Chlamydia trachomatis infection and risk of cervical intraepithelial neoplasia

Matti Lehtinen, Kevin A Ault, Erika Lyytikainen, Joakim Dillner, Suzanne M Garland, Daron G Ferris, Laura A Koutsky, Heather L Sings, Shuang Lu, Richard M Haupt, Jorma Paavonen, FUTURE I and II Study Group, Matti Lehtinen, Kevin A Ault, Erika Lyytikainen, Joakim Dillner, Suzanne M Garland, Daron G Ferris, Laura A Koutsky, Heather L Sings, Shuang Lu, Richard M Haupt, Jorma Paavonen, FUTURE I and II Study Group

Abstract

Objectives: High-risk human papillomavirus (hrHPV) is the primary cause of cervical cancer. As Chlamydia trachomatis is also linked to cervical cancer, its role as a potential co-factor in the development of cervical intraepithelial neoplasia (CIN) grade 2 or higher was examined.

Methods: The placebo arms of two large, multinational, clinical trials of an HPV6/11/16/18 vaccine were combined. A total of 8441 healthy women aged 15-26 years underwent cervicovaginal cytology (Papanicolaou (Pap) testing) sampling and C trachomatis testing at day 1 and every 12 months thereafter for up to 4 years. Protocol-specified guidelines were used to triage participants with Pap abnormalities to colposcopy and definitive therapy. The main outcome measured was CIN.

Results: At baseline, 2629 (31.1%) tested positive for hrHPV DNA and 354 (4.2%) tested positive for C trachomatis. Among those with HPV16/18 infection (n = 965; 11.4%) or without HPV16/18 infection (n = 7382, 87.5%), the hazard ratios (HRs) associated with development of any CIN grade 2 according to baseline C trachomatis status were 1.82 (95% CI: 1.06 to 3.14) and 1.74 (95% CI 1.05 to 2.90), respectively. The results were comparable when only the 12 most common hrHPV infections were considered, but the excess risk disappeared when the outcome was expanded to include CIN grade 3 or worse.

Conclusion: Further studies based on larger cohorts with longitudinal follow-up in relation to the C trachomatis acquisition and a thorough evaluation of temporal relationships of infections with hrHPV types, C trachomatis and cervical neoplasia are needed to demonstrate whether and how in some situations C trachomatis sets the stage for cervical carcinogenesis. Trial registration NCT00092521 and NCT00092534.

Conflict of interest statement

Competing interests: ML, KAA, JD, SMG, DGF and LAK have received funding through their institutions to conduct HPV vaccine studies for Merck. KAA has received consultancy and advisory board fees from Merck, and has received funding through his institution to conduct HPV-related research for Roche, Gen Probe and GlaxoSmithKline. JD has received consultancy fees, lecture fees and research grants from Merck and Sanofi Pasteur MSD. SMG has received advisory board fees and grant support from Commonwealth Serum Laboratories and GlaxoSmithKline, and lecture fees from Merck. DGF has received consultancy fees and funding through his institution to conduct HPV vaccine studies for GlaxoSmithKline, and lecture fees from Merck. JP has received consultancy fees and travel grants from Merck and GlaxoSmithKline. HLS, SL and RMH are employees of Merck and potentially own stock and/or stock options in the company.

References

    1. Walboomers JMM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–19
    1. Anttila T, Saikku P, Koskela P, et al. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 2001;285:47–51
    1. Wallin KL, Wiklund F, Luostarinen T, et al. A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma. Int J Cancer 2002;101:371–4
    1. Quint KD, de Koning MN, Geraets DT, et al. Comprehensive analysis of Human Papillomavirus and Chlamydia trachomatis in in-situ and invasive cervical adenocarcinoma. Gynecol Oncol 2009;114:390–4
    1. Naucler P, Chen H-C, Persson K, et al. Seroprevalence of human papillomavirus and Chlamydia trachomatis and cervical cancer risk: nested case-control study. J Gen Virol 2007;88:814–22
    1. Paavonen J, Purola E. Cytological findings in cervical chlamydial infection. Med Biol 1980;58:174–8
    1. Luostarinen T, Lehtinen M, Bjorge T, et al. Joint effects of different human papillomaviruses and Chlamydia trachomatis infections on risk of squamous cell carcinoma of the cervix uteri. Eur J Cancer 2004;40:1058–65
    1. Arnheim L. Immunological Responses in Genital HPV Infections and Etiology of Cervical Cancer. Stockholm, Sweden: Karolinska Institutet, 2005:1–75 (accessed 22 Oct 2009).
    1. Agrawal T, Vats V, Wallace L. Role of cervical dendritic cell subsets, co-stimulatory molecules, cytokine secretion profile and beta-estradiol in development of sequalae to Chlamydia trachomatis infection. BMC Reproduct Biol Endocrinol 2008;6:46
    1. Silins I, Ryd W, Strand A, et al. Chlamydia trachomatis infection and persistence of human papillomavirus. Int J Cancer 2005;116:110–15
    1. Samoff E, Koumans EH, Markowitz LE, et al. Association of Chlamydia trachomatis with persistence of high-risk types of human papillomavirus in a cohort of female adolescents. Am J Epidemiol 2005;162:668–75
    1. Velicer C, Zhu X, Vuocolo S, et al. Prevalence and incidence of HPV genital infection in women. Sex Transm Dis 2009;36:696–703
    1. Shew ML, Fortenberry JD, Tu W, et al. Association of condom use, sexual behaviors, and sexually transmitted infections with the duration of genital human papillomavirus infection among adolescent women. Arch Pediatr Adolesc Med 2006;160:151–6
    1. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928–43
    1. The FUTURE II Study Group Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:1915–27
    1. International Patent Numbers WO 2003/019143 A2, WO 2006/116276 A2 and WO 2006/116303 A2. (accessed 5 May 2010).
    1. Villa LL, Costa RLR, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6:271–8
    1. Mao C, Koutsky LA, Ault KA, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 2006;107:18–27
    1. Li N, Franscheski S, Howell-Jones R, et al. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer 2011;128:927–35
    1. Cox DR. Regression models and life tables. J R Stat Soc Ser B Methodological 1972;34:187–220
    1. Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 1992;327:1272–8
    1. Lehtinen M, Dillner J, Knekt P, et al. Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study. Br Med J 1996;312:537–9
    1. Schiffman M, Clifford G, Buonaguro FM. Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 2009;4:8.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa