, L. F. The value of high-resolution anoscopy in the diagnosis of anal cancer precursor lesions in HIV-positive patients. Arg Gastroenterol. 2011;48(2):136-45. Read More