Université Libre de Bruxelles
Faculté de Médecine
Infection with high risk Human
Papillomavirus (HRHPV) among
HIV-positive women: epidemiology, natural
history and impact of combined
antiretroviral therapy
Dr Deborah Konopnicki
Infectious Diseases Department
Saint-Pierre University Hospital
Thesis Director: Professor Nathan Clumeck, ULB
Jury members: Professor Jean-Paul Sculier, ULB (President) Professor Anne Op De Beeck, ULB (Secretary) Professor Jean-Christophe Goffard, ULB Professor Robert Snoeck, ULB
Professor Philippe Delvenne, Université de Liège Professor Marleen Temmerman, Ghent University
page
Acknowledgments
5
Thesis
Résumé
7Summary
9
Abbreviations
11
1/ Introduction
15
1.1 Virology of HPV
19
1.2 HIV favoring HPV infection
27
1.3 HIV favoring HPV-induced lesions
33
1.4 HPV infection favoring HIV acquisition
37
2/ Objectives and methods
41
3/ Epidemiology of HRHPV among HIV-positive women in Belgium
3.1 Prevalence and incidence of HRHPV infection
47
3.2 Genotype distribution of HRHPV infection
55
4/ Impact of combined antiretroviral therapy on HRHPV infection
and on HPV-induced lesions
4.1 Impact of CART on HRHPV infection
65
4.2 Impact of CART on cervical dysplasia
75
5/ Discussion
5.1 Possible epidemiological links between HPV & HIV epidemics
89
5.2 Implication of our results on screening for HPV-induced lesions
1035.3 Controversies on the role of combined antiretroviral therapy
1095.4 Should HIV-infected women be vaccinated against HPV?
1216/ Conclusion and future perspectives
127
7/ References
1308/
Supplement
8.1 Curriculum Vitae
141
8.2 Publications and presentations
149
Acknowledgments
I wish to thank:Dr Yannick Manigart, Dr Christine Gilles and Dr Patricia Barlow, the gynecologists that have performed all the gynecological samples; they have been fully involved in the management and care of HIV positive women for two decades or more and the collaboration with them has always been excellent and joyful.
Dr Francesco Feoli, Professor Denis Larsimont and former Professor Alain Verest, the pathologists that have analyzed all the cytological and histological samples and have always supported and advised my research.
Robert Scheen and Godelieve Verhaegen from the Molecular Biology Laboratory who have performed all the HPV detection and Dr De Marchin and Professor Olivier Vandenberg that have validated and supervised these results.
Marc Delforge, biostatistician, who has performed all the statistical analysis. The Andre Vésale Foundation for medical research that has given me a Grant for my research.
The whole team of the Infectious Diseases Department from St-Pierre-University hospital that has given me the opportunity to work on this thesis.
Professor Stephane De Wit (my husband) for his professional and personal never-ending support.
Professor Clumeck that has encouraged me since the first day to do medical research and has advised me at each step of this research and thesis.
Résumé
L’infection persistante par les papillomavirus (HPV) dits « à haut risque » induit le cancer du col. Chez les femmes infectées par le VIH, les infections par ces HPV oncogènes et les lésions associées, allant des dysplasies au cancer invasif, sont plus fréquentes, plus sévères et de moins bon pronostic que chez les femmes non porteuses du VIH. Etonnamment, alors qu’il a été clairement établi que l’importance de la pathologie liée à HPV est directement proportionnelle au degré d’immunodépression des patientes porteuses du VIH, il n’a pas pu être démontré qu’un traitement antirétroviral efficace contre le VIH permettant d’améliorer l’immunité, diminue l’infection par ces HPV.
Entre janvier 2002 et décembre 2012, nous avons constitué une cohorte
prospective de dépistage et de suivi de l’infection cervicale par HPV à haut risque incluant plus de 900 femmes traitées à la consultation du Centre de Référence SIDA de l’hôpital Saint-Pierre. Nos résultats montrent que chez ces femmes pour la plupart d’origine Africaine et traitée avec succès pour le VIH depuis plusieurs années, la prévalence et l’incidence de l’infection par HPV oncogène sont
Summary
Persistent infection with human papillomavirus (HPV) called “at high risk” induces cervical cancer. In HIV-positive women, infection with these oncogenic HPV and HPV-induced lesions ranging from cervical dysplasia to invasive cancer are more frequent, more severe and have a worst outcome than in HIV-negative women. An intriguing paradox is that, although it has been clearly demonstrated that high risk HPV infection and associated diseases are increased by progressive immune deficiency, the introduction of efficient therapy against HIV leading to improved immunity has not been associated with a decrease in oncogenic HPV infection or HPV-induced lesions.
Abbreviations
AIN Anal intraepithelial neoplasia
ASCH Atypical squamous cells that cannot exclude HSIL ASCUS Atypical squamous cells of unknown origin
Bl Baseline
cART Combined antiretroviral therapy CC Cervical cancer
CI Confidence intervals
CIN Cervical intraepithelial neoplasia
cp copies
EACS European AIDS Clinical Society
FU Follow up
HC Hybrid Capture
HIV Human immunodeficiency virus HPV Human papillomavirus
HR High risk
HRHPV High risk HPV
HG High grade
HGCIN High grade CIN
HSIL High grade squamous intraepithelial lesion HSV Herpes Simplex Virus
ICC Invasive cervical cancer IQ Interquartile range
LR Low risk
LRHPV Low risk HPV LSIL low grade SIL
Nb Number
NR Not reported
NCHST Non cancerous hysterectomy OHR Other high risk type
OI Opportunistic infection
OR Odds ratio
p. Patients
Pap smear Papanicolaou smear RR Relative risk
SIL Squamous intraepithelial lesion STI Sexually transmitted Infection
Th T helper
US United State of America
VL Viral load
Vs. Versus