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Infection with high risk Human Papillomavirus (HRHPV) among HIV-positive women: epidemiology, natural history and impact of combined antiretroviral therapy

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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

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page

Acknowledgments

5

Thesis

Résumé

7

Summary

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

103

5.3 Controversies on the role of combined antiretroviral therapy

109

5.4 Should HIV-infected women be vaccinated against HPV?

121

6/ Conclusion and future perspectives

127

7/ References

130

8/

Supplement

8.1 Curriculum Vitae

141

8.2 Publications and presentations

149

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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.

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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

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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.

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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

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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

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