Detection of High-Risk Human Papillomavirus in Cervix Sample in an 11.3-year Follow-Up after Vaccination against HPV 16/18

Abstract

Purpose the aim of this study was to evaluate the pattern of human papillomavirus (HPV) detection in an 11.3-year post-vaccination period in a cohort of adolescent and young women vaccinated or not against HPV 16/18.

Methods a subset of 91 women from a single center participating in a randomized clinical trial (2001–2010, NCT00689741/00120848/00518336) with HPV 16/18 AS04-adjuvanted vaccine was evaluated. All women received three doses of the HPV vaccine (n = 48) or a placebo (n = 43), and cervical samples were collected at 6-month intervals. Only in this center, one additional evaluation was performed in 2012. Up to 1,492 cervical samples were tested for HPV-DNA and genotyped with polymerase chain reaction (PCR). The vaccine group characteristics were compared by Chi-square or Fisher exact or Mann-Whitney test. The high-risk (HR)-HPV 6-month-persistent infection rate was calculated. The cumulative infection by HPV group was evaluated by the Kaplan-Meier method and the log-rank test.

Results the cumulative infection with any type of HPV in an 11.3-year period was 67% in the HPV vaccine group and 72% in the placebo group (p = 0.408). The longitudinal analysis showed an increase of 4% per year at risk for detection of HR-HPV (non-HPV 16/18) over time (p = 0.015), unrelated to vaccination. The cumulative infection with HPV 16/18 was 4% for the HPV vaccine group and 29% for the placebo group (p = 0.003). There were 43 episodes of HR-HPV 6-month persistent infection, unrelated to vaccination.

Conclusions this study showed the maintenance of viral detection rate accumulating HR-HPV (non-HPV-16–18) positive tests during a long period post-vaccination, regardless of prior vaccination. This signalizes that the high number of HPV-positive tests may be maintained after vaccination.

Resumo

Objetivos avaliar o padrão de detecção do papilomavírus humano (HPV) em um período de 11.3 anos após a vacinação em uma coorte de adolescentes e mulheres jovens vacinadas ou não contra HPV 16/18.

Métodos avaliou-se um subgrupo de 91 mulheres de um único centro, participantes de ensaio clínico randomizado (2001–2010, NCT00689741/00120848/00518336) com a vacina contra HPV 16/18 com adjuvante AS04. Todas as mulheres receberam três doses de vacina contra HPV (n = 48) ou placebo (n = 43), e tiveram amostras cervicais coletadas em intervalos de 6 meses. Somente neste centro, uma avaliação adicional foi realizada em 2012. Um total de 1.492 amostras cervicais foram testadas para DNA-HPV e genotipadas com reação em cadeia da polimerase (RCP). As características dos grupos de vacina contra HPV ou placebo foram comparadas pelo teste de Qui-quadrado ou teste exato de Fisher ou teste de Mann-Whitney. A infecção persistente por 6 meses pelo HPV de alto risco (AR) foi calculada. A infecção cumulativa por grupo foi avaliada pelo método de Kaplan-Meier e pelo teste log-rank.

Resultados a infecção cumulativa com qualquer tipo de HPV em 11.3 anos foi de 67% no grupo vacina contra HPV e de 72% no grupo placebo (p = 0,408). A análise longitudinal mostrou um aumento de 4% ao ano no risco de detecção de HR-HPV (não-HPV 16/18) ao longo do tempo (p = 0,015), não relacionado com a vacinação. A infecção cumulativa com HPV 16/18 foi de 4% para o grupo vacina contra HPV e 29% para o grupo placebo (p = 0,003). Houve 43 episódios de infecção persistente por 6 meses por HR-HPV, não relacionados com a vacinação.

Conclusões este estudo mostrou a manutenção da taxa de detecção viral, acumulando testes positivos de HR-HPV (não HPV-16–18) durante longo período pós-vacinação, independentemente da vacinação prévia. Isto sinaliza que a alta positividade dos testes de HPV pode ser mantida após a vacinação.

Keywords

human papillomavirus - cervix uteri - papillomavirus vaccines - human papillomavirus vaccine 16 and 18 L1 VLP - HPV DNA tests - polymerase chain reaction

Palavras-Chave

papilomavírus humano - colo uterino - vacinas contra papilomavírus - vacina contra papilomavírus humano16 e 18 VLP L1 - testes de DNA-HPV - reação em cadeia da polimerase

Financial Support

This study was partially funded by FAEPEX (Unicamp) 519292–1016/13.

• References

• 1 Walboomers JM, Jacobs MV, Manos MM. , et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189 (01) 12-19
• 2 Kjaer SK, van den Brule AJ, Paull G. , et al. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 2002; 325 (7364): 572
• 3 Tabrizi SN, Brotherton JM, Kaldor JM. , et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis 2012; 206 (11) 1645-1651
• 4 Markowitz LE, Hariri S, Lin C. , et al. Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010. J Infect Dis 2013; 208 (03) 385-393
• 5 Kavanagh K, Pollock KG, Potts A. , et al. Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. Br J Cancer 2014; 110 (11) 2804-2811
• 6 Mesher D, Panwar K, Thomas SL, Beddows S, Soldan K. Continuing reductions in HPV 16/18 in a population with high coverage of bivalent HPV vaccination in England: an ongoing cross-sectional study. BMJ Open 2016; 6 (02) e009915
• 7 Stanley M, Lowy DR, Frazer I. Chapter 12: Prophylactic HPV vaccines: underlying mechanisms. Vaccine 2006; 24 (Suppl. 03) S3 , 106–113
• 8 Markowitz LE, Hariri S, Unger ER, Saraiya M, Datta SD, Dunne EF. Post-licensure monitoring of HPV vaccine in the United States. Vaccine 2010; 28 (30) 4731-4737
• 9 Stanley M. Human papillomavirus vaccines versus cervical cancer screening. Clin Oncol (R Coll Radiol) 2008; 20 (06) 388-394
• 10 Ronco G, Dillner J, Elfström KM. , et al; International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383 (9916): 524-532
• 11 El-Zein M, Richardson L, Franco EL. Cervical cancer screening of HPV vaccinated populations: Cytology, molecular testing, both or none. J Clin Virol 2016; 76 (Suppl. 01) S62-S68
• 12 Harper DM, Franco EL, Wheeler C. , et al; GlaxoSmithKline HPV Vaccine Study Group. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004; 364 (9447): 1757-1765
• 13 Romanowski B, de Borba PC, Naud PS. , et al; GlaxoSmithKline Vaccine HPV-007 Study Group. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009; 374 (9706): 1975-1985
• 14 Naud PS, Roteli-Martins CM, De Carvalho NS. , et al. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination. Hum Vaccin Immunother 2014; 10 (08) 2147-2162
• 15 Quint WG, Scholte G, van Doorn LJ, Kleter B, Smits PH, Lindeman J. Comparative analysis of human papillomavirus infections in cervical scrapes and biopsy specimens by general SPF(10) PCR and HPV genotyping. J Pathol 2001; 194 (01) 51-58
• 16 Clart Human Papillomavirus 2 [Internet]. Genotyping of human papillomavirus via genomic identification for in vitro diagnosis. 2013 [cited 2015 Feb 6]. Available from: http://genomica.es/en/documents/CLARTHPV2V10Feb2013English.pdf
• 17 Brasil. Ministério da Saúde. Conselho Nacional de Saúde. Comissão Nacional de Ética em Pesquisa [Internet]. Resolução N° 196/96 versão 2012. 2012 [citado 2015 Fev 6]. Disponível em: http://conselho.saude.gov.br/web_comissoes/conep/aquivos/resolucoes/23_out_versao_final_196_ENCEP2012.pdf
• 18 Hand DJ, Crowder MJ. Practical longitudinal data analysis. London: Chapman & Hall; 1996
• 19 SAS Institute. The SAS System for Windows (Statistical Analysis System), version 9.2. Cary: SAS Institute Inc; ; 2002– 2008
• 20 Muñoz N, Méndez F, Posso H. , et al; Instituto Nacional de Cancerologia HPV Study Group. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results. J Infect Dis 2004; 190 (12) 2077-2087
• 21 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 2006; 24 (Suppl. 03) S3 , 78–89
• 22 Hestbech MS, Lynge E, Kragstrup J, Siersma V, Vazquez-Prada Baillet M, Brodersen J. The impact of HPV vaccination on future cervical screening: a simulation study of two birth cohorts in Denmark. BMJ Open 2015; 5 (08) e007921