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Persistent High-Risk Human Papillomavirus Infections and Other End-Point Markers of Progressive Cervical Disease Among Women Prospectively Followed up in the New Independent States of the Former Soviet Union and the Latin American Screening Study Cohorts
  1. Kari SyrjÄNen, MD, PhD, FIAC*,
  2. Irena Shabalova, MD, PhD, MiAC,
  3. Paulo Naud, MD, PhD,§,
  4. Vladimir Kozachenko, MD, PhD,
  5. Sophie Derchain, MD, PhD,
  6. Sergej Zakharchenko, MD,
  7. Cecilia Roteli-Martins, MD, PhD#,
  8. Raisa Nerovjna, MD**,
  9. Adhemar Longatto-Filho, PhD††,‡‡,
  10. Ludmila Kljukina, MD§§,
  11. Silvio Tatti, MD, PhD∥∥,
  12. Marina Branovskaja, MD¶¶,
  13. Luciano Serpa Hammes, MD, PhD,§,
  14. Margherita Branca, MD, PhD, MiAC##,
  15. Valerija Grunjberga***,†††,
  16. Mojca ErŽEn, PhD‡‡‡,
  17. Luis Otavio Sarian, PhD§§§,
  18. Anna Juschenko, MD***,†††,
  19. Silvano Costa, MD, PhD∥∥∥,
  20. Jurij Podistov, MD¶¶¶,
  21. Stina SyrjÄNen, DDS, PhD###,
  22. the NIS and LAMS Study Research Groups
  1. *Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland;
  2. Russian Academy of Post-Graduate Medical Education, Moscow, Russia;
  3. Hospital de Clinicas de Porto Alegre, and
  4. §Department of Gynecology and Obstetrics, Federal University of Rio Grande do Sul, Porto Alegre;
  5. Universidade Estadual de Campinas, Campinas, Brazil;
  6. Department of Gynaecology, Novgorod Municipal Dermato-venereological Dispensary, Novgorod, Russia;
  7. #Hospital Leonor M de Barros, Sao Paulo, Brazil;
  8. **Department of Gynaecology, Novgorod Female Consultative Outpatient Hospital, Novgorod, Russia;
  9. ††Instituto Adolfo Lutz, Sao Paulo, Brazil;
  10. ‡‡Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal;
  11. §§Research Institute of Oncology and Medical Radiology, Republican Centre of Clinical Cytology, Minsk, Belarus;
  12. ∥∥First Chair Gynecology Hospital de Clinicas, Buenos Aires, Argentina;
  13. ¶¶Department of Gynaecology and Obstetrics, Minsk State Medical Institute, Minsk, Belarus;
  14. ##Unit of Cytopathology, National Centre of Epidemiology, Surveillance and Promotion of Health, National Institute of Health (ISS) Rome, Italy;
  15. ***Department of Gynaecology, Latvian Cancer Centre;
  16. †††Laboratory of Cytology, Riga, Latvia;
  17. ‡‡‡SIZE Diagnostic Center, Ljubljana, Slovenia;
  18. §§§Universidade Estadual de Campinas, Campinas, Brazil;
  19. ∥∥∥Department of Obstetrics and Gynecology, S. Orsola-Malpighi Hospital, Bologna, Italy;
  20. ¶¶¶N.N. Blokhin Cancer Research Centre, Russian Academy of Medical Sciences, Moscow, Russia; and
  21. ###Department of Oral Pathology, Institute of Dentistry, University of Turku, Finland.
  1. Address correspondence and reprint requests to Kari Syrjänen, MD, PhD, FIAC, Department of Oncology and Radiotherapy, Turku University Hospital, Savitehtaankatu 1, FIN-20521 Turku, Finland. E-mail: kari.syrjanen{at}


Background: New end points are needed in future human papillomavirus (HPV) vaccine efficacy studies that accurately predict disease progression.

Objectives: Potential intermediate end points were analyzed in the combined New Independent States of the Former Soviet Union (NIS) and the Latin American Screening (LAMS) study cohorts.

Study Design and Methods: Data files of 2 international screening trials, the NIS (n = 3187) and the LAMS (n = 12,114) study cohorts, were combined, and a subcohort of 1865 (n = 854 and n = 1011 for the NIS and the LAMS, respectively) women prospectively followed up for 19.7 (median, 22.2) months was analyzed for different intermediate end-point markers of disease progression to squamous intraepithelial lesion (SIL), cervical intraepithelial neoplasia grade 1 and higher (CIN1+), and CIN grade 2 and higher (CIN2+) as terminal events.

Results: Altogether, 131 (7.0%), 90 (4.8%), and 39 (2.1%) cases progressed to SIL, CIN1+, and CIN2+, respectively, progression times being equal in the NIS (11.9, 16.8, and 19.6 months) and LAMS (13.6, 14.1, and 15.4 months) cohorts (P = 0.931, P = 0.335, and P = 0.535). The 2 most powerful end-point markers of disease progression to CIN2+ were high-grade squamous intraepithelial lesions based on Papanicolaou test results at 6-month (odds ratio [OR] = 47.1; 95% confidence interval [CI], 17.3-128.7) and 12-month (OR = 21.5; 95% CI, 5.1-90.8) follow-up visits, with longitudinal positive and negative predictive values of 42.1% and 98.0% (6 months) and 33.3% and 97.7% (12 months). Of the virological end points, more than 6 months of persistent high-risk HPV (HR-HPV) was the most powerful predictor of progression to CIN1+ (OR = 18.6; 95% CI, 2.5-136.5), with longitudinal positive and negative predictive values of 10.3% and 99.4%, respectively. No additional benefit was obtained using more than 12 months of persistent HR-HPV end point.

Conclusions: High-grade squamous intraepithelial lesion based on a Papanicolaou test results at 6- or 12-month follow-up visits was the most powerful end point, either considering cytological end points alone or in comparison to any of the virological end points. Of the virological end points, more than 6-month HR-HPV persistence criteria give the most powerful estimate of a progressive disease.

  • HPV
  • Cervical infections
  • Prospective follow-up
  • Progression
  • Intermediate end points
  • NIS cohort
  • LAMS study

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  • The New Independent States of the Former Soviet Union cohort study was supported by the International Cooperation-Copernicus Program of the European Commission (contract No. ERB IC15-CT98-0321); and the Latin American Screening study, by the European Commission, International Cooperation with Developing Countries Programme (contract No. ICA4-CT-2001-10013).