M.G. Galitskaya, A.G. Gaivoronskaya

Scientific Center of Children’s Health, Moscow, Russian Federation

Enhancing vaccinal prevention of the human papilloma viral (HPV) infection: protecting people of different age and sex from a range of HPV-associated diseases

Author affiliation:
Galitskaya Marina Gennad'evna, MD, head of the vaccinal prevention department for children with medical issues at the FSBI RAMS “SCCH”
Address: 2/62, Lomonosovskii ave., Moscow, 119991, tel.: +7 (499) 134 20 92
Article received: 09.10.2012 accepted for publication: 15.01.2013

HPV is the most widespread sexually transmitted infection. HPV affects men and women regardless of age and leads to the development of various anogenital area diseases. International studies proved a wide clinical range of the tetravalent HPV vaccine protection and allowed recommending it for the prevention of not only cervical cancer, but also of vulvar, vaginal and anal cancer and anogenital condylomae in patients of both sexes. 42 countries have already introduced national HPV-vaccination programs in compliance with WHO recommendations. Anogenital area cancer morbidity reduction in these countries is expected in 10-15 years. However, a reduction or even complete disappearance of anogenital condylomae among the population has already been noted in a range of countries because the incubation period of this disease is short; this is the first marker of vaccination efficacy in a population. 
Keywords: human papilloma virus, cervical cancer, senior women, genital condylomae, HPV types, sexual activity, vaccinal prevention, tetravalent vaccine.
Causative agent
Human papillomavirus – HPV – belongs to papillomavirus genus, papillomavirus family and the group of DNA-containing viruses with double-stranded DNA. Papillomavirus is relatively small, its double-stranded circular DNA is encapsidated (enclosed into a protein tunic) [1].
More than 130 different HPV types have yet been identified, 30 out of which are capable of infecting the genital tract’s mucous tunic. There 2 main HPV types: of high and low oncogenic risk. The first group is comprised of viruses leading to cancer diseases. The second group is comprised of viruses leading to benign lesions of mucous tunic (most often of cervix uteri) and cutaneous coverings (development of condylomae); occasionally, these types may cause malignant tumors.
The most widespread high risk types are 16, 18, 31, 33, 35, 39, 45, 51, 52 etc. with types 16 and 18 being the crucial. HPV 16 and 18 are responsible for more than 70% of CC worldwide [2, 3].
The low risk group is comprised of viruses of types 6, 11, 36, 42 etc. “Low” oncogenic risk viruses are predominantly identified at pointed and flat condylomae, mild dysplasia and rarely – at invasive cancer. Almost all genital condyloma cases are caused by HPV 6 and 11 [4].
HPV-infection transmission
HPV is transmitted only human-to-human. Most often the infection is transmitted sexually. Chance of infection at sexual contact is 60-66% [5]. Infection rate is directly proportional to the number of sexual partners: HPV is revealed in 17-21% of women with 1 partner and in 69-83% of women with 5 and more partners [6]. Other infection transmission routes are extremely rare: vertical (mother-to-child), through skin and objects and surfaces, which may also be infected [7]. HPV genital-oral transmission route’s rate is also significant. The rate of HPV-associated oropharyngeal cancer has been increasing in recent decades [8].
The studies showed that HPV-infection risk starts from the moment of sexual debut and continues throughout life. It should be mentioned that the risk of infection in the beginning of sexual life is higher due to a more susceptible genital tract’s epithelium in young women [9]. However, while the infection risk reduces with age, HPV-infection persistence risk increases [10]. The 5-year cumulative risk of cervical HPV infection of any type in the cohort of 1,600 women from Bogota, Colombia, reduced from 42% in 15-19-year-old women to 22% in 30-44-year-old women; this indicates a reduced, yet still significant risk in the older group [11]. The second HPV DNA prevalence peak was observed in women of the second and fifth life decades [12]. It is unclear whether this second peak was caused by the latent infection’s reactivation, cohort-specific effect or new HPV infection, however, the Colombian cohort study confirms the possibility of new HPV infection [11].
Sexual behavior change in the last 30 years, characterized by an older age of first-time marriage and increase in divorce rate, has led to widespread premarital sexual relations and new sexual partners in middle age [13]. The published works show that almost 40% of men and women in the USA divorced by 55 years of age, while 25% of these people remarried at least once [14]. This means that there is a risk of infection and HPV-caused diseases in women in the third, fourth and fifth life decades.
Studies of HPV infection rate in heterosexual women’s partners are of utmost interest. There are data of the 2 male population studies conducted in Italy in 1999. The examination included visual inspection, colposcope-aided penisoscopy and biopsy. The first study analyzed 163 partners of women observed for 6 years with genital HPV infection and HPV-associated premalignant lesions. HPV infection was revealed in 30.4% of male partners [15]. The second study included 210 men, whose sexual partners had cervical premalignant lesions of different degrees. Subclinical genital lesions were revealed in 70% of the examined men [16]. Such a high percentage of lesions in men and scatter of readings depending on the partner’s degree of genital lesion undoubtedly claims the need in mutual examination and treatment of partners with HPV and also raises the need in preventing HPV infection of both women and men.
HPV-infection course
Most HPV-infection cases occur spontaneously. Ca. 80% of people recover from HPV in 9-15 months after infection without any therapeutic procedures (transitory infection). Progression of the infection is very rare. HPV-infection may long persist only in a small amount of the infected (ca. 0.5%). Given wide spread of this infection, there is a big absolute amount of patients, in whom the infection persists for years and lead to premalignant and cancer lesions. It is known that HPV 16 and 18 (in comparison with other HPV types) are capable of longer persistence – a precondition for the development of cervical cancer (CC) and cancer of other localizations in women and men [4, 17]. Cofactors play a particular role in the progression of lesions at the persistent HPV-infection: smoking, early sexual debut, big number of sexual partners, long-term intake of oral contraceptives, immunosuppression (e.g., because of HPV-infection, in post-transplantation period, because of a long-term intake of systemic glucorticosteroids) [3].
Clinical manifestations
Papillomaviral infection may be clinically manifested, take a subclinical course or be latent.
At the average, incubation period lasts for 3 months. The virus exists in the infected cell in 2 forms: episomal (outside of cell’s chromosomes), which is considered benign, and introsomal-integrated (built in the cell’s genome), which is classified as a malignant form of viral parasitizing. Clinical manifestations of epithelial lesion caused by human papillomavirus are very variable; this is caused by various serotypes of this infection. In most cases the disease takes a clinically asymptomatic course [9].
Cervical cancer
Cervical cancer is the second and in several countries the most widespread malignant tumor worldwide after breast cancer affection young females [18]. More than 500,000 new cervical cancer cases are worldwide diagnosed annually, one woman dies of cervical cancer every 2 minutes. Every day, 20 women die of this disease in Russia [19]. More than 70% of all cervical cancer cases both worldwide and in Russia are caused by types 16 and 18 [8, 20]. 
Vulvar and vaginal cancer
More than 40,000 vulvar and vaginal cancer cases are annually registered worldwide. Unfortunately, there are no data on vulvar and vaginal cancer morbidity and mortality in Russia; however, it is known that these diseases make up 5% of all anogenital area cancers. HPV 16 and 18 cause more than 1/3 of all vulvar cancer cases (36%) and more than a half of all vaginal cancer cases (58%). Almost every 10th vaginal cancer case (9.3%) is caused by HPV 6 and 11 considered low-oncogenic [11].
Anal cancer
More than 100,000 anal cancer cases are annually registered worldwide. In women it is observed 1.5 more often than in men. Anal cancer in men is primarily observed in homosexuals, although there are anal cancer cases in heterosexual men as well. The studies showed that anal HPV-infection is most often associated with anal sex, although there are other transmission routes (manual, contact) [21-24].
HPV 16 and 18 cause almost 75% of all anal cancer cases. Percentage of other HPV types is 0.1-3.5% [8].
Penile cancer
Penile cancer is not well registered in many countries, including Russia. WHO estimates that penile cancer takes 0.5% of all oncological diseases in men. Geographic correlation between penile cancer and cervical cancer cases and the correlation of these 2 types of neoplasms in married couples induced an assumption on their common etiology [25].
HPV 16 and 18 cause 38% of all penile cancer cases, HPV 6 and 11 – 5%, role of the other HPV types is insignificant [8].
Anogenital warts – condylomae
More than 90% of all cases of anogenital warts are caused by HPV 6 and 11 [5]. According to WHO, more than 42mn cases of anogenital warts are annually registered worldwide.
Results of the first all-Russian study “Spread of anogenital warts in clinical practice of specialists in the RF” (data not published) were presented (V.N. Prilepskaya, M.A. Gomberg) 26 September 2012 in the course of the Forum “Mother and child” (tb. 1).
Analyzing the obtained data, we may confirm high condylomae spread with the condition that the analysis did not take into consideration patients who did not seek medical help. Interestingly, men and women equally suffer from genital condylomae, unlike malignant genital lesions. The spread of anogenital warts in the RF among men and women of 18-60 year of age is 9.2% at the average, while the maximal spread is observed in young females of 18-24 years of age (14.5%).
Recurrent respiratory papillomatosis (RRP)
When being born, a child may get infected with types 6 and 11 while going through maternal passages; these types cause the development of 99.6% of recurrent respiratory papillomatosis cases in children. RRP often relapses and children may be subject to 20-100 operations annually for laryngeal papillomata removal. Almost 100% of RRP cases are caused by HPV 6 and 11 [5]. Oral-genital HPV transmission route is conductive of RRP development in adults.
Diagnostics
Papillomaviral infection diagnosis is established on the basis of:
•	clinical manifestations;
•	histologic study;
•	colposcopy data;
•	Virus’s DNA identification by polymerase chain reaction .
HPV-infection treatment
The comprehensive therapy method is considered to be the most efficient and prospective, when local removal of altered tissues is conducted in the setting of systemic treatment. There is no specific antiviral therapy, so the treatment cannot protect from disease relapses, i.e. in whole the treatment is symptomatic.
Prevention
Use of antiviral HPV-vaccines takes a special place in primary papillomaviral infection prevention.
At present there are 2 HPV-vaccines: a tetravalent vaccine protecting from the most widespread HPV types: 6, 11, 16, 18; and a bivalent, which protects from types 16 and 18. Initially, both vaccines were indicated for girls and young females. Given the fact that HPV affects people of both sexes in any age and causes a wide range of diseases, there have been extended clinical studies, which scientifically proved wider HPV vaccination capabilities. As a result, a tetravalent vaccine has the following indications to use: prevention of cervical, vulvar, vaginal, anal cancers and anogenital condylomae, and it is allowed for females of 9-45 years of age and males of 9-26 years of age [26].
Anogenital cancer’s protection range extension
24,358 females of 9-45 years of age from Europe, North and South America, Africa and Asia took part in the tetravalent vaccine’s clinical studies [27-29]. Protection of the vaccinated from precancer and cervical cancer was 98%, from premalignant lesions and vulvar and vaginal cancers – 100%, from the development of anogenital condylomae – 99% [30, 31].
Tetravalent vaccine was efficient in older women (24-45 years of age) to prevent persistent infections, premalignant lesions, anogenital condylomae in 88.7% of cases [15].
Vaccination of males
4,055 boys and young males of 9-26 years of age were vaccinated with a tetravalent HPV vaccine or placebo in the course of the international randomized, double blind, placebo-controlled study [29, 32].
Tetravalent vaccine prevented external genital lesions (anogenital condylomae and premalignant lesions of perineal, perianal area and penis) caused by HPV 6, 11, 16, 18 in males in 90.6% of cases and premalignant anal canal lesions in 77.5% of cases.
Vaccination efficiency on the country level
HPV vaccination proved its efficacy and safety in clinical studies, which is why HPV-vaccination is WHO-recommended for introduction into vaccination calendars of all countries. Several countries have already made the first national vaccination programs’ results public (Australia, USA, Sweden, Germany, Belgium).
A large-scale population study conducted in Australia gathered data on the morbidity of anogenital condylomae in patients seeking medical help in sexual health clinics in 2004-2011. This parameter did not change among heterosexual men and women in the first 3 study years (2004-2006 – before vaccination introduction). Since the massive vaccination of young females began in 2007, a gradual rate reduction of condyloma cases in young females up to their complete disappearance has been noted (pic.). Moreover, the reduction in condyloma cases by 28% occurred in heterosexual (not vaccinated) young males as well. Genital condyloma identification reduction occurred on the population level – this is the first epidemiologic market of the vaccination program efficacy.
The Center of Family Vaccinal Prevention at the RAMS SCCH already conducts vaccination of young males and women older than 26 years of age with a tetravalent vaccine. The gathered vaccination experience speaks for its good tolerance and safety for patients of both sexes and age.
Conclusion
HPV causes a wide range of diseases both in men and women. In the modern world there is a possibility of vaccinal prevention of HPV-associated diseases: cervical, vulvar, vaginal and anal cancers, anogenital condylomae, as proved by large-scale clinical studies. Given high burden of these diseases, WHO recommends including HPV-vaccination into vaccination calendars of all countries.

Age (years)	Spread (%)	
	Women (95% CI)	Men (95%)	
18-24	14.5 (12.6; 16.5)	11.0 (9.4; 12.7)	
25-29	12.6 (10.3; 14.8)	11.4 (8.9; 13.9)	
30-34	8.9 (6.7; 11.2)	12.1 (9.1; 15.1)	
35-39	6.0 (3.7; 8.3)	8.7 (5.9; 11.5)	
40-44	4.6 (2.5; 6.8)	6.0 (3.5; 8.5)	
45-49	3.0 (1.0; 5.1)	3.5 (1.0; 6.0)	
50-54	1.9 (0; 3.9)	2.4 (0.5; 4.2)	
>54	1.5 (0; 4.5)	2.8 (0; 5.9)	

Pic. Dynamics of anogenital warts’ (AW) rate reduction in a population (data for Australia)

REFERENCES
1. Munoz N., Castellsague X., Bosch F.X., Tafur L., de Sanjose S., Aristizabal N., Ghaffari A.M., Shah K.V. Difficulty in elucidating the male role in cervical cancer in Colombia, a high-risk area for the disease. J Natl Cancer Inst. 1996; 88 (15): 1068–75.
2. Castellsague X., Ghaffari A., Daniel R. W., Bosch F. X., Munoz N., Shah K. V. Prevalence of penile human papillomavirus DNA in husbands of women with and without cervical neoplasia: a study in Spain and Colombia. J Infect Dis. 1997; 176 (2): 353–61.
3. Burd E. M. Clin Microbiol Rev. 2003; 16: 1–17.
4. Bosch F. X., Burchell A. N., Schiffman M., Giuliano A. R. et al. Epidemiology and natural history of human papillomavirus infections and typespecific implications in cervical neoplasia. Vaccine. 2008; 26S: K1–K16.
5. Brown D. R. et al. J Clin Microbiol. 1999; 37: 3316–3322.
6. Koutsky L. Am J Med. 1997; 102: 3–8.
7. Strauss S., Sastry P., Sonnex C., Edwards S., Gray J. Contamination of environmental surfaces by genital human papillomaviruses. Sex Transm Infect. 2002; 78: 135–138.
8. GLOBOCAN 2010. WHO/ICO Information Centre on HPV and Cervical Cancer (HPV Information Centre). Human Papillomavirus and Related Cancers in World. Summary Report 2010. Accessed on 09.09.2012.
9. Aslamazyan L.K., Namazova L.S., Galitskaya M.G. Genital warts. Prevalence, etiology, treatment and prevention. Pediatricheskaya farmakologiya – Pediatric pharmacology. 2008; 5 (5): 14–17.
10. Castle P. E. et al. J Infect Dis. 2005; 191: 808–816.
11. Munoz N., Mendez F., Posso H. et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis. 2004; 15: 2077–87.
12. de Sanjose S., Diaz M., Castellsague X. et al. Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis. 2007; 7: 453–59.
13. Wellings K., Collumbien M., Slaymaker E. et al. Sexual behaviour in context: a global perspective. Lancet. 2006; 368: 1706–28.
14. Betsey Stevenson, Justin Wolfers. Marriage and divorce: changes and their driving forces. J Econ Pers. 2006; 21: 27–52.
15. Atlante M., Pagnini M., Villaccio B. et al. L’infezione da HPV come malattia di coppia. Prevalenza dell’infezionenel partner maschile. Minerva Ginecol. 1999; 51 (5): 161–164.
16. Frega A., Stentella P., Villani C. et al. Correlation between cervical intraepithelial neoplasia and human papillomavirus male infections: a longitudinal study. Eur J Gynaecol Oncol. 1999; 20 (3): 228–230.
17. Parkin D. M., Bray F. Vaccine. 2006; 24 (Suppl. 3): S11.
18. Namazova L.S. A new vaccine that prevents cervical cancer. Pediatricheskaya farmakologiya – Pediatric pharmacology. 2006; 3 (6): 55–57.
19. Ferlay J., Shin H. R., Bray F., Forman D., Mathers C. D., Parkin D. GLOBOCAN 2008. Cancer Incidence and Mortality Worldwide. IARC CancerBase. Lyon, France. 2010; 10.
20. Rogovskaya S.I. Prevalence of human papillomavirus infection in Russia. Epidemiologiya i vaktsinoprofilaktika – Epidemiology and vaccination. 2012; 1 (62).
21. Palefsky J. M. Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J NatI Cancer Inst Monogr. 1998; 23: 15–20.
22. Palefsky J. M., Holly E. A., Ralston M. L., Da Costa M., Greenblatt R. M. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HlV)-
positive and high-risk HIV-negative women. J Infect Dis. 2001; 183 (3): 383–91.
23. Xi L. F., Critchlow C. W., Wheeler C. M., Koutsky L. A., Galloway D. A., Kuypers J. et al. Risk of anal carcinoma in situ in relation to human papillomavirus type 16 variants. Cancer Res.
1998; 58 (17): 3839–44.
24. Critchlow C. W., Hawes S. E., Kuypers J. M., Coldbaum G. M., Holmes K. K., Surawicz C. M. et al. Effect of HIV infection on the natural history of anal human papillomavirus infection. AIDS. 1998; 12 (10): 1177–84.
25. Micali С., Nasca М. K., Innocenzi О., Schwartz R.A. Penile cancer. J Ат Acad Оегmatol. 2006; 54 (3): 369–91.
26. Instruktsiya po primeneniyu lekarstvennogo preparata dlya meditsinskogo primeneniya «Gardasil» (08.06.2012) [Instructions for Use of the Drug for Medical Use "Gardasil"].
27. Paavonen J. et al. Baseline demographic characteristics of subjects enrolled in international quadrivalent HPV (types 6/11/16/18) vaccine clinical trials. Current medical research and
opinion. 2008; 24 (6): 1623–1634.
28. Castellsague X. et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine in adult women 24–45 years of age. British
Journal of Cancer. 2011. Р. 1–10.
29. Giuliano A. R., Palefsky J. M., Goldstone S. et al. Efficacy of Quadrivalent HPV Vaccine against HPV Infection and Disease in Males. N Engl J Med. 2011; 5: 364.
30. Kjaer S. K. et al. A pooled analysis of continued prophylactic efficacy of quadrivalent HPV (types 6/11/16/18) L1 VLP vaccine against high-grade cervical and external genital lesions through endof study. Cancer Prev Res. 2009; 2 (10).
31. The FUTURE I/II Study Group. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomized controlled trial. BMJ. 2010; 340: 3493.
32. Giuliano A. R., Tortolero-Luna G. Epidemiology of Human Papillomavirus infection in men, cancers other than cervical and benign conditions. Vaccine. 2008; 26: 17–27.