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Cervical and oral human papillomavirus infection in women living with human immunodeficiency virus (HIV) and matched HIV-negative controls in Brazil

Cervical and oral human papillomavirus infection in women living with human immunodeficiency... Background: Despite the demonstrated role of human Papillomavirus (HPV) in the etiology of cervical cancer and the strong evidence suggesting the importance of HPV in the development of oropharyngeal cancer, several aspects of the interrelationship between HPV infection in both body sites remain unknown, specifically in female human immunodeficiency virus (HIV)-positive (HIV+) patients. We aimed to assess the prevalence, distribution, and concordance of cervical and oral HPV in HIV+ women and matched HIV-negative (HIV-) controls in Brazil. Material and methods: Cervical and endocervical samples for cytological screening and HPV detection and oral samples were collected from 115 HIV+ women using highly active antiretroviral therapy (HAART) and 139 HIV- matched controls (HIV-) in Maringá City, Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding HIV infection were obtained from the patients’ medical records. HPV detection and typing were performed using the Kit Multiplex XGEN Multi HPV Chip HS12. Results: HIV infection was well controlled in this cohort, but women who exhibited detectable HIV loads were significantly associated with HPV-positive status overall (P = 0.03) and in cervical mucosa (P = 0.01). HIV+ women had significantly more abnormal cytological findings (P = 0.04) than HIV- women. Of the 115 HIV+ women, 48.7% were positive for cervical and/or oral HPV DNA; of the 139 HIV- women, 41% were positive for cervical and/or oral HPV (P = 0.25). Both HIV+ and HIV- women had a statistically higher prevalence of cervical HPV infection than oral infection. The concurrent HPV infection in two anatomical sites was similar in HIV+ and HIV- women; however, HPV type concordance was not observed. HPV type distribution was different between the anatomical sites in both groups, and HIV+ women presented less common types, mainly in oral mucosa. (Continued on next page) * Correspondence: melconsolaro@gmail.com Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 2 of 11 (Continued from previous page) Conclusion: Our data support the importance of testing HPV infection in HIV+ women, even when the HIV infection is well controlled. Prospective studies are required to better understand the natural history of HPV infection in both anatomical sites, specifically in HIV+ women. Keywords: HPV, HIV, Oral, Cervical Background only a few studies have addressed concurrent cervical and The association between persistent high-risk human Pap- oral HPV prevalence [24–26]. Despite the demonstrated illomavirus (hrHPV), squamous cervical cancer (CC), and role of HPV in the etiology of CC and the strong evidence some vaginal and anal cancers has been well-established suggesting the importance of HPV in the development of [1–3]. Additionally, recent data demonstrated that HPV is OPC [27–30], several aspects of the interrelationship be- also associated with a subset of head and neck cancers tween oral and cervical infections remain unknown, specif- (HNCs), including a worldwide range ~20–80% of oro- ically in HIV+ female patients. pharyngeal cancers (OPCs) [4, 5]. Individuals living with The present study aimed to assess the prevalence, dis- human immunodeficiency virus (HIV+) are more suscep- tribution, and concordance of cervical and oral HPV in tible to infection, less likely to clear the virus and have a HIV+ women and matched HIV- controls in the south- higher risk of HPV-related cancers than HIV-negative ern region of Brazil, a geographic area with a high inci- (HIV-) individuals [6, 7]. Although the incidence of overall dence of HIV and CC. cancer has decreased in HIV+ individuals with the advent of highly active antiretroviral therapy (HAART), HPV- Methods related CC risk is higher among HIV+ individuals [8, 9]. Study population Moreover, in HIV+ women, CC tends to respond poorly Participants included 115 HIV+ women receiving to recommended therapies, becomes more aggressive, and HAART and 139 HIV- aged 19 to 66 years who attended may have a worse prognosis [6]. With the increase in sur- the Specialized Assistance Service (SAE) for sexually vival of HIV+ women due to HAART, progression of transmitted diseases (STD/AIDS in Maringá, southern oncogenic viral infection into malignancy may result in an Brazil) from September 2017 to May 2018. Women with increased incidence of HPV-associated oropharyngeal, the following characteristics were included in this study: genital, and anal cancers [8–10]. women with confirmed HIV/AIDS diagnosis using two Currently, the HIV/acquired immunodeficiency syn- different methods were included in the HIV+ group and drome (AIDS) pandemic impacts the poorest and the youn- women with two HIV/AIDS negative results using two gest in low-resource settings [11]. HIV+ young women are different methods were included in the HIV- group. key populations at high risk for developing HPV-related Exclusion criteria include: women with previous hyster- cancers, particularly in low- and middle-income countries ectomy, pregnant, younger than 19 years, and women such as Brazil [12, 13]. With the recent approval of the 9- with no history of sexual intercourse. valent HPV vaccine, the risks of persistent HPV infection Of the 778 HIV+ women enrolled in the SAE, 324 and HPV-related cervical precancerous lesions and malig- were eligible for the study. The sample size was calcu- nancies are expected to decrease significantly [14]. With lated with a HPV cervical prevalence of 50% in HIV+ the appropriate vaccination rate thresholds, this vaccine women [19], a 95% confidence interval (CI), and an error provides a logical rationale for increasing screening inter- estimate of 5%. With an increase of 10% for possible vals considering the anticipated decrease in the burden of participant losses, the total sample size was fixed at 138 disease [15]. Therefore, understanding the specific preva- randomly selected women. SAE also provides other ser- lence, distribution and concordance of cervical and oral vices and HIV screening. Therefore, to obtain a compar- HPV in at-risk women in specific geographic locations will able sample, 138 matched controls from the list of provide further insight into the effectiveness of this new patients served by the SAE were identified. The controls vaccine against oral HPV infection, which has not been were matched by age. Written informed consent was proven yet. Considering the high burden of HPV-related obtained from 254 women, and based on their HIV ser- cancers among HIV+ women and the possible effectiveness ology status, participants were assigned to the HIV+ of a 9-valent HPV vaccine [16], it is critical to understand (n = 115) or HIV- group (n = 139). Participants were the prevalence and types of HPV infections in oral and cer- interviewed using a standardized questionnaire to obtain vical mucosa in HIV+ women (and matched controls). demographic information (e.g., age, educational attain- However, while several studies on HIV+ women have re- ment, household income, race/ethnicity); tobacco and al- ported cervical, oral, or anal HPV type distribution [17–23], cohol use/abuse; obstetric and gynecologic history (e.g., Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 3 of 11 Table 1 Characteristics of the study population with paired cervical and oral samples, stratified by human immunodeficiency virus (HIV) status HIV+ N = 115 HIV- N = 139 OR (CI) P N (%) N (%) Age cohort (years) Mean 42.17 41.4 0.8 0.4 18–30 16 (13.9) 31 (22.3) 1 31–40 36 (31.3) 37 (26.6) 1.93 (0.88–4.08) 0.09 > 40 63 (54.8) 71 (51.1) 1.72 (0.84–3.36) 0.12 School education (years) < 8 45 (39.1) 26 (18.7) 2.79 (1.55–5.00) 0.0003 ≥ 8 70 (60.9) 113 (81.3) 1 – Marital status Married 53 (46.1) 68 (48.9) 1 Unmarried 45 (39.1) 66 (47.5) 1.14 (0.67–1.95) 0.69 Widowed 17 (14.8) 5 (3.6) 0.22 (0.08–0.61) 0.004 Skin color White 48 (41.7) 81 (58.2) 1 Not white 67 (58.2) 58 (41.7) 1.94 (1.17–3.24) 0.009 Menarche (years) < 13 56 (48.7) 78 (56.1) 1 ≥ 13 59 (51.3) 61 (43.9) 1.34 (0.80–2.18) 0.25 Age of sexual debut (years) < 18 79 (68.7) 78 (56.1) 1.71 (1.02–2.89) 0.04 ≥ 18 36 (31.3) 61 (43.9) 1 Sexual partners (number) 1 6 (5.2) 24 (17.3) 1 2–7 77 (66.9) 82 (59) 3.75 (1.43–9.28) 0.004 > 7 32 (27.9) 33 (23.7) 3.87 (1.36–10.68) 0.007 Parity (number) 0 3 (2.6) 26 (18.7) 1 1–2 59 (51.3) 77 (55.4) 6.64 (2.14–21.50) 0.0006 ≥ 3 53 (46.1) 36 (25.9) 12.76 (3.84–41.68) < 0.0001 History of cytology in the past three years Yes 42 (36.5) 73 (52.5) 1 No 73(63.5) 66 (47.5) 1.92 (1.15–3.20) 0.01 Hormonal contraceptive use Yes 20 (17.4) 37 (26.6) 1 No 95 (82.6) 102 (73.4) 1.72 (0.93–3.19) 0.08 Gynecologic infections Yes 30 (26.1) 29 (20.8) 1 No 85 (73.9) 110 (79.1) 1.33 (0.74–2.40) 0.37 Cigarette smoking Yes 30 (26.1) 32 (23) 1 No 56 (48.7) 85 (61.1) 1.2 0.3 Ex-smoker 29 (25.2) 22 (15.8) 0.6 0.1 Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 4 of 11 Table 1 Characteristics of the study population with paired cervical and oral samples, stratified by human immunodeficiency virus (HIV) status (Continued) HIV+ N = 115 HIV- N = 139 OR (CI) P N (%) N (%) HIV diagnosis (years) < 5 73 (63.5) –– – -10 42 (36.5) –– – > 10 0 (0) –– – HAART compliance Yes 93 (80.9) –– – No 22 (19.1) –– – Current CD4 (cells/mm ) < 200 3 (2.6) –– – 200–350 17 (14.8) –– – > 350 95 (82.6) –– – Most recent viral load Undetectable 99 (86.1) –– – Detectable 16 (13.9) –– – HAART, highly active antiretroviral therapy; OR = Odds ratio; CI = confidence interval age at menarche, contraceptive use, number of pregnan- The multiplex detected the following 36 HPV types: 18 cies); CC screening, and sexual behaviors (e.g., age at hrHPV (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, first intercourse, number of sexual partners). Data re- 59, 66, 68, 73 e 82) and 18 low-risk HPV (lrHPV) (6, 11, garding HIV infection and adherence to HAART were 40, 42, 43, 44, 54, 55, 61, 62, 67, 69, 70, 71, 72, 81, 84 e obtained from SAE medical records. 89). An additional HPV universal probe was used to de- tect other, non-specified types of HPV. Samples with in- Sample collection valid outcomes were retested, and the second result was Nursing staff contacted all women, administered the considered definitive. Women were considered positive questionnaire, and collected the cervical and oropharyn- for oropharyngeal HPV if one of the samples, oral and/ geal samples. Ecto−/endocervical samples were collected or scraping, was positive for HPV. Furthermore, women using an Ayre’s spatula and cytobrush for cervical cy- were considered negative for oropharyngeal HPV if their tology and polymerase chain reaction (PCR) for HPV; oral and scraping samples were negative for HPV. the samples for HPV testing were stored in ThinPrep® Pap Test solution. The conventional cytological smears Statistical analysis were sent to the Clinical Cytology Laboratory at State Statistical analyses were performed using the Graph- University of Maringá (UEM) and were graded according Pad Prism 6.0 (San Diego, California, USA) software. to the Bethesda System [31]. All variables were expressed as absolute and relative Full-mouth oral/oropharyngeal scraping, including the frequencies. For univariate analysis (unadjusted odds cheeks, tongue, palate, tonsils, and oropharynx, was per- ratios [ORs]), categorical variables were compared formed using a sterile brush with soft bristles; samples with HPV infection using the chi-squared and Fisher’s were stored in ThinPrep® Pap Test solution. Moreover, a exact test. Crude ORs and 95% confidence intervals gargle sample was obtained by having the participant (CIs) were calculated. A P-value < 0.05 was considered gargle with 10 mL of 0.9% sterile saline for a total of 30 s significant. (10s, rinse; 5 s, gargle; 10s rinse; 5 s, gargle), collected in a sterile cup and stored at − 4°C [20, 32]. All oral/oro- pharyngeal samples will be referred as “oral samples.” Results A total of 254 (115 HIV+ and 139 HIV-) women were in- HPV DNA testing cluded in the study, with all 254 cervical and 508 oral Detection and typing of HPV were performed using the samples (oral scraping and gargle) having sufficient DNA Kit Multiplex XGEN MULTI HPV CHIP HS12 (Mobius for HPV assessment. All 254 (100%) participants had con- Life Science), following the manufacturer’s instructions. clusive HPV test results from both anatomical sites. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 5 of 11 Demographic and clinical characteristics of the two Table 2 Prevalence of human papillomavirus (HPV) status in the cervical and oral mucosa of human immunodeficiency virus groups of patients are presented in Table 1. The median (HIV)-positive and HIV-negative women age was 42.17 ± 10.18 years old for HIV+ women and Cervical Oral N P-value comparing cervical and oral 41.4 ± 12.31 years old for HIV- women. Compared to N (%) (%) HPV prevalence HIV- women, HIV+ women were significantly more HIV + (n = 115) likely to have less than 8 years of schooling (P = 0.0003), Overall non-white skin color (P = 0.009), their first sexual inter- course at < 18 years old (P = 0.04), more than two sexual Positive 51 (44.4) 17 < 0.0001 (14.8) partners (P = 0.004 for 2–7 partners and P = 0.007 for > 7 partners), and a higher number of parities (P = 0.0006 64 (55.6) 98 Negative (85.2) for 1–2 parities and P 0.0001 for ≥3 parities), and were High-Risk HPV less likely to report screening for CC within the past three years (P = 0.01). HIV- women were, however, more Positive 23 (20.0) 7 (6.1) 0.0028 likely to be a widowed (P = 0.004). 92 (80.0) 108 Most HIV+ women presented excellent control of the Negative (94.0) HIV infection based on their compliance with HAART Low-Risk HPV (80.9%), preserved CD4+ T lymphocyte count (82.6% Positive 37 (32.2) 9 (7.8) < 0.0001 with > 350 cells/mm ), and suppressed current viral 78 (67.8) 106 loads (86.1% undetectable). Additionally, most of the Negative (92.2) HIV+ women had had documented HIV infections for < Universal HPV 5 years (63.5%) (Table 1). Positive 17 (14.8) 7 (6.1) 0.028 Cytology showed no signs of malignancy in most 98 (85.2) 108 women from both groups. Overall, 13.0% of HIV+ women Negative (93.9) and 5.0% of HIV- women presented abnormal cytological Multiple types Infections findings (P = 0.04). Atypical squamous cells of undeter- 28 (24.3) 5 (4.4) < 0.0001 mined significance (ASC-US) were observed in 2.6% of Positive HIV+ women and in 1.4% of HIV- women (P =0.66); low- 87 (75.7) 110 grade squamous intraepithelial lesions (LSIL) were ob- Negative (95.6) served in 7.8% of HIV+ women and in 2.8% of HIV- HIV - (n = 139) women (P = 0.15); high-grade squamous intraepithelial le- Overall sions (HSIL) were observed in 2.6% of HIV+ women and 0.8% of HIV- women (P =0.33). Positive 52 (37.4) 13 < 0.0001 (9.4) Overall, 56 (48.7%) of the 115 HIV+ women were positive 87 (62.6) 126 for cervical and/or oral HPV DNA, while 57 (41%) of the Negative (90.6) 139 HIV- women were positive for cervical and/or oral HPV High-Risk HPV (P = 0.25). Both HIV+ and HIV- women had a statistically higher prevalence of cervical HPV infection than oral infec- Positive 33 (23.7) 5 (3.6) < 0.0001 tion, including higher rates of hrHPV, lrHPV, universal HPV, 106 (76.3) 134 Negative (96.4) and infection by multiple HPV types in cervical samples compared to oral ones, as shown in Table 2. Low-Risk HPV HPV DNA was detected in oral samples from 17 Positive 29 (20.9) 5 (3.6) < 0.0001 (14.8%) HIV+ women and 13 (9.4%) HIV- women (P = 110 (79.1) 134 0.24) (Table 3). Multiple HPV infections were detected Negative (96.4) in five samples (4.4%) from HIV+ women and in four Universal HPV samples (2.9%) from HIV- women (Table 2). Statistical Positive 22 (15.8) 4 (2.9) 0.0003 analysis did not reveal an association between HIV+ sta- 117 (84.2) 135 tus and the presence of HPV DNA in the oral mucosa Negative (97.1) (P = 0.83). Multiple types infections Fifty-one (44.3%) HIV+ women and 52 (37.4%) HIV- Positive 29 (20.9) 4 (2.9) women had HPV-positive cervical samples (P =0.48) 110 (79.1) 135 < 0.0001 (Table 3). Multiple HPV types were detected in 28 (24.3%) Negative (97.1) of HIV+ and in 29 (20.9%) of HIV- patients (Table 2). There was no significant difference between the HIV+ and HIV- women with regard to HPV types. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 6 of 11 To better understand the association between cervical and abnormal cytological findings than HIV- women. HPV oral HPV infection, the prevalence of concurrent HPV infec- type distribution was different between the anatomical tion in this population was investigated. Eight (7.0%) HIV+ sites within both groups, and HIV+ women commonly women and 7 (5.0%) HIV- women had concurrent HPV in- presented with narrower HPV type distributions, mainly fection in their cervical and oral samples (P =0.6) (Table 3). in the oral mucosa. Finally, the frequency of concurrent Concordance between HPV types in the cervical and oral HPV infection in both sites was low, and HPV type con- samples was not observed in either group. cordance was not observed. In the HIV+ group, the most frequent cervical hrHPV Our results showed that the prevalence of cervical types observed were HPV18, HPV45, and HPV58 (14.8% HPV infection was 44.3% in HIV+ women and 37.4% in each). In the oral site, the most prevalent hrHPV was HIV- women. Studies across different populations HPV39 (33.3%) followed by HPV18, HPV45, HPV52, present varying rates of HPV infection: 45–97.1% in and HPV68 (16.6% each). The most prevalent cervical HIV+ women and 44.9–86.5% in HIV- women in the lrHPV found in this group was HPV6 (17.5%), followed cervical site [20, 24, 25, 33]. The high prevalence of HPV by HPV61 (12.5%), and in oral mucosa, the most preva- in HIV-negative women in this study can be explained, lent lrHPV was also HPV6 (28.6%), followed by HPV62 at least in part, by the fact they were recruited from a and HPV81 (21.4%) (Fig. 1). Specialized Assistance Service (SAE) for sexually trans- In the HIV- group, the most prevalent hrHPV in mitted diseases, and were therefore at higher risk for the cervical mucosa was HPV18 (14.2%), followed by sexually transmitted infections, including HPV. Add- HPV16 and HPV68 (11.9% each). In the oral site, itionally, the rates of oral HPV infection in HIV+ women HPV51 and HPV66 were the most prevalent hrHPV and HIV- control were 14.8 and 9.4%, respectively. (33.3% each). The most prevalent lrHPVs in the Other studies have shown that the prevalence of HPV cervical site were HPV81 (29.0%) and HPV54 and infection in the oral site can vary significantly (12–68.5% HPV70 (16.1% each), and the most prevalent lrHPV in HIV+ women and 2–31.4% in HIV- women) [20, 24, in the oral site was HPV6 (30.0%), followed by 33]. HPV43 (20%) (Fig. 2). Although HIV infections were well controlled and cy- HIV+ women with recent detectable HIV loads were tology results showed no malignancies, abnormal cyto- significantly associated with HPV-positive status overall logical findings were significantly higher in HIV+ (OR = 3.75; CI = 1.22–11.10; P = 0.03) and in cervical women than in HIV- women. These data are consistent mucosa (OR = 4.61; CI = 1.50–13.66; P = 0.01) (Table 4). with the results of the previous studies showing that When the characteristics of the HIV+ women were an- HIV+ women are less likely to eliminate the virus, have alyzed in relation to HPV status, only current smoking subsequent persistent hrHPV infections and have higher was associated with overall (OR = 3.80; CI = 1.22–10.42; risk of developing precancerous lesions and malignan- P = 0.01) and cervical HPV-positive status (OR = 3.94; cies, even with the appropriate use of antiretroviral ther- CI = 1.31–11.76; P = 0.01 for both), as shown in Table 5. apy, than HIV- women [8, 9, 19, 34, 35]. Our results demonstrated no significant difference in Discussion HPV detection in the uterine cervix or oral mucosa be- In the present study, we aimed to determine the HPV tween HIV+ women and HIV- women; however, HPV prevalence, distribution, and type concordance between infection was significantly higher in the cervical mucosa cervical and oral samples of HIV+ women and HIV- than in the oral site in both groups. These findings are matched controls in the southern region of Brazil, a geo- consistent with previous studies suggesting that the nat- graphic area with high incidences of HIV and CC. Our ural history of HPV infection varies by anatomical site, data demonstrated that HIV+ and HIV- women had a and a higher prevalence of HPV infection is observed in similar and high HPV prevalence in cervical and in oral the cervical mucosa than in the oral mucosa in HIV+ sites. However, HIV+ women had higher prevalence of women [36–38]. This can be explained, at least in part, Table 3 Detection of human papillomavirus (HPV) infection in the oral mucosa and uterine cervix of human immunodeficiency virus (HIV) + and HIV- women HIV+ (N = 115) HIV- (N = 139) P N (%) N (%) Oral mucosa 17 (14.8) 13 (9.4) 0.24 Uterine cervix 51 (44.3) 52 (37.4) 0.48 Positive samples from oral mucosa of patients with infected uterine cervix 8 (7.0) 7 (5.0) 0.6 Positive samples from oral mucosa of patients with uninfected uterine cervix 3 (2.6) 5 (3.6) 0.73 Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 7 of 11 Fig. 1 Human Papillomavirus (HPV) type distribution of cervical and oral infections detected in the human immunodeficiency virus-positive group. a High-risk HPV type distribution. b Low-risk HPV type distribution by the evidence that the oral cavity is a hostile environ- significantly higher concentrations of immunoregulatory ment for the establishment of infectious agents due to factors that were related to the adaptive and cell- the presence of both mechanical and molecular mecha- mediated immune response than the cervix, which may nisms related to digestion [39]. More specifically, Fakhry in part explain the significantly lower burden of sexually et al. [39] conducted a study that directly compared the transmitted infections such as Chlamydia trachomatis, local immunologic profiles of the oral cavities and cervi- HPV, and HIV-1 in the oral cavity than in the cervix. ces of healthy women using paired secretion specimens. According to the authors, these findings provide add- This study showed that the oral cavity contained itional information to better understand the differences Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 8 of 11 important to reduce the risk of developing HPV-related cancers, specifically in the HIV+ population. Unlike the distribution of HPV types in cervical sam- ples, HPV type concordance between the HIV+ and HIV- groups was not observed in oral samples. hrHPV39 was the most common hrHPV detected in oral samples of HIV+ women, followed by hrHPV18, hrHPV45, hrHPV52, and hrHPV68, with these types being also fre- quently found in cervical samples in the same group. However, in HIV- women, the oral hrHPV types ob- served were totally different, with hrHPV51 and hrHPV66 being the most frequently detected hrHPV. Current evidence has shown that hrHPV16 and hrHPV18 contribute to the majority (approximately 85%) of HNC cases worldwide, while the remaining can- cers are caused by hrHPV33, hrHPV35, hrHPV52, hrHPV45, hrHPV39, and hrHPV58 [41, 42]. Examination of concurrent HPV infections in different anatomical sites has been limited. Hence, we concur- rently investigated the prevalence of HPV infection and HPV type distribution in cervical and oral sites to better understand their clinical significance. Simultaneous HPV cervical and oral infection was low in both HIV+ and HIV- women. Moreover, HPV type concordance was not observed, a finding consistent with previous studies [20, 24]. Taken together, these observations suggest that vari- ous HPV types are more likely to occur in a different anatomical sites, and/or that the two anatomical sites can clear certain HPV types or distinct exposures, while allowing other HPV types to cause persistent oral and cervical HPV infections. Fig. 2 Human Papillomavirus (HPV) type distribution of cervical and Prior investigations have demonstrated that engagement oral infections detected in the human immunodeficiency virus- in some high-risk behaviors may facilitate HPV infection negative group. a High-risk HPV type distribution. b Low-risk HPV type distribution and act as a cofactor for viral persistence, contributing to cancer progression in the oral and cervical mucosa. In the in the etiology and natural history of pathogenic agents present study, we found that current smoking was associ- that are capable of colonizing both the oral cavity and ated with overall and cervical HPV infection in HIV+ female reproductive tract. women. Several studies have already demonstrated that The most prevalent HPV types in the cervical samples smoking status acts as a predictor and cofactor in cervical from both HIV+ and HIV- women were hrHPV18 and HPV infection, which is possibly due to the alteration of hrHPV58; however, hrHPV45 and hrHPV16 were fre- the mucosa cells, making them more susceptible to infec- quently detected in HIV+ women and HIV- women, re- tion, changing the immune mediators, causing DNA dam- spectively. Prevalence studies around the world have age, and promoting the integration of HPV DNA into the shown that hrHPV types 16, 18, 31, 33, 35, 52, and 58 host genome [42–45]. are the most commonly detected hrHPVs in CC, with hrHPV16 being the most common in all populations, Conclusion and future perspectives with the exception of HIV+ people [1]. Data have con- Our study demonstrated that HIV+ and HIV- women in sistently shown that HIV+ women are frequently more southern Brazil had high HPV prevalence in cervical and infected with other hrHPV types than hrHPV16 and oral sites. In this population, HIV+ women had more ab- hrHPV18, such as hrHPV52 and hrHPV58 [40]. The normal cytological findings than HIV- women. This high prevalence of non-vaccine hrHPV types of 2-valent study provides important epidemiological data about the and 4-valent vaccines in the cervical and oral mucosa potential risk of developing CC. Furthermore, the high found in our study suggests that the 9-valent HPV vac- prevalence of non-vaccine hrHPV types of the 2-valent cine is significantly required, which is considered and 4-valent vaccines in the cervical and oral mucosa of Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 9 of 11 Table 4 Prevalence of cervical and oral HPV infection according to the HIV-related parameters Variables HPV+ OR (CI) P Cervical HPV+ OR (CI) P Oral HPV+ (N = 11) OR (CI) P (N = 56) (N = 51) N (%) N (%) N (%) Documented HIV infection (years) < 5 39/73 (53.4) 1.68 (0.79–3.60) 0.24 36/73 (49.3) 1.75 (0.81–3.71) 0.18 7/73 (9.6) 1.00 (0.28–3.23) > 0.99 5–10 17/42 (40.5) 1 – 15/42 (35.7) 1 4/42 (9.5) 1 > 10 0/0 (0) –– – – – – – Compliance to HAART Yes 42/93 (45.2) 0.46 (0.18–1.17) 0.15 39/93 (41.9) 0.60 (0.22–1.50) 0.34 9/93 (9.7) 1.07 (0.23–5.25) > 0.99 No 14/22 (66.6) 1 – 12/22 (54.5) 1 2/22 (9.1) 1 Most recent CD4 (cells/mm ) < 200 3/3 (100) –– 3/3 (100) –– 0/3 (0) –– 200–350 9/17 (52.9) 1.30 (0.47–3.78) 0.79 8/17 (47.1) 1.22 (0.41–3.34) 0.79 2/17 (11.8) 1.27 (0.25–6.01) 0.67 > 350 44/95 (46.3) 1 – 40/95 (42.1) 1 9/95 (9.5) 1 Most recent viral load Undetectable 44/99 (44.4) 1 – 39/99 (39.4) 1 11/99 (11.1) 1 – Detectable 12/16 (75.0) 3.75 (1.22–11.10) 0.03 12/16 (75.0) 4.61 (1.50–13.66) 0.01 0/16 (0) – HPV = human papillomavirus, HIV = human immunodeficiency virus, HAART, highly active antiretroviral therapy; OR = Odds ratio; CI = confidence interval Table 5 Possible predictors of cervical and oral human papillomavirus (HPV) infection, stratified by HPV status in human immunodeficiency virus (HIV)-positive women Predictors of HPV HPV+ (N = 56) OR (CI) P Cervical HPV+ (N = 51) OR (CI) P Oral HPV+ (N = 11) OR (CI) P infection N (%) N (%) N (%) Age (years) 18–29 7/13 (58.4) 1 – 7/13 (58.3) 1 0/13 (0) –– 30–50 35/76 (46.1) 0.60 (0.19–2.01) 0.53 30/76 (39.5) 0.46 (0.15–1.54) 0.34 8/76 (10.5) 1 > 50 14/27 (51.8) 0.76 (0.20–3.02) 0.74 14/27 (51.8) 0.76 (0.19–3.03) 0.74 3/27 (11.1) 1.06 (0.26–4.33) > 0.99 Race White 24/48 (50.0) 0.54 (0.16–1.69) 0.39 22/48 (45.8) 0.46 (0.14–1.45) 0.26 6/48 (12.5) 2.28 (0.25–20.51) 0.66 Brown 21/49 (42.9) 0.40 (0.12–1.26) 0.16 18/49 (36.7) 0.31 (0.09–0.99) 0.05 4/49 (8.2) 1.42 (0.14–13.70) > 0.99 Black 11/17 (64.7) 1 – 11/17 (64.7) 1 1/17 (5.9) 1 Asian 0 (0) –– 0 (0) –– 0 (0) –– Sexual debut (years) < 16 22/45 (48.9) 1 – 21/45 (46.7) 1 4/ (8.9) 1 ≥ 16 34/70 (48.6) 0.98 (0.47–2.06) 1 30/70 (42.9) 1.16 (0.55–2.44) 0.70 7/70 (10.0) 1.14 (0.31–4.13) > 0.99 Smoking status Never smoker 26/56 (46.4) 1.64 (0.62–4.08) 0.35 25/56 (44.6) 2.11 (0.80–5.58) 0.16 3/56 (5.4) 0.49 (0.09–2.60) 0.40 Current smoker 20/30 (66.7) 3.80 (1.22–10.42) 0.01 18/30 (60.0) 3.94 (1.31–11.76) 0.01 5/30 (16.7) 1.73 (0.38–7.02) 0.70 Ex-smoker 10/29 (34.5) 1 – 8/29 (27.6) 1 3/29 (10.3) 1 Lifetime number of sexual partners < 5 25/51 (49.0) 1 – 25/51 (49.0) 1 5/51 (9.8) 1 ≥ 5 31/64 (48.4) 0.97 (0.48–1.98) 1 26/64 (40.6) 0.71 (0.34–1.50) 0.45 6/64 (9.4) 1.19 (0.31–4.46) > 0.99 Use of hormonal Contraceptives Yes 11/20 (55.0) 1 – 9/20 (45.0) 1 2/20 (10.0) 1 No 45/95 (47.4) 0.73 (0.29–1.98) 0.9 42/95 (44.2) 0.96 (0.36–2.55) > 0.99 9/95 (9.5) 0.94 (0.18–4.73) > 0.99 OR = Odds ratio; CI = confidence interval Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 10 of 11 HIV+ and mainly in HIV- women found in our study Received: 10 February 2020 Accepted: 5 May 2020 highlights the importance of the 9-valent vaccine. Con- current HPV infection in both sites was uncommon, and References HPV type concordance was not observed, likely reflect- 1. Biological agents. Volume 100 B. A review of human carcinogens. IARC ing the differences in the risk factors and the natural his- Monogr Eval Carcinog risks to humans. France; 2012;100:1–441. tory of HPV infection at the two anatomical sites. These 2. Stier EA, Baranoski AS. Human papillomavirus-related diseases in HIV- infected individuals. Curr Opin Oncol. 2008;20:541–6. findings confirm the prevalence of HPV infection in 3. Spangle JM, Munger K. The human papillomavirus type 16 E6 oncoprotein HIV+ women. Prospective studies are required to better activates mTORC1 signaling and increases protein synthesis. 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Ortiz AP, Perez-Irizarry J, Soto-Salgado M, Suarez E, Perez N, Cruz M, et al. All the authors contributed to the manuscript. TTS, GMZFD, ED, and MELC Human papillomavirus-related cancers among people living with AIDS in searched the literature and prepared the manuscript. SMP collected the Puerto Rico. Prev Chronic Dis. 2014;11:E80. biological samples from the women. TTS and MELC wrote the manuscript. 11. WHO. Fact sheet on adolescent health. Geneva; 2014. Available from: http:// MELC, WH, RF, VRSS, SMP, LLRAR, MAPS, and ICS participated in the research www.unaids.org/en/media/unaids/contentassets/documents/factsheet/2 design and execution. TTS and ED performed the statistical analysis. GMZFD, 012/20120417_FS_adolescentsyoungpeoplehiv_en.pdf. ED, WH, RAAF, VRSS, SMP, and ICS were involved in revising the manuscript 12. Dellar RC, Dlamini S, Karim QA. Adolescent girls and young women: key to include critically important intellectual content. 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Cervical and oral human papillomavirus infection in women living with human immunodeficiency virus (HIV) and matched HIV-negative controls in Brazil

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Abstract

Background: Despite the demonstrated role of human Papillomavirus (HPV) in the etiology of cervical cancer and the strong evidence suggesting the importance of HPV in the development of oropharyngeal cancer, several aspects of the interrelationship between HPV infection in both body sites remain unknown, specifically in female human immunodeficiency virus (HIV)-positive (HIV+) patients. We aimed to assess the prevalence, distribution, and concordance of cervical and oral HPV in HIV+ women and matched HIV-negative (HIV-) controls in Brazil. Material and methods: Cervical and endocervical samples for cytological screening and HPV detection and oral samples were collected from 115 HIV+ women using highly active antiretroviral therapy (HAART) and 139 HIV- matched controls (HIV-) in Maringá City, Brazil. Risk factors were assessed using a standardized questionnaire, and the data regarding HIV infection were obtained from the patients’ medical records. HPV detection and typing were performed using the Kit Multiplex XGEN Multi HPV Chip HS12. Results: HIV infection was well controlled in this cohort, but women who exhibited detectable HIV loads were significantly associated with HPV-positive status overall (P = 0.03) and in cervical mucosa (P = 0.01). HIV+ women had significantly more abnormal cytological findings (P = 0.04) than HIV- women. Of the 115 HIV+ women, 48.7% were positive for cervical and/or oral HPV DNA; of the 139 HIV- women, 41% were positive for cervical and/or oral HPV (P = 0.25). Both HIV+ and HIV- women had a statistically higher prevalence of cervical HPV infection than oral infection. The concurrent HPV infection in two anatomical sites was similar in HIV+ and HIV- women; however, HPV type concordance was not observed. HPV type distribution was different between the anatomical sites in both groups, and HIV+ women presented less common types, mainly in oral mucosa. (Continued on next page) * Correspondence: melconsolaro@gmail.com Laboratory of Clinical Cytology, Department of Clinical Analysis and Biomedicine, State University of Maringá, Paraná, Brazil Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 2 of 11 (Continued from previous page) Conclusion: Our data support the importance of testing HPV infection in HIV+ women, even when the HIV infection is well controlled. Prospective studies are required to better understand the natural history of HPV infection in both anatomical sites, specifically in HIV+ women. Keywords: HPV, HIV, Oral, Cervical Background only a few studies have addressed concurrent cervical and The association between persistent high-risk human Pap- oral HPV prevalence [24–26]. Despite the demonstrated illomavirus (hrHPV), squamous cervical cancer (CC), and role of HPV in the etiology of CC and the strong evidence some vaginal and anal cancers has been well-established suggesting the importance of HPV in the development of [1–3]. Additionally, recent data demonstrated that HPV is OPC [27–30], several aspects of the interrelationship be- also associated with a subset of head and neck cancers tween oral and cervical infections remain unknown, specif- (HNCs), including a worldwide range ~20–80% of oro- ically in HIV+ female patients. pharyngeal cancers (OPCs) [4, 5]. Individuals living with The present study aimed to assess the prevalence, dis- human immunodeficiency virus (HIV+) are more suscep- tribution, and concordance of cervical and oral HPV in tible to infection, less likely to clear the virus and have a HIV+ women and matched HIV- controls in the south- higher risk of HPV-related cancers than HIV-negative ern region of Brazil, a geographic area with a high inci- (HIV-) individuals [6, 7]. Although the incidence of overall dence of HIV and CC. cancer has decreased in HIV+ individuals with the advent of highly active antiretroviral therapy (HAART), HPV- Methods related CC risk is higher among HIV+ individuals [8, 9]. Study population Moreover, in HIV+ women, CC tends to respond poorly Participants included 115 HIV+ women receiving to recommended therapies, becomes more aggressive, and HAART and 139 HIV- aged 19 to 66 years who attended may have a worse prognosis [6]. With the increase in sur- the Specialized Assistance Service (SAE) for sexually vival of HIV+ women due to HAART, progression of transmitted diseases (STD/AIDS in Maringá, southern oncogenic viral infection into malignancy may result in an Brazil) from September 2017 to May 2018. Women with increased incidence of HPV-associated oropharyngeal, the following characteristics were included in this study: genital, and anal cancers [8–10]. women with confirmed HIV/AIDS diagnosis using two Currently, the HIV/acquired immunodeficiency syn- different methods were included in the HIV+ group and drome (AIDS) pandemic impacts the poorest and the youn- women with two HIV/AIDS negative results using two gest in low-resource settings [11]. HIV+ young women are different methods were included in the HIV- group. key populations at high risk for developing HPV-related Exclusion criteria include: women with previous hyster- cancers, particularly in low- and middle-income countries ectomy, pregnant, younger than 19 years, and women such as Brazil [12, 13]. With the recent approval of the 9- with no history of sexual intercourse. valent HPV vaccine, the risks of persistent HPV infection Of the 778 HIV+ women enrolled in the SAE, 324 and HPV-related cervical precancerous lesions and malig- were eligible for the study. The sample size was calcu- nancies are expected to decrease significantly [14]. With lated with a HPV cervical prevalence of 50% in HIV+ the appropriate vaccination rate thresholds, this vaccine women [19], a 95% confidence interval (CI), and an error provides a logical rationale for increasing screening inter- estimate of 5%. With an increase of 10% for possible vals considering the anticipated decrease in the burden of participant losses, the total sample size was fixed at 138 disease [15]. Therefore, understanding the specific preva- randomly selected women. SAE also provides other ser- lence, distribution and concordance of cervical and oral vices and HIV screening. Therefore, to obtain a compar- HPV in at-risk women in specific geographic locations will able sample, 138 matched controls from the list of provide further insight into the effectiveness of this new patients served by the SAE were identified. The controls vaccine against oral HPV infection, which has not been were matched by age. Written informed consent was proven yet. Considering the high burden of HPV-related obtained from 254 women, and based on their HIV ser- cancers among HIV+ women and the possible effectiveness ology status, participants were assigned to the HIV+ of a 9-valent HPV vaccine [16], it is critical to understand (n = 115) or HIV- group (n = 139). Participants were the prevalence and types of HPV infections in oral and cer- interviewed using a standardized questionnaire to obtain vical mucosa in HIV+ women (and matched controls). demographic information (e.g., age, educational attain- However, while several studies on HIV+ women have re- ment, household income, race/ethnicity); tobacco and al- ported cervical, oral, or anal HPV type distribution [17–23], cohol use/abuse; obstetric and gynecologic history (e.g., Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 3 of 11 Table 1 Characteristics of the study population with paired cervical and oral samples, stratified by human immunodeficiency virus (HIV) status HIV+ N = 115 HIV- N = 139 OR (CI) P N (%) N (%) Age cohort (years) Mean 42.17 41.4 0.8 0.4 18–30 16 (13.9) 31 (22.3) 1 31–40 36 (31.3) 37 (26.6) 1.93 (0.88–4.08) 0.09 > 40 63 (54.8) 71 (51.1) 1.72 (0.84–3.36) 0.12 School education (years) < 8 45 (39.1) 26 (18.7) 2.79 (1.55–5.00) 0.0003 ≥ 8 70 (60.9) 113 (81.3) 1 – Marital status Married 53 (46.1) 68 (48.9) 1 Unmarried 45 (39.1) 66 (47.5) 1.14 (0.67–1.95) 0.69 Widowed 17 (14.8) 5 (3.6) 0.22 (0.08–0.61) 0.004 Skin color White 48 (41.7) 81 (58.2) 1 Not white 67 (58.2) 58 (41.7) 1.94 (1.17–3.24) 0.009 Menarche (years) < 13 56 (48.7) 78 (56.1) 1 ≥ 13 59 (51.3) 61 (43.9) 1.34 (0.80–2.18) 0.25 Age of sexual debut (years) < 18 79 (68.7) 78 (56.1) 1.71 (1.02–2.89) 0.04 ≥ 18 36 (31.3) 61 (43.9) 1 Sexual partners (number) 1 6 (5.2) 24 (17.3) 1 2–7 77 (66.9) 82 (59) 3.75 (1.43–9.28) 0.004 > 7 32 (27.9) 33 (23.7) 3.87 (1.36–10.68) 0.007 Parity (number) 0 3 (2.6) 26 (18.7) 1 1–2 59 (51.3) 77 (55.4) 6.64 (2.14–21.50) 0.0006 ≥ 3 53 (46.1) 36 (25.9) 12.76 (3.84–41.68) < 0.0001 History of cytology in the past three years Yes 42 (36.5) 73 (52.5) 1 No 73(63.5) 66 (47.5) 1.92 (1.15–3.20) 0.01 Hormonal contraceptive use Yes 20 (17.4) 37 (26.6) 1 No 95 (82.6) 102 (73.4) 1.72 (0.93–3.19) 0.08 Gynecologic infections Yes 30 (26.1) 29 (20.8) 1 No 85 (73.9) 110 (79.1) 1.33 (0.74–2.40) 0.37 Cigarette smoking Yes 30 (26.1) 32 (23) 1 No 56 (48.7) 85 (61.1) 1.2 0.3 Ex-smoker 29 (25.2) 22 (15.8) 0.6 0.1 Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 4 of 11 Table 1 Characteristics of the study population with paired cervical and oral samples, stratified by human immunodeficiency virus (HIV) status (Continued) HIV+ N = 115 HIV- N = 139 OR (CI) P N (%) N (%) HIV diagnosis (years) < 5 73 (63.5) –– – -10 42 (36.5) –– – > 10 0 (0) –– – HAART compliance Yes 93 (80.9) –– – No 22 (19.1) –– – Current CD4 (cells/mm ) < 200 3 (2.6) –– – 200–350 17 (14.8) –– – > 350 95 (82.6) –– – Most recent viral load Undetectable 99 (86.1) –– – Detectable 16 (13.9) –– – HAART, highly active antiretroviral therapy; OR = Odds ratio; CI = confidence interval age at menarche, contraceptive use, number of pregnan- The multiplex detected the following 36 HPV types: 18 cies); CC screening, and sexual behaviors (e.g., age at hrHPV (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, first intercourse, number of sexual partners). Data re- 59, 66, 68, 73 e 82) and 18 low-risk HPV (lrHPV) (6, 11, garding HIV infection and adherence to HAART were 40, 42, 43, 44, 54, 55, 61, 62, 67, 69, 70, 71, 72, 81, 84 e obtained from SAE medical records. 89). An additional HPV universal probe was used to de- tect other, non-specified types of HPV. Samples with in- Sample collection valid outcomes were retested, and the second result was Nursing staff contacted all women, administered the considered definitive. Women were considered positive questionnaire, and collected the cervical and oropharyn- for oropharyngeal HPV if one of the samples, oral and/ geal samples. Ecto−/endocervical samples were collected or scraping, was positive for HPV. Furthermore, women using an Ayre’s spatula and cytobrush for cervical cy- were considered negative for oropharyngeal HPV if their tology and polymerase chain reaction (PCR) for HPV; oral and scraping samples were negative for HPV. the samples for HPV testing were stored in ThinPrep® Pap Test solution. The conventional cytological smears Statistical analysis were sent to the Clinical Cytology Laboratory at State Statistical analyses were performed using the Graph- University of Maringá (UEM) and were graded according Pad Prism 6.0 (San Diego, California, USA) software. to the Bethesda System [31]. All variables were expressed as absolute and relative Full-mouth oral/oropharyngeal scraping, including the frequencies. For univariate analysis (unadjusted odds cheeks, tongue, palate, tonsils, and oropharynx, was per- ratios [ORs]), categorical variables were compared formed using a sterile brush with soft bristles; samples with HPV infection using the chi-squared and Fisher’s were stored in ThinPrep® Pap Test solution. Moreover, a exact test. Crude ORs and 95% confidence intervals gargle sample was obtained by having the participant (CIs) were calculated. A P-value < 0.05 was considered gargle with 10 mL of 0.9% sterile saline for a total of 30 s significant. (10s, rinse; 5 s, gargle; 10s rinse; 5 s, gargle), collected in a sterile cup and stored at − 4°C [20, 32]. All oral/oro- pharyngeal samples will be referred as “oral samples.” Results A total of 254 (115 HIV+ and 139 HIV-) women were in- HPV DNA testing cluded in the study, with all 254 cervical and 508 oral Detection and typing of HPV were performed using the samples (oral scraping and gargle) having sufficient DNA Kit Multiplex XGEN MULTI HPV CHIP HS12 (Mobius for HPV assessment. All 254 (100%) participants had con- Life Science), following the manufacturer’s instructions. clusive HPV test results from both anatomical sites. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 5 of 11 Demographic and clinical characteristics of the two Table 2 Prevalence of human papillomavirus (HPV) status in the cervical and oral mucosa of human immunodeficiency virus groups of patients are presented in Table 1. The median (HIV)-positive and HIV-negative women age was 42.17 ± 10.18 years old for HIV+ women and Cervical Oral N P-value comparing cervical and oral 41.4 ± 12.31 years old for HIV- women. Compared to N (%) (%) HPV prevalence HIV- women, HIV+ women were significantly more HIV + (n = 115) likely to have less than 8 years of schooling (P = 0.0003), Overall non-white skin color (P = 0.009), their first sexual inter- course at < 18 years old (P = 0.04), more than two sexual Positive 51 (44.4) 17 < 0.0001 (14.8) partners (P = 0.004 for 2–7 partners and P = 0.007 for > 7 partners), and a higher number of parities (P = 0.0006 64 (55.6) 98 Negative (85.2) for 1–2 parities and P 0.0001 for ≥3 parities), and were High-Risk HPV less likely to report screening for CC within the past three years (P = 0.01). HIV- women were, however, more Positive 23 (20.0) 7 (6.1) 0.0028 likely to be a widowed (P = 0.004). 92 (80.0) 108 Most HIV+ women presented excellent control of the Negative (94.0) HIV infection based on their compliance with HAART Low-Risk HPV (80.9%), preserved CD4+ T lymphocyte count (82.6% Positive 37 (32.2) 9 (7.8) < 0.0001 with > 350 cells/mm ), and suppressed current viral 78 (67.8) 106 loads (86.1% undetectable). Additionally, most of the Negative (92.2) HIV+ women had had documented HIV infections for < Universal HPV 5 years (63.5%) (Table 1). Positive 17 (14.8) 7 (6.1) 0.028 Cytology showed no signs of malignancy in most 98 (85.2) 108 women from both groups. Overall, 13.0% of HIV+ women Negative (93.9) and 5.0% of HIV- women presented abnormal cytological Multiple types Infections findings (P = 0.04). Atypical squamous cells of undeter- 28 (24.3) 5 (4.4) < 0.0001 mined significance (ASC-US) were observed in 2.6% of Positive HIV+ women and in 1.4% of HIV- women (P =0.66); low- 87 (75.7) 110 grade squamous intraepithelial lesions (LSIL) were ob- Negative (95.6) served in 7.8% of HIV+ women and in 2.8% of HIV- HIV - (n = 139) women (P = 0.15); high-grade squamous intraepithelial le- Overall sions (HSIL) were observed in 2.6% of HIV+ women and 0.8% of HIV- women (P =0.33). Positive 52 (37.4) 13 < 0.0001 (9.4) Overall, 56 (48.7%) of the 115 HIV+ women were positive 87 (62.6) 126 for cervical and/or oral HPV DNA, while 57 (41%) of the Negative (90.6) 139 HIV- women were positive for cervical and/or oral HPV High-Risk HPV (P = 0.25). Both HIV+ and HIV- women had a statistically higher prevalence of cervical HPV infection than oral infec- Positive 33 (23.7) 5 (3.6) < 0.0001 tion, including higher rates of hrHPV, lrHPV, universal HPV, 106 (76.3) 134 Negative (96.4) and infection by multiple HPV types in cervical samples compared to oral ones, as shown in Table 2. Low-Risk HPV HPV DNA was detected in oral samples from 17 Positive 29 (20.9) 5 (3.6) < 0.0001 (14.8%) HIV+ women and 13 (9.4%) HIV- women (P = 110 (79.1) 134 0.24) (Table 3). Multiple HPV infections were detected Negative (96.4) in five samples (4.4%) from HIV+ women and in four Universal HPV samples (2.9%) from HIV- women (Table 2). Statistical Positive 22 (15.8) 4 (2.9) 0.0003 analysis did not reveal an association between HIV+ sta- 117 (84.2) 135 tus and the presence of HPV DNA in the oral mucosa Negative (97.1) (P = 0.83). Multiple types infections Fifty-one (44.3%) HIV+ women and 52 (37.4%) HIV- Positive 29 (20.9) 4 (2.9) women had HPV-positive cervical samples (P =0.48) 110 (79.1) 135 < 0.0001 (Table 3). Multiple HPV types were detected in 28 (24.3%) Negative (97.1) of HIV+ and in 29 (20.9%) of HIV- patients (Table 2). There was no significant difference between the HIV+ and HIV- women with regard to HPV types. Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 6 of 11 To better understand the association between cervical and abnormal cytological findings than HIV- women. HPV oral HPV infection, the prevalence of concurrent HPV infec- type distribution was different between the anatomical tion in this population was investigated. Eight (7.0%) HIV+ sites within both groups, and HIV+ women commonly women and 7 (5.0%) HIV- women had concurrent HPV in- presented with narrower HPV type distributions, mainly fection in their cervical and oral samples (P =0.6) (Table 3). in the oral mucosa. Finally, the frequency of concurrent Concordance between HPV types in the cervical and oral HPV infection in both sites was low, and HPV type con- samples was not observed in either group. cordance was not observed. In the HIV+ group, the most frequent cervical hrHPV Our results showed that the prevalence of cervical types observed were HPV18, HPV45, and HPV58 (14.8% HPV infection was 44.3% in HIV+ women and 37.4% in each). In the oral site, the most prevalent hrHPV was HIV- women. Studies across different populations HPV39 (33.3%) followed by HPV18, HPV45, HPV52, present varying rates of HPV infection: 45–97.1% in and HPV68 (16.6% each). The most prevalent cervical HIV+ women and 44.9–86.5% in HIV- women in the lrHPV found in this group was HPV6 (17.5%), followed cervical site [20, 24, 25, 33]. The high prevalence of HPV by HPV61 (12.5%), and in oral mucosa, the most preva- in HIV-negative women in this study can be explained, lent lrHPV was also HPV6 (28.6%), followed by HPV62 at least in part, by the fact they were recruited from a and HPV81 (21.4%) (Fig. 1). Specialized Assistance Service (SAE) for sexually trans- In the HIV- group, the most prevalent hrHPV in mitted diseases, and were therefore at higher risk for the cervical mucosa was HPV18 (14.2%), followed by sexually transmitted infections, including HPV. Add- HPV16 and HPV68 (11.9% each). In the oral site, itionally, the rates of oral HPV infection in HIV+ women HPV51 and HPV66 were the most prevalent hrHPV and HIV- control were 14.8 and 9.4%, respectively. (33.3% each). The most prevalent lrHPVs in the Other studies have shown that the prevalence of HPV cervical site were HPV81 (29.0%) and HPV54 and infection in the oral site can vary significantly (12–68.5% HPV70 (16.1% each), and the most prevalent lrHPV in HIV+ women and 2–31.4% in HIV- women) [20, 24, in the oral site was HPV6 (30.0%), followed by 33]. HPV43 (20%) (Fig. 2). Although HIV infections were well controlled and cy- HIV+ women with recent detectable HIV loads were tology results showed no malignancies, abnormal cyto- significantly associated with HPV-positive status overall logical findings were significantly higher in HIV+ (OR = 3.75; CI = 1.22–11.10; P = 0.03) and in cervical women than in HIV- women. These data are consistent mucosa (OR = 4.61; CI = 1.50–13.66; P = 0.01) (Table 4). with the results of the previous studies showing that When the characteristics of the HIV+ women were an- HIV+ women are less likely to eliminate the virus, have alyzed in relation to HPV status, only current smoking subsequent persistent hrHPV infections and have higher was associated with overall (OR = 3.80; CI = 1.22–10.42; risk of developing precancerous lesions and malignan- P = 0.01) and cervical HPV-positive status (OR = 3.94; cies, even with the appropriate use of antiretroviral ther- CI = 1.31–11.76; P = 0.01 for both), as shown in Table 5. apy, than HIV- women [8, 9, 19, 34, 35]. Our results demonstrated no significant difference in Discussion HPV detection in the uterine cervix or oral mucosa be- In the present study, we aimed to determine the HPV tween HIV+ women and HIV- women; however, HPV prevalence, distribution, and type concordance between infection was significantly higher in the cervical mucosa cervical and oral samples of HIV+ women and HIV- than in the oral site in both groups. These findings are matched controls in the southern region of Brazil, a geo- consistent with previous studies suggesting that the nat- graphic area with high incidences of HIV and CC. Our ural history of HPV infection varies by anatomical site, data demonstrated that HIV+ and HIV- women had a and a higher prevalence of HPV infection is observed in similar and high HPV prevalence in cervical and in oral the cervical mucosa than in the oral mucosa in HIV+ sites. However, HIV+ women had higher prevalence of women [36–38]. This can be explained, at least in part, Table 3 Detection of human papillomavirus (HPV) infection in the oral mucosa and uterine cervix of human immunodeficiency virus (HIV) + and HIV- women HIV+ (N = 115) HIV- (N = 139) P N (%) N (%) Oral mucosa 17 (14.8) 13 (9.4) 0.24 Uterine cervix 51 (44.3) 52 (37.4) 0.48 Positive samples from oral mucosa of patients with infected uterine cervix 8 (7.0) 7 (5.0) 0.6 Positive samples from oral mucosa of patients with uninfected uterine cervix 3 (2.6) 5 (3.6) 0.73 Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 7 of 11 Fig. 1 Human Papillomavirus (HPV) type distribution of cervical and oral infections detected in the human immunodeficiency virus-positive group. a High-risk HPV type distribution. b Low-risk HPV type distribution by the evidence that the oral cavity is a hostile environ- significantly higher concentrations of immunoregulatory ment for the establishment of infectious agents due to factors that were related to the adaptive and cell- the presence of both mechanical and molecular mecha- mediated immune response than the cervix, which may nisms related to digestion [39]. More specifically, Fakhry in part explain the significantly lower burden of sexually et al. [39] conducted a study that directly compared the transmitted infections such as Chlamydia trachomatis, local immunologic profiles of the oral cavities and cervi- HPV, and HIV-1 in the oral cavity than in the cervix. ces of healthy women using paired secretion specimens. According to the authors, these findings provide add- This study showed that the oral cavity contained itional information to better understand the differences Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 8 of 11 important to reduce the risk of developing HPV-related cancers, specifically in the HIV+ population. Unlike the distribution of HPV types in cervical sam- ples, HPV type concordance between the HIV+ and HIV- groups was not observed in oral samples. hrHPV39 was the most common hrHPV detected in oral samples of HIV+ women, followed by hrHPV18, hrHPV45, hrHPV52, and hrHPV68, with these types being also fre- quently found in cervical samples in the same group. However, in HIV- women, the oral hrHPV types ob- served were totally different, with hrHPV51 and hrHPV66 being the most frequently detected hrHPV. Current evidence has shown that hrHPV16 and hrHPV18 contribute to the majority (approximately 85%) of HNC cases worldwide, while the remaining can- cers are caused by hrHPV33, hrHPV35, hrHPV52, hrHPV45, hrHPV39, and hrHPV58 [41, 42]. Examination of concurrent HPV infections in different anatomical sites has been limited. Hence, we concur- rently investigated the prevalence of HPV infection and HPV type distribution in cervical and oral sites to better understand their clinical significance. Simultaneous HPV cervical and oral infection was low in both HIV+ and HIV- women. Moreover, HPV type concordance was not observed, a finding consistent with previous studies [20, 24]. Taken together, these observations suggest that vari- ous HPV types are more likely to occur in a different anatomical sites, and/or that the two anatomical sites can clear certain HPV types or distinct exposures, while allowing other HPV types to cause persistent oral and cervical HPV infections. Fig. 2 Human Papillomavirus (HPV) type distribution of cervical and Prior investigations have demonstrated that engagement oral infections detected in the human immunodeficiency virus- in some high-risk behaviors may facilitate HPV infection negative group. a High-risk HPV type distribution. b Low-risk HPV type distribution and act as a cofactor for viral persistence, contributing to cancer progression in the oral and cervical mucosa. In the in the etiology and natural history of pathogenic agents present study, we found that current smoking was associ- that are capable of colonizing both the oral cavity and ated with overall and cervical HPV infection in HIV+ female reproductive tract. women. Several studies have already demonstrated that The most prevalent HPV types in the cervical samples smoking status acts as a predictor and cofactor in cervical from both HIV+ and HIV- women were hrHPV18 and HPV infection, which is possibly due to the alteration of hrHPV58; however, hrHPV45 and hrHPV16 were fre- the mucosa cells, making them more susceptible to infec- quently detected in HIV+ women and HIV- women, re- tion, changing the immune mediators, causing DNA dam- spectively. Prevalence studies around the world have age, and promoting the integration of HPV DNA into the shown that hrHPV types 16, 18, 31, 33, 35, 52, and 58 host genome [42–45]. are the most commonly detected hrHPVs in CC, with hrHPV16 being the most common in all populations, Conclusion and future perspectives with the exception of HIV+ people [1]. Data have con- Our study demonstrated that HIV+ and HIV- women in sistently shown that HIV+ women are frequently more southern Brazil had high HPV prevalence in cervical and infected with other hrHPV types than hrHPV16 and oral sites. In this population, HIV+ women had more ab- hrHPV18, such as hrHPV52 and hrHPV58 [40]. The normal cytological findings than HIV- women. This high prevalence of non-vaccine hrHPV types of 2-valent study provides important epidemiological data about the and 4-valent vaccines in the cervical and oral mucosa potential risk of developing CC. Furthermore, the high found in our study suggests that the 9-valent HPV vac- prevalence of non-vaccine hrHPV types of the 2-valent cine is significantly required, which is considered and 4-valent vaccines in the cervical and oral mucosa of Suehiro et al. Infectious Agents and Cancer (2020) 15:31 Page 9 of 11 Table 4 Prevalence of cervical and oral HPV infection according to the HIV-related parameters Variables HPV+ OR (CI) P Cervical HPV+ OR (CI) P Oral HPV+ (N = 11) OR (CI) P (N = 56) (N = 51) N (%) N (%) N (%) Documented HIV infection (years) < 5 39/73 (53.4) 1.68 (0.79–3.60) 0.24 36/73 (49.3) 1.75 (0.81–3.71) 0.18 7/73 (9.6) 1.00 (0.28–3.23) > 0.99 5–10 17/42 (40.5) 1 – 15/42 (35.7) 1 4/42 (9.5) 1 > 10 0/0 (0) –– – – – – – Compliance to HAART Yes 42/93 (45.2) 0.46 (0.18–1.17) 0.15 39/93 (41.9) 0.60 (0.22–1.50) 0.34 9/93 (9.7) 1.07 (0.23–5.25) > 0.99 No 14/22 (66.6) 1 – 12/22 (54.5) 1 2/22 (9.1) 1 Most recent CD4 (cells/mm ) < 200 3/3 (100) –– 3/3 (100) –– 0/3 (0) –– 200–350 9/17 (52.9) 1.30 (0.47–3.78) 0.79 8/17 (47.1) 1.22 (0.41–3.34) 0.79 2/17 (11.8) 1.27 (0.25–6.01) 0.67 > 350 44/95 (46.3) 1 – 40/95 (42.1) 1 9/95 (9.5) 1 Most recent viral load Undetectable 44/99 (44.4) 1 – 39/99 (39.4) 1 11/99 (11.1) 1 – Detectable 12/16 (75.0) 3.75 (1.22–11.10) 0.03 12/16 (75.0) 4.61 (1.50–13.66) 0.01 0/16 (0) – HPV = human papillomavirus, HIV = human immunodeficiency virus, HAART, highly active antiretroviral therapy; OR = Odds ratio; CI = confidence interval Table 5 Possible predictors of cervical and oral human papillomavirus (HPV) infection, stratified by HPV status in human immunodeficiency virus (HIV)-positive women Predictors of HPV HPV+ (N = 56) OR (CI) P Cervical HPV+ (N = 51) OR (CI) P Oral HPV+ (N = 11) OR (CI) P infection N (%) N (%) N (%) Age (years) 18–29 7/13 (58.4) 1 – 7/13 (58.3) 1 0/13 (0) –– 30–50 35/76 (46.1) 0.60 (0.19–2.01) 0.53 30/76 (39.5) 0.46 (0.15–1.54) 0.34 8/76 (10.5) 1 > 50 14/27 (51.8) 0.76 (0.20–3.02) 0.74 14/27 (51.8) 0.76 (0.19–3.03) 0.74 3/27 (11.1) 1.06 (0.26–4.33) > 0.99 Race White 24/48 (50.0) 0.54 (0.16–1.69) 0.39 22/48 (45.8) 0.46 (0.14–1.45) 0.26 6/48 (12.5) 2.28 (0.25–20.51) 0.66 Brown 21/49 (42.9) 0.40 (0.12–1.26) 0.16 18/49 (36.7) 0.31 (0.09–0.99) 0.05 4/49 (8.2) 1.42 (0.14–13.70) > 0.99 Black 11/17 (64.7) 1 – 11/17 (64.7) 1 1/17 (5.9) 1 Asian 0 (0) –– 0 (0) –– 0 (0) –– Sexual debut (years) < 16 22/45 (48.9) 1 – 21/45 (46.7) 1 4/ (8.9) 1 ≥ 16 34/70 (48.6) 0.98 (0.47–2.06) 1 30/70 (42.9) 1.16 (0.55–2.44) 0.70 7/70 (10.0) 1.14 (0.31–4.13) > 0.99 Smoking status Never smoker 26/56 (46.4) 1.64 (0.62–4.08) 0.35 25/56 (44.6) 2.11 (0.80–5.58) 0.16 3/56 (5.4) 0.49 (0.09–2.60) 0.40 Current smoker 20/30 (66.7) 3.80 (1.22–10.42) 0.01 18/30 (60.0) 3.94 (1.31–11.76) 0.01 5/30 (16.7) 1.73 (0.38–7.02) 0.70 Ex-smoker 10/29 (34.5) 1 – 8/29 (27.6) 1 3/29 (10.3) 1 Lifetime number of sexual partners < 5 25/51 (49.0) 1 – 25/51 (49.0) 1 5/51 (9.8) 1 ≥ 5 31/64 (48.4) 0.97 (0.48–1.98) 1 26/64 (40.6) 0.71 (0.34–1.50) 0.45 6/64 (9.4) 1.19 (0.31–4.46) > 0.99 Use of hormonal Contraceptives Yes 11/20 (55.0) 1 – 9/20 (45.0) 1 2/20 (10.0) 1 No 45/95 (47.4) 0.73 (0.29–1.98) 0.9 42/95 (44.2) 0.96 (0.36–2.55) > 0.99 9/95 (9.5) 0.94 (0.18–4.73) > 0.99 OR = Odds ratio; CI = confidence interval Suehiro et al. 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Ortiz AP, Perez-Irizarry J, Soto-Salgado M, Suarez E, Perez N, Cruz M, et al. All the authors contributed to the manuscript. TTS, GMZFD, ED, and MELC Human papillomavirus-related cancers among people living with AIDS in searched the literature and prepared the manuscript. SMP collected the Puerto Rico. Prev Chronic Dis. 2014;11:E80. biological samples from the women. TTS and MELC wrote the manuscript. 11. WHO. Fact sheet on adolescent health. Geneva; 2014. Available from: http:// MELC, WH, RF, VRSS, SMP, LLRAR, MAPS, and ICS participated in the research www.unaids.org/en/media/unaids/contentassets/documents/factsheet/2 design and execution. TTS and ED performed the statistical analysis. GMZFD, 012/20120417_FS_adolescentsyoungpeoplehiv_en.pdf. ED, WH, RAAF, VRSS, SMP, and ICS were involved in revising the manuscript 12. Dellar RC, Dlamini S, Karim QA. Adolescent girls and young women: key to include critically important intellectual content. MELC revised the final populations for HIV epidemic control. J Int AIDS Soc. 2015;18:19408. version of the manuscript and provided information and suggestions. All the 13. Saffier IP, Kawa H, Harling G. A scoping review of prevalence, incidence and authors read and approved the final draft of the manuscript. risk factors for HIV infection amongst young people in Brazil. BMC Infect Dis. 2017;17:675. Funding 14. Serrano B, Alemany L, Ruiz PA, Tous S, Lima MA, Bruni L, et al. Potential This work was supported through a research grant from the NCI impact of a 9-valent HPV vaccine in HPV-related cervical disease in 4 (P30CA013148-43S2). The funder had no role in the study design, data emerging countries (Brazil, Mexico, India and China). Cancer Epid. 2014;38: collection and analysis, decision to publish, or preparation of the manuscript. 748–56. 15. Brisson M, Kim JJ, Canfell K, Drolet M, Gingras G, Burger EA, et al. Impact of Availability of data and materials HPV vaccination and cervical screening on cervical cancer elimination: a All data are included in the manuscript. comparative modelling analysis in 78 low-income and lower-middle-income countries. The Lancet.2020; Published online January 30, 2020. Ethics approval and consent to participate 16. Joura EA, Giuliano AR, Iversen O-E, Bouchard C, Mao C, Mehlsen J, et al. A 9- The study involves human participants. This study was approved by the local valent HPV vaccine against infection and intraepithelial neoplasia in women. ethics committee (Committee for Ethics in Research Involving Humans at the N Engl J Med. Mass Medical Soc. 2015;372:711–23. State University of Maringá/UEM/Paraná, Brazil [Protocol Number CAAE: 17. Richter KL, van Rensburg EJ, van Heerden WFP, Boy SC. 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Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix

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