The role of human papillomavirus in cervical pre-neoplastic lesions: the relationship between virus genotype and persistence or clearance of the infection

Human papilloma virus (HPV) infection persistence is responsible for modifications that will lead to progression to a pre-neoplastic cervical lesion. This study examined persistence or clearance of HPV infection related to genotypes and to risk factors, like patients’ age, smoking habit, and use of oral contraceptives. The data of 90 patients, who had a positive high risk-HPV (HR-HPV) test for more than 18 months irrespective of the genotype, were taken from the pathology database of the Colposcopy Clinic and the presence of HPV was assessed by the linear array test which utilized amplification of target DNA by polymerase chain reaction (PCR) and nucleic acid hybridization. During the first visit a careful anamnesis was taken, with information about lifestyle. Clearance was observed in 25% of infections by low risk genotypes and in 43% of which by high risk and, among high oncogenic risk genotypes, HPV 16, 31, 33, 35, 39, 45, 51, and 59 were mostly associated to persistence of infection. Among persistent HPV infections, progression occurred with HPV16 in 50% of cases, with HPV18 in 44.4% of cases, with HPV31 and HPV35 in 33.3% of cases, with HPV33 in 28.5% of cases, with HPV45 in 41.7% of cases, with HPV51 in 25% of cases, and with HPV59 in 20%. There was no statistically significant difference between persistence of high risk and low risk genotypes and a significant association with the cited risk factors. A long period of follow-up, HPV-DNA detection by PCR, and the study of risk factors could lead to improve the diagnosis of persistent HPV infections.

HPV infection persistence; HPV infection clearance; Squamous intraepithelial lesion; Cervical intraepithelial neoplasia; HPV infection progression.

[1] zur Hausen H.: “Papillomaviruses and cancer: from basic studies to clinical application”. Nat. Rev. Cancer, 2002, 2, 342.

[2] Steben M., Duarte-Franco E.: “Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol. 2007. 107: S2–S5.

[3] zur Hausen H. Human papillomavirus and cervical cancer”. Indian J. Med. Res., 2009, 130, 209.

[4] Scardamaglia P., Carraro C., Mancino P., Stentella P.: “Effectiveness of the treatment with beta-glucan in the HPV-CIN 1 lesions”. Minerva Ginecol., 2010, 62, 389.

[5] Schettino M.T., Ammaturo F.P., Labriola D, De Franciscis P., Colacurci N., Torella M.: “Betulinic acid and possible influence on the clearance of Human Papilloma Virus: cytological and virological follow- up”. Minerva Ginecol., 2013, 65, 661.

[6] Castle P.E., Schiffman M., Herrero R., Hildesheim A., Rodriguez A.C., Bratti M.C., et al.: “A prospective study of age trends in cervical human papillomavirus acquisition and persistence in Guanacaste, Costa Rica”. J. Infect Dis., 2005. 191, 1808.

[7] Colacurci N., De Franciscis P., Atlante M., Mancino P., Monti M., Volpini G., et al.: “Endometrial, breast and liver safety of soy isoflavones plus Lactobacillus sporogenes in post-menopausal women”. Gynecol. Endocrinol., 2013, 29, 209.

[8] Gravitt P.E.: “The known unknowns of HPV natural history”. J. Clinical Invest., 2011, 121, 4593.

[9] Arnheim Dahlström L., Andersson K., Luostarinen T., Thoresen S., Ögmundsdottír H., Tryggvadottír L., et al.: “Prospective seroepidemiologic study of human papillomavirus and other risk factors in cervical cancer”. Cancer Epidemiol Biomarkers Prev., 2011, 20, 2541.

[10] Yetimalar H., Kasap B., Cukurova K., Yildiz A., Keklik A., Soylu F.: “Cofactors in human papillomavirus infection and cervical carcinogenesis”. Arch, Gynecol, Obstet., 2012., 285, 805.

[11] Koshiol J., Lindsay L., Pimenta J.M., Poole C., Jenkins D., Smith J.S.: “Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis”. Am. J. Epidemiol., 2008, 168, 123.

[12] Igidbashian S., Schettino M.T., Boveri S., Barberis M., Sandri M.T., Carinelli S., et al.: “Tissue genotyping of 37 in situ and invasive cervical cancer with a concomitant negative HC2 HPV DNA test”. J. Low Genit. Tract Dis., 2014, 18, 87.

[13] Bosch F.X., Lorincz A., Muñoz N., Meijer C.J., Shah K.V.: “The causal relation between human papillomavirus and cervical cancer”. J. Clin. Pathol., 2002, 55, 244.

[14] Franco E.L., Villa L.L., Sobrinho J.P., Prado J.M., Rousseau M.C., Désy M., et al.: “Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer”. J. Infect. Dis., 1999, 180, 1415.

[15] Woodman C.B.J., Collins S., Winter H., et al.: “Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study”. Lancet, 2001, 357, 1831.

[16] Muñoz N., Méndez F., Posso H., Molano M., van den Brule A.J., Ronderos M., 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, 190, 2077.

[17] Banura C., Sandin S., van Doorn L.J., Quint W., Kleter B., Wabwire- Mangen F., et al.: “Type-specific incidence, clearance and predictors of cervical human papillomavirus infections (HPV) among young women: a prospective study in Uganda”. Infect. Agents Cancer, 2010, 5, 7.

[18] Sammarco M.L., Del Riccio I., Tamburro M., Grasso M.G., Ripabelli G.: “Type-specific persistence and associated risk factors of human papillomavirus infections in women living in central Italy”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2013, 168, 222.

[19] Howe E.R., Li Z., McGlennen R.C., Hellerstedt W., Downs L.S.: “Type-specific prevalence and persistence of human papillomavirus in women in the United States who are referred for typing as a component of cervical cancer screening”. Am. J. Obstet. Gynecol., 2009, 200, 245.

[20] Carcopino X., Bolger N., Henry M., Mancini J., Boubli L., Olive D., et al.: “Evaluation of type-specific HPV persistence and high-risk HPV viral load quantitation in HPV positive women under 30 with normal cervical cytology”. J. Medical Virol., 2011, 83, 637.

[21] Nielsen A., Kjaer S.K., Munk C., Osler M., Iftner T.: “Persistence of high-risk human papillomavirus infection in a population-based cohort of Danish women”. J. Med. Virol., 2010, 82, 616.

[22] Trottier H., Mahmud S., Prado J.C., Sobrinho J.S., Costa M.C., Rohan T.E., et al.: “Type-specific duration of human papillomavirus infection: implications for human papillomavirus screening and vaccination”. J Infect Dis 2008. 197: 1436–1447.

[23] Castle P.E., Rodríguez A.C., Burk R.D., Herrero R., Wacholder S., Hildesheim A., et al.: “Long term persistence of prevalently detected human papillomavirus infections in the absence of detectable cervical precancer and cancer”. J. Infect. Dis., 2011, 203, 814.

[24] Schmeink C.E., Massuger L.F., Lenselink C.H., Quint W.G., Witte B.I., Berkhof J., et al.: “Prospective follow-up of 2065 young unscreened women to study human papillomavirus incidence and clearance”. Int. J. Cancer, 2013, 133, 172.

[25] Schettino M.T., Ammaturo F. P., Grimaldi E., Legnante A., Marcello A., Donnarumma G., et al.: “Persistent papillomavirus type-31 and type-45 infections predict the progression to squamous intraepithelial lesion”. Taiwan J. Obstet. Ginecol., 2014, 53, 494.

[26] Jensen K.E., Schmiedel S., Norrild B., Frederiksen K., Iftner T., Kjaer S.K.: “Parity as a cofactor for high-grade cervical disease among women with persistent human papillomavirus infection: a 13-year follow-up”. Br. J. Cancer, 2013, 108, 234.