Cervical, anal and oral human papillomavirus (HPV) infection in young women: A case control study between women with perinatally HIV infection and women with non-perinatally HIV infection

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European Journal of Obstetrics & Gynecology and Reproductive

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Please cite this article as: Gilles C, Buljubasic M, Konopnicki D, Manigart Y, Barlow P, Rozenberg S, Cervical, anal and oral Human papillomavirus (HPV) infection in young women: a case control study between women with perinatally HIV infection and women with non-perinatally HIV infection, European Journal of Obstetrics and amp; Gynecology and Reproductive Biology (2019), doi: https://doi.org/10.1016/j.ejogrb.2019.11.022

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TITLE PAGE Cervical, anal and oral Human papillomavirus (HPV) infection in young women: a case control study between women with perinatally HIV infection and women with nonperinatally HIV infection.

Human papillomavirus in HIV young women Christine Gilles1*and Marie Buljubasic1*, Déborah. Konopnicki2, Yannick Manigart1, Patricia Barlow1, Serge Rozenberg1 Department of Gynecology, Saint Pierre University Hospital, Brussels, Belgium

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1

Université Libre de Bruxelles (ULB) - Free University of Brussels (ULB-VUB) 2

Infectious Diseases Department, Saint Pierre University Hospital, Brussels, Belgium

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Unversité Libre de Bruxelles (ULB) - Free University of Brussels (ULB-VUB)

322 Rue haute, 1000 Brussels, Belgium

[email protected]

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0032 25353400

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Corresponding author : Christine Gilles

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These authors have contributed equally to the work *

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E-mail adresses of authors:

MB : [email protected]

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DK : [email protected] YM : [email protected] PB : [email protected] SR : [email protected]

ABSTRACT

Cervical, anal and oral Human papillomavirus (HPV) infection in young women: a case control study between women with perinatally HIV infection and women with nonperinatally HIV infection.

Human papillomavirus in HIV young women Christine Gilles1*and Marie Buljubasic1*, Déborah. Konopnicki2, Yannick Manigart1, Patricia Barlow1, Serge Rozenberg1

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Objectives

HPV infection may differ in women who are HIV-positive since birth (perinatally infected, PHIV) and those who acquire HIV later in life (non-perinatally infected, NP-HIV). We assessed the

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HPV prevalence in relation to the HIV acquisition route and HPV vaccination status. Study design

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Case control study comparing 22 P-HIV with 22 NP-HIV patients. Cervical, anal and oral

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specimen were collected for HPV PCRs. The primary outcome was the prevalence of cervical, oral and anal HPV in P-HIV and NP-HIV patients. The secondary outcome was to identify risk factors for HPV infection. Comparative statistics for two independent groups, univariate and multivariable

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logistic regression analyses were used.

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Results

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There were no differences between perinatally and non-perinatally infected women. Cervical dysplasia was found in 12/44 (27%) patients and high-risk HPV (hrHPV) in 30% of cervical (of which 89% were hrHPV other than 16 and 18), in 3% of oral and 65% of anal specimens. All woman were using combined antiretroviral therapy (cART) and 64% had HIVRNA <20 cp/ml. A CD4 count <350/mm³ was associated with cytological abnormalities (OR: 13.52, p=0.002) and with cervical HPV (OR: 6.11; p=0.04); anal HPV was associated with a previous cervical

dysplasia and concomitant cervical HPV infection. None of thirteen vaccinated patients had a 6/11/16/18 HPV infection. Conclusion In this small series of women under cART, we did not observe a difference in HPV infection in relation to the route of HIV acquisition. The high prevalence of hrHPV other than 16 and 18

Table of abbreviations

ASCUS: Atypical Squamous cells of Undetermined Significance

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support the use of a 9-valent vaccine.

ASCH: Atypical Squamous cells in which a high-grade squamous intraepithelial lesion cannot be

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excluded

C. trachomatis : Chlamydia trachomatis

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cART: combined antiretroviral therapy

HIV RNA: Human Immunodeficiency Virus ribonucleic acid

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HPV: Human Papillomavirus hrHPV: high-risk Human papillomavirus

HPV PCR: Human Papillomavirus Polymerase Chain reaction

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HSIL: High Grade Squamous Intraepithelial Lesions LSIL: Low Grade Squamous Intraepithelial Lesions N. gonorrhoeae: Neisseria gonorrhoeae

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NP-HIV: non-perinatally Human Immunodeficiency Virus infected Pap Test: Papanicolau Test

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P-HIV: Perinatally Human Immunodeficiency Virus infected STD: sexually transmitted disease

Keywords: HPV, Vaccination, HIV, Female, Young Adult

MAIN TEXT

1. Introduction

HIV infected women, even ones who use appropriate combination antiretroviral therapy (cART), have an increased risk of being infected by HPV and of developing both pre-cancerous cervical lesions and other HPV related cancers [1-4]. The only available primary prevention is the vaccination before the first sexual contact. The earliest generation of vaccines protected women against either HPV 16 /18 (bivalent) or HPV 6/11/16/18 (quadrivalent) whereas a second generation of vaccines, protects against 6/11/16/18/31/33/45/52/58 (9-valent) [5]. We, like other

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authors, previously observed that HIV positive women were more prone to infection by other high risk HPV (hrHPV) genotypes than by HPV 16 and 18, [6,7]. Although much has been done to reduce the risk of vertical transmission, it was estimated in 2015 that there were still about 150.000 living people who had been infected at birth [8, 9]. Women who had perinatally acquired HIV (P-

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HIV) might also be at increased risk of HPV infection. Firstly, they probably present a longer duration of HIV infection which is known to be a risk factor for HPV related diseases. Secondly,

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due to their lifelong jeopardized immune system, they may have developed a reduced immunity against HPV. For some of these P-HIV women, HIV therapy initiation may have been delayed or administered using sub-optimal regimens, leading to an insufficient suppression of viral

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replication. Being young, they may also have been more prone to low compliance to therapy [911].

This study aims to assess the prevalence of cervical, anal and oral HPV infection in a cohort of

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young women who were infected at birth (P-HIV, perinatally infected) compared to women who were infected by HIV during adulthood (NP-HIV, non-perinatally infected), whether or not they

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were vaccinated against HPV.

2. Material and Method

Design: This cross-sectional – case control study was conducted between December 2016 and April 2017. Patients: P-HIV women needed to have been followed at our hospital since childhood, be sexually active and be patients at our gynecological outpatient clinic. Out of a cohort of 84 P-HIV women followed since childhood, 22 women met these selection criteria. Out of our patient data base, we selected 22 control patients who had been non-perinatally HIV infected. They were chosen,

without knowledge of their HPV or cytology results, based on the following matching criteria: the patients’ age, ethnic origin and their last known CD4. Procedures : A cervical smear for cytology (PAP test Bethesda) and for HPV detection (BD SurePath™ liquid-based Pap test) (12), cervical smears for PCR detection of C. trachomatis and N. gonorrhoeae, an anal smear (Rovers® Anex® Brush) and an oral detection through gargling (Greiner Bio-One Saliva Collection System®)(13) were collected during a gynecological consultation. Analyses : The HPV detection occurred after DNA extraction and PCR detection for 18 HPV genotypes of which 14 are considered to be hrHPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) and 4 as low risk (6, 11, 53 and 67) according to the technique described by Depuydt et

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al (14). Clinical data: Demographic and clinical data pertaining to gynecological and infectious history (HIV as well as CD4 levels and viral load, medication, other past STDs, history of abnormal PAPtest, and HPV vaccination) were extracted from the patients’ databases. Both nadir CD4 and

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current CD4 levels and CD4/CD8 ratio (at enrollment) were collected. Supplementary data regarding their lifestyle (age at first intercourse, number of partners, smoking habits, contraception

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that was used, level of education, employment, ethnic origin of the patient and of the current partner, years living in Belgium, health insurance) were collected using a specific questionnaire. Primary Outcomes: The prevalence of cervical, oral and anal HPV in P-HIV and NP-HIV patients.

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Secondary outcomes: risk factors for HPV infection

Statistical analyses: Control patients were selected based on their age, ethnic origin and most recent CD4 levels, in order to match the vertically infected patients. Because we were unable to

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match patients for other confounding factors such as cervical cytology, we used comparative statistics for two independent groups, rather than paired tests. Descriptive statistics are expressed

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using mean values and range for quantitative measurements and percentages for qualitative measurements. Fisher’s exact test and the chi-square test were used. The risk factors for cytology

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anomalies and HPV infection were evaluated using univariate logistics regression and were adjusted in multivariable logistic regression analysis for any parameter with a p value < 0.05. We analyzed the data related to the HPV genotypes that could be potentially covered by the bivalent and quadrivalent vaccines (genotypes 6, 11, 16, 18 versus other genotypes) or by the 9-valent vaccine (genotypes 6, 11, 16, 18, 31, 33, 45, 52, 58). We calculated the proportion of HIV infected women for whom an HPV infection would have been prevented, had they been vaccinated. We used two hypotheses: one conservative approach in which a woman is considered to be protected if all of the HPV genotypes found in her cervix, oral or anal samples are included in the vaccine and

another, more optimistic approach in which a woman could benefit from vaccination if at least one of her HPV genotypes is included in the vaccine. Statistical power : We calculated that in order to detect a clinically significant difference in HPV infection rates between the perinatally (50% prevalence) versus non-perinatally infected patients (30% prevalence), with a power of 80% and a p<0.05 significance, 200 patients should be included. All analyses were conducted using SPSS software version 11. Ethical approval: The study was approved by the local ethical review board (nr B076201630190). All of the participants in the study provided a written informed consent.

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3. Results

The main demographic and clinical characteristics of the two groups of patients are presented in Table 1. Their age distribution and ethnic origin (most were of African origin) did not differ.

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Perinatally infected women had lived longer in Belgium, had a higher level of education, were more frequently financially autonomous, smoked more, had had fewer sexual partners, were more

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likely to use combined oestrogen-progestin contraception, had more rarely had an induced abortion and were more often nulli-gravida than horizontally infected women. Data on HIV infection are shown in Table 2. Perinatally infected women had been diagnosed at a younger age and had had a

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longer cumulative period of undetectable viral loads, but they were more prone to discontinuing their HIV treatment than were non-perinatally infected women.

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Cervical cytology and histology

There were no differences between perinatally and non-perinatally infected women. Globally, 12 (6 in each group) out of 44 smears (27%) were pathological: ASCUS (Atypical Squamous cells of

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Undetermined Significance) (n=1), ASCH (i.e. Ascus where HSIL can’t be excluded) (n=1), LSIL (Low Grade Squamous Intraepithelial Lesions) (n=9) and HSIL (High Grade Squamous

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Intraepithelial Lesions) (n=1). At least one hrHPV was identified in nine of the cases. Five patients had a biopsy, showing high grade dysplasia (n=2), low grade dysplasia (n=2) or no dysplasia (n=1).

Cervical HPV In 6 patients, the DNA (deoxyribonucleic acid) concentration control was too low to exclude false negative samples. Eleven patients (six P-HIV and 5 NP-HIV) out of 36 (30%) for whom the HPV

research analyze was valid, were infected by at least one hrHPV. Seven patients were infected by only one type of hrHPV, and four had been infected by several HPV subtypes. No HPV 16 was found in any of these patients and HPV 18 was found in only one. Eighty-nine percent of the observed HPV genotypes were different hrHPV genotypes.

Oral HPV. We found HPV 58 in an oral sample from only one P-HIV who had the same HPV in the cervix. The patient refused to have an anal sampling.

Anal HPV

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Thirty-two patients (73%) accepted an anal smear (14 P-HIV and 18 NP-HIV). Twenty-one patients (8 P-HIV and 13 NP-HIV) (65%) were infected with at least one HPV of which 19 were hrHPV (59%).

Six were infected by a single type of hrHPV and 13 co-infected by several HPV subtypes of which

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44 were hrHPV. In two patients HPV 16 and 18 were found (one patient in the group P-HIV for HPV 16 and one patient among the NP-HIV for HPV 16 and 18). Eighty four percent of the

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observed HPV genotype were other hrHPVs than 16-18.

Eight patients were concomitantly HPV infected in the cervix , with 7 presenting at least one of the

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same genotypes as in the cervix.

The HPV distribution in the various sampling sites is illustrated in figure 1 and 2.

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Risk factors of cytology anomalies and HPV infection. Using an univariate logistics regression, we found that the following were risk factors for

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pathological cervical cytology: a viral load higher than 20 copies/ml (p<0.05), CD4 levels lower than 350/mm³ (p< 0.01), a CD4/CD8 ratio lower than 0.5 (p<0.01), a history of pathological

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cervical cytology or histology (p<0.01), cervical- and anal infection by HPV (p<0.05). The following were found to be risk factors for a cervical HPV infection: CD4 levels lower than 350/mm³ (p<0.05), a history of condylomata (genital warts) (p<0.05), a history of pathological cytology (p<0.01), a co-infection by anal HPV (p<0.01). The only risk factor that remained using a multivariate analysis was a history of pathological cytology.

Cervical cytology and HPV in relation to vaccination.

Twelve patients out of 22 within the P-HIV group had been vaccinated using a quadrivalent vaccine at a median age of 16 years and one in the NP-HIV group had been vaccinated using the bivalent vaccine. None of the vaccinated women were infected with the genotypes included in these two vaccines. However, six out of 13 were infected with hrHPV other than 6, 11, 16 and 18, and two of these patients presented high grade cervical dysplasia. Respectively 11 and 21 women were HPV infected at the cervical or anal site. Therefore, using a conservative approach, we observed that respectively 5/11 (45%, cervical site) women and 3/21 (14%, anal site) would be protected by the 9-valent vaccine. Whereas, with an optimistic approach, we observed that 9/11 (82% cervical site) and 12/21 (57%, anal) women would be protected.

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4. Comment

In this study, more than one fourth of the HIV patients suffered from a cervical pathology and one third had a hrHPV infection, although no differences were observed between perinatally and non-

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perinatally HIV infected women.

These results are comparable to some other studies reporting similar rates of abnormal cytology

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and HPV infection [15], although other studies reported rates that were twice higher [16]. This may be due to the younger age and to differences of genotypes (hrHPV 16/18/52/59 were the most frequent genotypes found) (16).

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We observed and confirmed in this study, that when an HPV was found, it was in most cases an HPV genotype other than 16 or 18, [6]. This may be due to the fact that HPV genotype distribution

Saharian Africa.

from sub-

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differs according to geographical origins and that our patients originated mostly

Our data differ therefore from a meta-analysis, which reported that HPV 16 was the more

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prevalent genotype even if underrepresented in HIV infected women as compared to uninfected ones [17]. We observed that 59 % of the women who were tested carried anal hrHPV and these

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results are comparable to those observed by Heard et al, [18]. Unfortunately in our study, we did not assess anal cytology. Palefsky et al detected HPV DNA in the anal samples of 76% of the HIV-positive women and 42% of the HIV-negative ones. A low count of lymphocytes T-CD4+ (< 200 cells/mm3) and a concomitant HPV cervical infection were identified as risk factors for anal HPV [19]. Similarly, we also found an association between a past or present pathological cervical smear or the presence of cervical HPV and the presence of anal HPV. In seven patients, we observed concomitant cervical and anal infections by the same HPV genotypes, confirming the results of Hessol et al (2013) who reported that HIV-infected women were more likely to have the same HPV genotype in the anus and cervix than were HIV-uninfected women [20].

We found oral HPV in only one P-HIV with the same genotype in the cervix which is in accordance with Moscicki et al who also found a very low prevalence of oral HPV (2%) in a series of P-HIV patients aged 15-18 years and no association between oral HPV and sexual activity. [21]. On the other hand, two other publications reported a higher prevalence of oral HPV (11% and 19%) in P-HIV women [16, 22]. Discrepancies between sampling techniques might account for these differences in prevalence rates. None of the vaccinated women were infected by the HPV genotype included in the bi- or quadrivalent vaccines. Most cervical or anal HPV genotypes that we found are included in the 9valent vaccine. This study is hampered by several limitations. First, the small number of patients reduces our

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power to detect differences. Secondly, it was not possible to match patients for other confounding factors such as cervical cytology results, smoking status, or hormonal contraception. On the other hand, one strength of this study is that there are few data published on HPV infection in perinatally infected women and we could provide results not only on cervical but also on anal and oral

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infections.

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5. Conclusion

In this small series of women using cART and with adequate immunity, we did not observe a difference in prevalence of cervical dysplasia, HPV oral, anal or cervical infection in relation to

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the route of HIV acquisition. However, the high prevalence of HPV infection other than 16 and 18

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supports the use of 9-valent vaccination.

Declaration of interests

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Acknowledgements

This study was supported by the King Baudouin Foundation, Iris Grant which was not involved in the collection, analysis and interpretation of data and in the writing of the manuscript.

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Papillomavirus– Associated Cancer Precursors in a Contemporary Cohort of Asymptomatic HIVInfected Women. Clin Infect Dis. 2015; 60: 1559-68. 19. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and Risk Factors for Anal Human Papillomavirus Infection in Human Immunodeficiency Virus (HIV)– Positive and High‐Risk HIV‐Negative Women. J Infect Dis 2001; 183: 383–91. 20.Hessol NA, Holly EA, Efird JT, Minkoff H, Weber KM, Darragh TM, Burk RD, Strickler HD, Greenblatt RM, Palefsky JM. Concomitant anal and cervical human papillomavirus infections and intraepithelial neoplasia in HIV-infected and uninfected women. AIDS 2013; 27: 1743-51.

21 Moscicki A-B, Farhat S, Yao T-J, Ryder MI, Russell JS, Van Dyke RB, et al. Oral Human Papillomavirus in Youth From the Pediatric HIV/AIDS Cohort Study: Sex Transm Dis 2016; 43: 498–500. 22. Kahn JA, Rudy BJ, Xu J, Secord EA, Kapogiannis BG, Thornton S, et al. Behavioral, Immunologic, and Virologic Correlates of Oral Human Papillomavirus Infection in HIV-Infected

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Figure captions

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Figure 1: HPV genotype distribution in PHIV and NP HIV Cervical samples

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Figure 2: HPV genotype distribution in PHIV and NP HIV Anal samples

Table Table 1: Demographic characteristics of perinatally acquired HIV (PHIV ) and non-perinatally acquired HIV (NPHIV) patients

Global population (n=44)

PHIV (n=22)

NPHIV (n=22)

p 0.106‡

Age

Median (IQR)

28 (24 – 30)

26 (23 – 29)

29 (25 – 32)

Origin

Europe Sub-Saharan Africa North Africa Other

3 (7%) 38 (86%) 1 (2%) 2 (5%)

1 (5%) 18 (82%) 1 (5%) 2 (9%)

2 (9%) 20 (91%) 0 (0%) 0 (0%)

Years living in Belgium

Median (IQR)

15 (4 – 21)

20 (17 – 23)

4 (2 – 7)

< 0.001*

2 (5%) 8 (18%) 21 (48%) 13 (30%)

0 (0%) 0 (0%) 11 (50%) 11 (50%)

2 (9%) 8 (36%) 10 (45%) 2 (9%)

0.001§*

Level of instruction

Not scholared Elementary school Primary school High School/ University

In need of financial support

Yes No

21 (48%) 23 (52%)

6 (27%) 16 (73%)

15 (68%) 7 (32%)

0.015†*

Employment

Yes No

13 (30%) 31 (70%)

9 (41%) 13 (59%)

4 (18%) 18 (82%)

0.185†

Tobacco Use

No Yes past

31 (70%) 10 (23%) 3 (7%)

12 (54%) 7 (32%) 3 (14%)

19 (86%) 3 (14%) 0 (0%)

0.045§*

Median (IQR)

17 (15 – 18)

17 (16 – 18)

16 (14 – 18)

0.114‡

< 14 15 – 19 ≥ 20

7 (16%) 31 (70%) 6 (14%)

1 (5%) 17 (77%) 4 (18%)

6 (27%) 14 (64%) 2 (9%)

0.104§

Median (IQR)

4 (3 – 10)

4 (3 – 5)

6 (3 – 13)

0.050‡*

25 (57%) 7 (16%) 6 (14%) 6 (14%)

16 (73%) 3 (14%) 2 (9%) 1 (5%)

9 (41%) 4 (18%) 4 (18%) 5 (23%)

0.143§

Number of sexual partners

1–4 5–9 10 – 15 > 15

Condom use

never sometimes always

13 (30%) 19 (43%) 12 (27%)

7 (32%) 8 (36%) 7 (32%)

6 (27%) 11 (50%) 5 (23%)

0.643§

Contraceptive method

none Condom Oral Contraceptive Implant IUD Tubal ligature

18 (41%) 3 (7%) 11 (25%) 1 (2%) 10 (23%) 1 (2%)

5 (23%) 2 (9%) 9 (41%) 0 (0%) 5 (23%) 1 (5%)

13 (39%) 1 (5%) 2 (9%) 1 (5%) 5 (23%) 0 (0%)

0.031†* 1.000† 0.034†* 1.000† 1.000† 1.000†

Nulligest

16 (36%)

14 (64%)

2 (9%)

0.001†*

Nulliparous Primi/multiparous

23 (52%) 21 (48%)

16 (73%) 6 (27%)

7 (32%) 15 (68%)

0.015†* 0.015†*

≥ 1 abortion

12 (27%)

3 (14%)

9 (41%)

0.044†*

C. trachomatis Herpes Hepatitis B Condyloma

5 (11%) 4 (9%) 13 (30%) 5 (11%)

4 (18%) 1 (5%) 5 (23%) 2 (0,9%)

1 (5%) 3 (14%) 8 (36%) 3 (14%)

0.345† 0.607† 0.510†

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Past history of STD other than HPV

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Parity

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Age at first intercourse (years)

0.329§

Table 2 History of HIV infection in perinatally acquired HIV (PHIV) and non-perinatally HIV (NPHIV) patients.

Median (IQR)

Global population PVIH (n=44) (n=22) 18 ans (7 – 24) 7 ans (4 – 11)

24 ans (21 – 27)

0.001‡*

0 – 9 years 10 – 19 years 20 – 29 years 30 – 39 years

13 (30%) 12 (27%) 14 (32%) 5 (11%)

13 (59%) 8 (36%) 1 (5%) 0 (0%)

0 (0%) 4 (18%) 13 (59%) 5 (23%)

0.001§*

Yes

20 (45%)

15 (68%)

5 (23%)

0.006†*

Yes

6 (14%)

5 (23%)

1 (5%)

0.185†

Yes

38 (86%)

21 (95%)

17 (77%)

0.185†

Median (IQR)

2 years (1 – 5)

4 years (2 – 7)

1 year (0 – 3)

0.002‡*

Median (IQR)

19 050 (50 – 119 250)

17 900 (50 – 108 250)

20 400 (253 – 136 000)

0.778‡

Nadir of lymphocytes CD4 (cells/mm3)

Median (IQR)

301 (170 – 504)

280 (159 – 522)

402 (190 – 474)

0.690‡

Current CD4/CD8 ratio

Median (IQR)

0,70 (0,50 – 1)

0,65 (0,43 – 1)

0,8 (0,6 – 1,10)

0.247‡

Current Viral load

Undetectable

28 (64%)

14 (64%)

14 (64%)

1.000†

Median (IQR)

500 (380 – 850)

470 (366 – 858)

539 (441 – 839)

0.589 ‡

< 200 200 – 350 350 – 500 > 500

5 (11%) 5 (11%) 12 (28%) 22 (50%)

3 (14%) 2 (9%) 7 (32%) 10 (45%)

2 (9%) 3 (14%) 5 (23%) 12 (55%)

0.822§

re

Current lymphocytes CD4 (cells/ mm3)

Jo

ur

na

lP

† Fisher exact test ; ‡ Mann-Whitney test; §Pearson Khi2 *p<0.05 NPHIV : non perinatally acquired HIV , PHIV : perinatally acquired HIV Current : at time of cervical, anal and oral sampling for the study Undetectable viral load: <50 cp/ml

P

ro of

Previous treatment discontinuation Previous AIDS event Undetectable viral load at least once Cumulative time of undetectable viral load Maximal viral load (copies/mL)

-p

Age at time of diagnostic

NPVIH (n=22)