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HPV type infection in different anogenital sites among HIV-positive Brazilian women

HPV type infection in different anogenital sites among HIV-positive Brazilian women Objectives: To evaluate the prevalence of human papillomavirus (HPV) types, and risk factors for HPV positivity across cervix, vagina and anus, we conducted a study among 138 women with human immunodeficiency virus (HIV). Goal: Compare the prevalence of different HPV types and the risk factors for HPV positivity in three sites. Results: The most frequently detected HPV types in all sites were, in decreasing order, HPV16, 53, 18, 61 and 81. Agreement between the cervix and vagina was good (kappa 0.60 – 0.80) for HPV16 and 53 and excellent (Kappa > 0.80) for HPV18 and 61. HPV positivity was inversely associated with age for all combinations including the anal site. Conclusion: In HIV positive women, HPV18 is the most spread HPV type found in combinations of anal and genital sites. The relationship of anal to genital infection has implications for the development of anal malignancies. Thus, the efficacy of the current HPV vaccine may be considered not only for the cervix, but also for prevention of HPV18 anal infection among immunossuppressed individuals. advent of antiretroviral drugs in Brazil, median survival Background More than 1.7 million people were living with human time for people diagnosed with AIDS has increased from immunodeficiency virus (HIV) infection in Latin America 18 to 58 months [2]. at the end of 2004, and Brazilian women made up more than one-third (610,000) of this population [1]. Among Epidemiological and laboratory data have demonstrated women from 15–24 years of age, the prevalence of HIV that persistent infection with high-risk human papilloma- infection in Brazil is estimated to be 0.5%. With the virus (HPV) types (like 16, 18, 31, 33, 39, 45, 52, 53, 56, Page 1 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 58, 59, 66, 68, 73, 82) is an essential step in the develop- HPV detection and typing ment of invasive cervical cancer and the majority of anal After collection, cells remaining in the collection devices cancer [3]. Compared to HIV-negative women, HIV-posi- were washed out into a sterile buffered solution and kept tive women have an increased incidence and persistence at -20°C for HPV analysis. Beta-globin amplification was of HPV infection and a concomitant increased risk of used to assess specimen adequacy for HPV DNA detec- developing squamous intraepithelial lesions and cervical tion. Polymerase chain reaction (PCR)-based assays were cancer [4-7]. carried out in the Laboratorio de Patologia e Hemoterapia do Hospital do Cancer, Fundação Antonio Prudente, São In addition, compared to HIV-negative women, HIV-pos- Paulo, Brazil [15]. itive women show a higher occurrence of multiple-type HPV infection [8-10] and a relatively lower proportion of PCR-positive samples were further typed by restriction HPV16 [11]. Little information is available on the con- fragment length polymorphism according to Bernard et al. comitant prevalence of HPV infection in different ano- [16], allowing the recognition of more than 42 HPV types genital sites [12], notably in the anal area [13,14]. (HPV6,11, 13, 16, 18, 26, 31, 32, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 64, 66, In this study we have compared the prevalence of different 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, LVX100 and HPV types and the risk factors for HPV positivity in three CP6108). The following restriction enzymes were used: sites (i.e., cervical, vaginal and anal area). Bam HI, Dde I, Hae III, Hinf I, Pst I, Rsa I and Sau 3a I (Gibco BRL-Life Technologies, Los Angeles, California, USA). The identification of HPV types was performed by Methods Patients comparing the pattern of amplified bands with those Study methods have been reported elsewhere [8]. Briefly, attributed to each virus type. HPV types were classified as a cross-sectional study was conducted among 138 HIV- high-risk (or probably high-risk) and low-risk types as in positive women, aged 19–57 (mean age = 31 years), who Muñoz et al. [17]. Other HPV types that could not be iden- attended the Center of Reference in AIDS of Santos, São tified in this study were considered unidentified (HPVX). Paulo, Brazil between June 1996 and April 1997. Patients Statistical analysis who reported previous hysterectomy, virgins or those who were not able to provide an informed consent form were The Kappa statistic was used to calculate the agreement excluded from the study. All women underwent HIV sero- between HPV positivity at the cervical vs vaginal or anal logical testing with Western blot confirmation (Cam- sites. The concordance rate was considered fair to good if bridge Biotech Corporation, Worcester, Massachusetts, Kappa values were between 0.60–0.80, and excellent if USA). CD4 cell count was performed on the date of the greater than 0.80. Agreement for any HPV type is defined visit or within three months thereafter. CD4 counts were as presence of at least one common HPV type in the 2 or > 500 cells/mm in 24.6% women, between 200–499 3 combined sites. ORs for detection of HPV infection and 3 3 cells/mm in 37.0%, and < 200 cells/mm in 38.4%. corresponding 95% CIs were calculated separately for each anogenital site and for each combination of 2 or 3 The same gynecologist applied a standard questionnaire sites by means of unconditional regression equations for all patients to elicit information on sociodemographic adjusted for age (< 25, 25–34, ≥ 35). The analyses were characteristics, smoking habits, history of drug addiction, repeated with adjustment for age and CD4 count (< 200, sexual behavior and use of condom. The Ethics Commit- 200–499, ≥ 500). tee of the Medical School of the University of São Paulo, Brazil, approved the study protocol, and all participants Results HPV prevalence by anogenital site signed informed consent forms. The prevalence of HPV infection among HIV-positive Sample collection women did not differ significantly between the three ano- The same gynecologist collected exfoliated cells from 1) genital sites under study. The prevalence was 61.6% in the ectocervix, 2) vagina and 3) anal area, in that order, with cervix, 65.9% in the vagina, and 63.7% in the anal area. separate sterile brushes, and stored in separate flasks in The same similarity is seen when high-risk HPV types are phosphate-buffered saline solution (PBS). To obtain sam- considered, in the cervix (36.2%), vagina (42.8%) and the ples for anal collection, individual disposable brushes anal area (43.1%). In respect to low-risk HPV types, the moistened in sterile PBS were inserted into the anal canal prevalence was 34.1% in the cervix, 35.5% in the vagina and were rotated 360° as they were withdrawn. and 33.3% in the anal area. Multiple HPV infections occurred in 41.2% of HPV-positive cervical samples, 48.4% of HPV-positive vaginal samples and 44.6% of HPV-positive anal samples. The prevalence of HPV types Page 2 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 according to the risk category in the studied female popu- Similarly, in the vagina, the most frequent high-risk HPV lation was described elsewhere [18]. types detected were HPV16, 53 and 18 (n = 17, 15 and 12, respectively) (Table 1), while the most frequent low-risk In the cervix, the most frequent high-risk HPV types were HPV types were HPV61 and 81 (n = 11 for each). Thirteen HPV16 and 53 (n = 13 each type) and HPV18 (n = 12) % of vaginal samples were HPV positive but the HPV type (Table 1). HPV61 and 81 were the most frequent low-risk could not be characterized. HPV types (n = 11 and 9 respectively). For 9.4% of the samples the HPV type could not be characterized. Table 1: Prevalence of 23 HPV types by collected site among 138 HIV-positive women. Santos, São Paulo, Brazil, 1996–1997 Site Cervix Vagina Anal Single Multiple Total (%) Single Multiple Total (%) Single Multiple Total (%) HPV - 53 (38.4) 47 (34.1) 37 (36.3) HPV + 50 35 85 (61.6) 47 44 91 (65.9) 36 29 65 (63.7) HR HPV+ 23 28 51 (37.0) 25 34 59 (42.8) 16 28 44 (43.1) LR HPV+ 24 23 47 (34.1) 19 30 49 (35.5) 15 20 35 (34.3) High-risk 16 7 6 13 (9.4) 6 11 17 (12.3) 4 5 9 (8.8) 18 4 8 12 (8.7) 4 8 12 (8.7) 2 10 12 (11.8) 31 0 5 5 (3.6) 1 5 6 (4.3) 2 1 3 (2.9) 33 3 4 7 (5.1) 1 7 8 (5.8) 2 4 6 (5.9) 39 0 1 1 (0.7) 1 0 1 (0.7) 0 1 1 (1.0) 45 0 2 2 (1.4) 0 2 2 (1.4) 0 1 1 (1.0) 52 0 1 1 (0.7) 0 2 2 91.4) 0 0 0 (0.0) 53 5 8 13 (9.4) 7 8 15 (10.9) 4 9 13 (12.7) 56 1 0 1 (0.7) 1 1 2 (1.4) 0 1 1 (1.0) 58 1 2 3 (2.2) 1 2 3 (2.2) 1 2 3 (2.9) 59 1 0 1 (0.7) 0 0 0 (0.0) 0 0 0 (0.00 66 0 3 3 (2.2) 0 3 3 (2.2) 0 4 4 (3.9) 68 1 1 2 (1.4) 3 1 4 (2.9) 1 0 1 (1.0) 73 0 1 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 82 0 2 2 (1.4) 0 2 2 (1.4) 0 0 0 (0.0) Subtotal 23 44 67 25 53 78 16 38 54 Low-risk 6 3 1 4 (2.9) 2 2 4 (2.9) 5 3 8 (7.8) 11 3 4 7 (5.1) 2 5 7 (5.1) 1 5 6 (5.5) 32 0 1 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 34 1 0 1 (0.7) 1 0 1 (0.7) 1 0 1 (1.0) 40 0 2 2 (1.4) 2 2 4 (2.9) 0 2 2 (1.8) 54 1 1 2 (1.4) 1 2 3 (2.2) 0 1 1 (1.0) 61 4 7 11 (8.0) 3 8 11 (8.0) 2 6 8 (7.3) 62 0 1 1 (0.7) 0 1 1 (0.7) 2 1 3 (2.7) 64 0 1 1 (0.7) 0 0 0 (0.0) 1 0 1 (1.0) 67 2 0 2 (1.4) 0 1 1 (0.7) 0 0 0 (0.0) 69 2 0 2 (1.4) 2 1 3 (2.2) 1 0 1 (1.0) 70 1 0 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 71 2 0 2 (1.4) 1 1 2 (1.4) 1 0 1 (1.0) 72 0 2 2 (1.4) 1 3 4 (2.9) 0 1 1 (1.0) 81 2 7 9 (6.5) 2 9 11 (8.0) 0 5 5 (4.6) 83 2 4 6 (4.3) 1 3 4 (2.9) 1 2 3 (2.7) 84 1 0 1 (0.7) 1 0 1 (0.7) 0 1 1 (1.0) Subtotal 24 31 55 19 40 59 15 27 42 Unknown 3 10 13 (9.4) 3 15 18 (13.0) 5 7 12 (11.8) Presented for 102 HIV-positive women. HPV = human papillomavirus; HIV = human immunodeficiency virus; HR = High-risk; LR = low-risk Page 3 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 In the anal area, the most frequently detected high-risk lence of HPV infection was similar in the cervix, vagina HPV types were, in decreasing order, HPV53 (n = 13), 18 and anal area. This also held true for the prevalence of the (n = 12), and 16 (n = 9). The most frequent low-risk HPV most frequently detected individual HPV types, notably types were HPV 61 and 6 (n = 8 for each). In 11.8% of anal HPV11, 16, 18, 53 and 61, and for the frequency of mul- samples the HPV type could not be characterized. HPV6, tiple-type infections. However, the same HPV type(s) were but not HPV11, tended to be more frequent in the anal not always present in the three examined anogenital areas area than in the cervix or vagina (7.8% in the anal area vs and the agreement in the detection of individual types was 2.9% in each other site). better between the cervix and the vagina than between the cervix and the anal area. The type most frequently detected In respect to cervical and vaginal sites, agreement for any at all three sites was HPV18, mainly on account of its high HPV type positivity was 78.3% (Kappa value = 0.53 for prevalence in the anal area. Recently, Castle et al. [19] any type) and varied from 92.8% (HPV16) to 98.6% reported that some HPV types (e.g., HPV61, 71 and 72), (HPV61 and HPV6). Kappa values above 0.80 were found were more frequently detected in vaginal specimens from for HPV18, 33 and 61. When cervical and anal sites were hysterectomized women compared to those who had not compared, agreement for positivity for any HPV type was undergone hysterectomy. Simultaneous HPV infection in found in 68.6% of women (Kappa value = 0.31) (Table 2). different anogenital sites is considered a risk factor for the The Kappa value was particularly low for HPV16 (0.11), concomitant occurrence of anal and cervical lesions, espe- but was relatively elevated for HPV18 (0.69), especially cially in HIV-positive women [20-22]. concerning the combination among the three sites (0.72). The factors most clearly associated with HPV positivity Risk factors for associations between sites for any HPV among HIV-positive women in our study agree with find- positivity ings from HIV-negative women [23,24]. Although the As shown in Table 3, HPV positivity were inversely associ- small number of women available did not allow most pre- ated with age in three combinations of anogenital sites sented ORs to reach statistical significance, we did show (cervical+anal; vaginal+anal and cervical+vaginal+anal), higher HPV positivity below age 25 than at age 35 or all of them including anal site. No association emerged in older, as well as among women who reported two recent any site between HPV positivity and smoking habits, his- sexual partners or more. These findings are consistent tory of drug addiction, commercial sex work and condom with the report that recent sexual partners are a stronger use, and number of years since HIV diagnosis. determinant of HPV positivity than the lifetime number of sexual partners [25]. No consistent relationship Anal intercourse showed an association of borderline sta- between HPV positivity and smoking habits or condom tistical significance in the combination vaginal + anal for use have emerged among HIV-negative women [23,24]. HPV positivity (OR: 2.4; 95% CI: 0.97–6.0), but not else- where. Nevertheless, condom use did not show associa- Two characteristics stand out as being more strongly asso- tions with HPV positivity at all sites. ciated with HPV positivity in the anal area than in the cer- vix and vagina, one being history of anal intercourse. This finding suggests that anal infection is associated among Discussion Approximately two-thirds of HIV-positive women in our women, as it is among bisexual and homosexual men, to study from Brazil were infected by HPV and the preva- direct HPV exposure [22,26]. Anal infection, however, can Table 2: Agreement of HPV type detection by collected site among 138 HIV-positive women. Santos, São Paulo, Brazil: 1996–1997 a a Cervix: Vagina Cervix: Anus Cervix, Vagina, Anus HPV type Cervix only Vagina only Both Agreement Cervix only Anal only Both Agreement Any of the All three Agreement (Kappa (Kappa three (Kappa value) value) value) 16 3 7 10 92.8 (0.63) 9 7 2 84.3 (0.11) 21 2 79.4 (0.32) 18 2 2 10 97.1 (0.82) 2 4 8 94.1 (0.69) 14 7 92.2 (0.72) 53 2 4 11 95.7 (0.76) 8 9 4 83.3 (0.23) 22 4 81.4 (0.45) 6 1 1 3 98.6 (0.74) 0 5 3 95.1 (0.52) 8 2 94.1 (0.55) 11 2 2 5 97.1 (0.70) 3 5 1 92.2 (0.16) 8 1 91.2 (0.33) 61 1 1 10 98.6 (0.90) 6 5 3 89.2 (0.29) 13 3 89.2 (0.54) Any type 12 18 73 78.3 (0.53) 17 15 50 68.6 (0.31) 83 45 59.8 (0.40) a b Available for 102 women only; Non-significant Kappa value. HPV = human papillomavirus; HIV = human immunodeficiency virus. Page 4 of 7 (page number not for citation purposes) a Table 3: ORs ofHPV positivity and corresponding 95% CIs according to selected characteristics among 138 HIV-positive women . Santos, São Paulo, Brazil, 1996–1997 b b b Cervical+Vaginal Cervical+Anal Vaginal+Anal Cervical+Vaginal+Anal c c c c Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Age (years) ≥ 35 39 38.5 1 30 10.0 1 30 13.3 1 30 6.7 1 25–34 75 49.3 1.6 0.7–3.4 55 27.3 3.4 0.9–12.8 55 34.6 3.4 1.0–11.3 55 27.3 5.3 1.1–24.8 < 25 24 58.3 2.2 0.8–6.3 17 47.1 8.0 1.7–36.8 17 41.2 4.6 1.1–19.0 17 35.3 7.6 1.3–43.8 p for trend 0.12 0.006 0.03 0.02 Tobacco smoking Never smoker 44 45.5 1 32 31.3 1 32 31.3 1 32 21.9 1 Ex-smoker 33 45.5 1.1 0.4–2.8 26 30.8 1.1 0.3–3.8 26 34.6 1.2 0.4–3.7 26 30.8 1.7 0.5–6.1 Current smoker 61 50.8 1.3 0.6–3.0 44 18.2 0.5 0.2–1.7 44 25.0 0.8 0.3–2.2 44 18.2 0.9 0.3–2.9 p for trend 0.46 0.22 0.52 0.60 Drug addict Never 79 45.6 1 62 25.8 1 62 25.8 1 62 21.0 1 Ex 36 52.8 1.3 0.6–2.8 24 29.2 1.1 0.4–3.2 24 45.8 2.2 0.8–6.2 24 29.2 1.4 0.5–4.2 Current 23 47.8 1.0 0.4–2.7 16 18.8 0.7 0.2–2.9 16 18.8 0.6 0.2–2.6 16 18.8 0.8 0.2–3.5 p for trend 0.80 0.70 0.99 0.98 Years since HIV diagnosis ≤ 1 54 46.3 1 40 27.5 1 40 32.5 1 40 22.5 1 2–4 43 39.5 0.8 0.4–1.9 34 60.529.4 1.3 0.4–3.8 34 32.4 1.0 0.4–2.8 34 26.5 1.3 0.4–4.2 ≥ 5 39 56.4 1.8 0.7–4.2 26 19.2 0.7 0.2–2.8 26 23.1 0.5 0.2–1.9 26 19.2 0.8 0.2–3.1 p for trend 0.25 0.73 0.38 0.81 CD4 count/mm ≥ 500 34 41.2 1 20 15.0 1 20 15.0 1 20 10.0 1 200–499 51 49.0 1.8 0.7–4.7 39 23.1 4.2 0.8–22.2 39 30.8 4.8 1.0–22.7 39 23.1 5.7 0.9–34.1 < 200 53 59.9 1.8 0.7–4.6 43 32.6 5.9 1.2–28.6 43 34.9 5.0 1.1–22.4 43 27.9 6.2 1.1–34.9 p for trend 0.24 0.03 0.06 0.06 Commercial sex worker Never 107 46.7 1 82 24.4 1 82 26.8 1 82 20.7 1 Ever 31 51.6 1.2 0.5–2.6 20 30.0 1.2 0.4–3.8 20 40.0 1.7 0.6–4.8 20 30.0 1.5 0.5–4.6 Lifetime number of sexual partners ≤ 2 34 41.2 1 26 26.9 1 26 30.8 1 26 26.9 1 3–5 44 52.3 1.5 0.6–3.8 35 25.7 0.9 0.3–2.9 35 25.7 0.7 0.2–2.3 35 17.1 0.5 0.1–1.8 ≥ 6 60 48.3 1.2 0.5–3.0 41 24.4 0.7 0.2–2.3 41 31.7 0.8 0.3–2.6 41 24.4 0.7 0.2–2.2 p for trend 0.63 0.32 0.85 0.53 Recent sexual partners 0 48 43.8 1 42 21.4 1 42 26.2 1 42 21.4 1 1 74 47.3 1.0 0.5–2.1 51 25.5 0.8 0.3–2.4 51 27.5 0.8 0.3–2.0 51 19.6 0.6 0.2–1.7 ≥ 2 13 76.9 3.5 0.8–15.0 9 44.4 2.2 0.5–10.7 9 55.6 2.6 0.5–12.0 9 44.4 2.0 0.4–9.5 p for trend 0.21 0.56 0.52 0.83 Condom use Yes 69 47.8 1 47 25.5 1 47 27.7 1 47 19.2 1 No 20 60.0 1.7 0.6–4.8 13 38.5 2.0 0.5–7.6 13 46.2 2.4 0.7–8.8 13 38.5 2.9 0.7–11.6 Anal intercourse Never 66 48.5 1 51 19.6 1 51 19.6 1 51 19.6 1 Ever 72 47.2 0.9 0.5–1.8 51 31.4 1.7 0.6–4.3 51 39.2 2.4 0.97–6.0 51 25.5 1.2 0.5–3.2 a b c d Some figures do not add up to the total due to missing values; Presented for 102 HIV-positive women; Adjusted for age. HPV = human papillomavirus; relative to the last 6 months preceding interview; HIV = human immunodeficiency virus; OR = odds ratio; CI = confidence intervals. Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 Page 5 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 9. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, Young also be detected in women who do not report anal inter- M, Melnick S, Miotti P, Burck R: Cervicovaginal human papillo- course, particularly if a concomitant infection occurs at a mavirus infection in human immunodeficiency virus-1 (HIV)- genital site [27,28]. The other factor that appeared more positive and high-risk HIV-negative women. J Natl Cancer Inst 1999, 91:226-236. strongly associated with anal than cervical or vaginal HPV 10. 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Publish with Bio Med Central and every scientist can read your work free of charge "BioMed Central will be the most significant development for disseminating the results of biomedical researc h in our lifetime." Sir Paul Nurse, Cancer Research UK Your research papers will be: available free of charge to the entire biomedical community peer reviewed and published immediately upon acceptance cited in PubMed and archived on PubMed Central yours — you keep the copyright BioMedcentral Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

HPV type infection in different anogenital sites among HIV-positive Brazilian women

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Springer Journals
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Copyright © 2008 by Gonçalves et al; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Infectious Diseases; Oncology
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1750-9378
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10.1186/1750-9378-3-5
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18341690
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Abstract

Objectives: To evaluate the prevalence of human papillomavirus (HPV) types, and risk factors for HPV positivity across cervix, vagina and anus, we conducted a study among 138 women with human immunodeficiency virus (HIV). Goal: Compare the prevalence of different HPV types and the risk factors for HPV positivity in three sites. Results: The most frequently detected HPV types in all sites were, in decreasing order, HPV16, 53, 18, 61 and 81. Agreement between the cervix and vagina was good (kappa 0.60 – 0.80) for HPV16 and 53 and excellent (Kappa > 0.80) for HPV18 and 61. HPV positivity was inversely associated with age for all combinations including the anal site. Conclusion: In HIV positive women, HPV18 is the most spread HPV type found in combinations of anal and genital sites. The relationship of anal to genital infection has implications for the development of anal malignancies. Thus, the efficacy of the current HPV vaccine may be considered not only for the cervix, but also for prevention of HPV18 anal infection among immunossuppressed individuals. advent of antiretroviral drugs in Brazil, median survival Background More than 1.7 million people were living with human time for people diagnosed with AIDS has increased from immunodeficiency virus (HIV) infection in Latin America 18 to 58 months [2]. at the end of 2004, and Brazilian women made up more than one-third (610,000) of this population [1]. Among Epidemiological and laboratory data have demonstrated women from 15–24 years of age, the prevalence of HIV that persistent infection with high-risk human papilloma- infection in Brazil is estimated to be 0.5%. With the virus (HPV) types (like 16, 18, 31, 33, 39, 45, 52, 53, 56, Page 1 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 58, 59, 66, 68, 73, 82) is an essential step in the develop- HPV detection and typing ment of invasive cervical cancer and the majority of anal After collection, cells remaining in the collection devices cancer [3]. Compared to HIV-negative women, HIV-posi- were washed out into a sterile buffered solution and kept tive women have an increased incidence and persistence at -20°C for HPV analysis. Beta-globin amplification was of HPV infection and a concomitant increased risk of used to assess specimen adequacy for HPV DNA detec- developing squamous intraepithelial lesions and cervical tion. Polymerase chain reaction (PCR)-based assays were cancer [4-7]. carried out in the Laboratorio de Patologia e Hemoterapia do Hospital do Cancer, Fundação Antonio Prudente, São In addition, compared to HIV-negative women, HIV-pos- Paulo, Brazil [15]. itive women show a higher occurrence of multiple-type HPV infection [8-10] and a relatively lower proportion of PCR-positive samples were further typed by restriction HPV16 [11]. Little information is available on the con- fragment length polymorphism according to Bernard et al. comitant prevalence of HPV infection in different ano- [16], allowing the recognition of more than 42 HPV types genital sites [12], notably in the anal area [13,14]. (HPV6,11, 13, 16, 18, 26, 31, 32, 33, 34, 35, 39, 40, 42, 44, 45, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 64, 66, In this study we have compared the prevalence of different 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, LVX100 and HPV types and the risk factors for HPV positivity in three CP6108). The following restriction enzymes were used: sites (i.e., cervical, vaginal and anal area). Bam HI, Dde I, Hae III, Hinf I, Pst I, Rsa I and Sau 3a I (Gibco BRL-Life Technologies, Los Angeles, California, USA). The identification of HPV types was performed by Methods Patients comparing the pattern of amplified bands with those Study methods have been reported elsewhere [8]. Briefly, attributed to each virus type. HPV types were classified as a cross-sectional study was conducted among 138 HIV- high-risk (or probably high-risk) and low-risk types as in positive women, aged 19–57 (mean age = 31 years), who Muñoz et al. [17]. Other HPV types that could not be iden- attended the Center of Reference in AIDS of Santos, São tified in this study were considered unidentified (HPVX). Paulo, Brazil between June 1996 and April 1997. Patients Statistical analysis who reported previous hysterectomy, virgins or those who were not able to provide an informed consent form were The Kappa statistic was used to calculate the agreement excluded from the study. All women underwent HIV sero- between HPV positivity at the cervical vs vaginal or anal logical testing with Western blot confirmation (Cam- sites. The concordance rate was considered fair to good if bridge Biotech Corporation, Worcester, Massachusetts, Kappa values were between 0.60–0.80, and excellent if USA). CD4 cell count was performed on the date of the greater than 0.80. Agreement for any HPV type is defined visit or within three months thereafter. CD4 counts were as presence of at least one common HPV type in the 2 or > 500 cells/mm in 24.6% women, between 200–499 3 combined sites. ORs for detection of HPV infection and 3 3 cells/mm in 37.0%, and < 200 cells/mm in 38.4%. corresponding 95% CIs were calculated separately for each anogenital site and for each combination of 2 or 3 The same gynecologist applied a standard questionnaire sites by means of unconditional regression equations for all patients to elicit information on sociodemographic adjusted for age (< 25, 25–34, ≥ 35). The analyses were characteristics, smoking habits, history of drug addiction, repeated with adjustment for age and CD4 count (< 200, sexual behavior and use of condom. The Ethics Commit- 200–499, ≥ 500). tee of the Medical School of the University of São Paulo, Brazil, approved the study protocol, and all participants Results HPV prevalence by anogenital site signed informed consent forms. The prevalence of HPV infection among HIV-positive Sample collection women did not differ significantly between the three ano- The same gynecologist collected exfoliated cells from 1) genital sites under study. The prevalence was 61.6% in the ectocervix, 2) vagina and 3) anal area, in that order, with cervix, 65.9% in the vagina, and 63.7% in the anal area. separate sterile brushes, and stored in separate flasks in The same similarity is seen when high-risk HPV types are phosphate-buffered saline solution (PBS). To obtain sam- considered, in the cervix (36.2%), vagina (42.8%) and the ples for anal collection, individual disposable brushes anal area (43.1%). In respect to low-risk HPV types, the moistened in sterile PBS were inserted into the anal canal prevalence was 34.1% in the cervix, 35.5% in the vagina and were rotated 360° as they were withdrawn. and 33.3% in the anal area. Multiple HPV infections occurred in 41.2% of HPV-positive cervical samples, 48.4% of HPV-positive vaginal samples and 44.6% of HPV-positive anal samples. The prevalence of HPV types Page 2 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 according to the risk category in the studied female popu- Similarly, in the vagina, the most frequent high-risk HPV lation was described elsewhere [18]. types detected were HPV16, 53 and 18 (n = 17, 15 and 12, respectively) (Table 1), while the most frequent low-risk In the cervix, the most frequent high-risk HPV types were HPV types were HPV61 and 81 (n = 11 for each). Thirteen HPV16 and 53 (n = 13 each type) and HPV18 (n = 12) % of vaginal samples were HPV positive but the HPV type (Table 1). HPV61 and 81 were the most frequent low-risk could not be characterized. HPV types (n = 11 and 9 respectively). For 9.4% of the samples the HPV type could not be characterized. Table 1: Prevalence of 23 HPV types by collected site among 138 HIV-positive women. Santos, São Paulo, Brazil, 1996–1997 Site Cervix Vagina Anal Single Multiple Total (%) Single Multiple Total (%) Single Multiple Total (%) HPV - 53 (38.4) 47 (34.1) 37 (36.3) HPV + 50 35 85 (61.6) 47 44 91 (65.9) 36 29 65 (63.7) HR HPV+ 23 28 51 (37.0) 25 34 59 (42.8) 16 28 44 (43.1) LR HPV+ 24 23 47 (34.1) 19 30 49 (35.5) 15 20 35 (34.3) High-risk 16 7 6 13 (9.4) 6 11 17 (12.3) 4 5 9 (8.8) 18 4 8 12 (8.7) 4 8 12 (8.7) 2 10 12 (11.8) 31 0 5 5 (3.6) 1 5 6 (4.3) 2 1 3 (2.9) 33 3 4 7 (5.1) 1 7 8 (5.8) 2 4 6 (5.9) 39 0 1 1 (0.7) 1 0 1 (0.7) 0 1 1 (1.0) 45 0 2 2 (1.4) 0 2 2 (1.4) 0 1 1 (1.0) 52 0 1 1 (0.7) 0 2 2 91.4) 0 0 0 (0.0) 53 5 8 13 (9.4) 7 8 15 (10.9) 4 9 13 (12.7) 56 1 0 1 (0.7) 1 1 2 (1.4) 0 1 1 (1.0) 58 1 2 3 (2.2) 1 2 3 (2.2) 1 2 3 (2.9) 59 1 0 1 (0.7) 0 0 0 (0.0) 0 0 0 (0.00 66 0 3 3 (2.2) 0 3 3 (2.2) 0 4 4 (3.9) 68 1 1 2 (1.4) 3 1 4 (2.9) 1 0 1 (1.0) 73 0 1 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 82 0 2 2 (1.4) 0 2 2 (1.4) 0 0 0 (0.0) Subtotal 23 44 67 25 53 78 16 38 54 Low-risk 6 3 1 4 (2.9) 2 2 4 (2.9) 5 3 8 (7.8) 11 3 4 7 (5.1) 2 5 7 (5.1) 1 5 6 (5.5) 32 0 1 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 34 1 0 1 (0.7) 1 0 1 (0.7) 1 0 1 (1.0) 40 0 2 2 (1.4) 2 2 4 (2.9) 0 2 2 (1.8) 54 1 1 2 (1.4) 1 2 3 (2.2) 0 1 1 (1.0) 61 4 7 11 (8.0) 3 8 11 (8.0) 2 6 8 (7.3) 62 0 1 1 (0.7) 0 1 1 (0.7) 2 1 3 (2.7) 64 0 1 1 (0.7) 0 0 0 (0.0) 1 0 1 (1.0) 67 2 0 2 (1.4) 0 1 1 (0.7) 0 0 0 (0.0) 69 2 0 2 (1.4) 2 1 3 (2.2) 1 0 1 (1.0) 70 1 0 1 (0.7) 0 1 1 (0.7) 0 0 0 (0.0) 71 2 0 2 (1.4) 1 1 2 (1.4) 1 0 1 (1.0) 72 0 2 2 (1.4) 1 3 4 (2.9) 0 1 1 (1.0) 81 2 7 9 (6.5) 2 9 11 (8.0) 0 5 5 (4.6) 83 2 4 6 (4.3) 1 3 4 (2.9) 1 2 3 (2.7) 84 1 0 1 (0.7) 1 0 1 (0.7) 0 1 1 (1.0) Subtotal 24 31 55 19 40 59 15 27 42 Unknown 3 10 13 (9.4) 3 15 18 (13.0) 5 7 12 (11.8) Presented for 102 HIV-positive women. HPV = human papillomavirus; HIV = human immunodeficiency virus; HR = High-risk; LR = low-risk Page 3 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 In the anal area, the most frequently detected high-risk lence of HPV infection was similar in the cervix, vagina HPV types were, in decreasing order, HPV53 (n = 13), 18 and anal area. This also held true for the prevalence of the (n = 12), and 16 (n = 9). The most frequent low-risk HPV most frequently detected individual HPV types, notably types were HPV 61 and 6 (n = 8 for each). In 11.8% of anal HPV11, 16, 18, 53 and 61, and for the frequency of mul- samples the HPV type could not be characterized. HPV6, tiple-type infections. However, the same HPV type(s) were but not HPV11, tended to be more frequent in the anal not always present in the three examined anogenital areas area than in the cervix or vagina (7.8% in the anal area vs and the agreement in the detection of individual types was 2.9% in each other site). better between the cervix and the vagina than between the cervix and the anal area. The type most frequently detected In respect to cervical and vaginal sites, agreement for any at all three sites was HPV18, mainly on account of its high HPV type positivity was 78.3% (Kappa value = 0.53 for prevalence in the anal area. Recently, Castle et al. [19] any type) and varied from 92.8% (HPV16) to 98.6% reported that some HPV types (e.g., HPV61, 71 and 72), (HPV61 and HPV6). Kappa values above 0.80 were found were more frequently detected in vaginal specimens from for HPV18, 33 and 61. When cervical and anal sites were hysterectomized women compared to those who had not compared, agreement for positivity for any HPV type was undergone hysterectomy. Simultaneous HPV infection in found in 68.6% of women (Kappa value = 0.31) (Table 2). different anogenital sites is considered a risk factor for the The Kappa value was particularly low for HPV16 (0.11), concomitant occurrence of anal and cervical lesions, espe- but was relatively elevated for HPV18 (0.69), especially cially in HIV-positive women [20-22]. concerning the combination among the three sites (0.72). The factors most clearly associated with HPV positivity Risk factors for associations between sites for any HPV among HIV-positive women in our study agree with find- positivity ings from HIV-negative women [23,24]. Although the As shown in Table 3, HPV positivity were inversely associ- small number of women available did not allow most pre- ated with age in three combinations of anogenital sites sented ORs to reach statistical significance, we did show (cervical+anal; vaginal+anal and cervical+vaginal+anal), higher HPV positivity below age 25 than at age 35 or all of them including anal site. No association emerged in older, as well as among women who reported two recent any site between HPV positivity and smoking habits, his- sexual partners or more. These findings are consistent tory of drug addiction, commercial sex work and condom with the report that recent sexual partners are a stronger use, and number of years since HIV diagnosis. determinant of HPV positivity than the lifetime number of sexual partners [25]. No consistent relationship Anal intercourse showed an association of borderline sta- between HPV positivity and smoking habits or condom tistical significance in the combination vaginal + anal for use have emerged among HIV-negative women [23,24]. HPV positivity (OR: 2.4; 95% CI: 0.97–6.0), but not else- where. Nevertheless, condom use did not show associa- Two characteristics stand out as being more strongly asso- tions with HPV positivity at all sites. ciated with HPV positivity in the anal area than in the cer- vix and vagina, one being history of anal intercourse. This finding suggests that anal infection is associated among Discussion Approximately two-thirds of HIV-positive women in our women, as it is among bisexual and homosexual men, to study from Brazil were infected by HPV and the preva- direct HPV exposure [22,26]. Anal infection, however, can Table 2: Agreement of HPV type detection by collected site among 138 HIV-positive women. Santos, São Paulo, Brazil: 1996–1997 a a Cervix: Vagina Cervix: Anus Cervix, Vagina, Anus HPV type Cervix only Vagina only Both Agreement Cervix only Anal only Both Agreement Any of the All three Agreement (Kappa (Kappa three (Kappa value) value) value) 16 3 7 10 92.8 (0.63) 9 7 2 84.3 (0.11) 21 2 79.4 (0.32) 18 2 2 10 97.1 (0.82) 2 4 8 94.1 (0.69) 14 7 92.2 (0.72) 53 2 4 11 95.7 (0.76) 8 9 4 83.3 (0.23) 22 4 81.4 (0.45) 6 1 1 3 98.6 (0.74) 0 5 3 95.1 (0.52) 8 2 94.1 (0.55) 11 2 2 5 97.1 (0.70) 3 5 1 92.2 (0.16) 8 1 91.2 (0.33) 61 1 1 10 98.6 (0.90) 6 5 3 89.2 (0.29) 13 3 89.2 (0.54) Any type 12 18 73 78.3 (0.53) 17 15 50 68.6 (0.31) 83 45 59.8 (0.40) a b Available for 102 women only; Non-significant Kappa value. HPV = human papillomavirus; HIV = human immunodeficiency virus. Page 4 of 7 (page number not for citation purposes) a Table 3: ORs ofHPV positivity and corresponding 95% CIs according to selected characteristics among 138 HIV-positive women . Santos, São Paulo, Brazil, 1996–1997 b b b Cervical+Vaginal Cervical+Anal Vaginal+Anal Cervical+Vaginal+Anal c c c c Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Tot. No Pos. (%) OR 95% CI Age (years) ≥ 35 39 38.5 1 30 10.0 1 30 13.3 1 30 6.7 1 25–34 75 49.3 1.6 0.7–3.4 55 27.3 3.4 0.9–12.8 55 34.6 3.4 1.0–11.3 55 27.3 5.3 1.1–24.8 < 25 24 58.3 2.2 0.8–6.3 17 47.1 8.0 1.7–36.8 17 41.2 4.6 1.1–19.0 17 35.3 7.6 1.3–43.8 p for trend 0.12 0.006 0.03 0.02 Tobacco smoking Never smoker 44 45.5 1 32 31.3 1 32 31.3 1 32 21.9 1 Ex-smoker 33 45.5 1.1 0.4–2.8 26 30.8 1.1 0.3–3.8 26 34.6 1.2 0.4–3.7 26 30.8 1.7 0.5–6.1 Current smoker 61 50.8 1.3 0.6–3.0 44 18.2 0.5 0.2–1.7 44 25.0 0.8 0.3–2.2 44 18.2 0.9 0.3–2.9 p for trend 0.46 0.22 0.52 0.60 Drug addict Never 79 45.6 1 62 25.8 1 62 25.8 1 62 21.0 1 Ex 36 52.8 1.3 0.6–2.8 24 29.2 1.1 0.4–3.2 24 45.8 2.2 0.8–6.2 24 29.2 1.4 0.5–4.2 Current 23 47.8 1.0 0.4–2.7 16 18.8 0.7 0.2–2.9 16 18.8 0.6 0.2–2.6 16 18.8 0.8 0.2–3.5 p for trend 0.80 0.70 0.99 0.98 Years since HIV diagnosis ≤ 1 54 46.3 1 40 27.5 1 40 32.5 1 40 22.5 1 2–4 43 39.5 0.8 0.4–1.9 34 60.529.4 1.3 0.4–3.8 34 32.4 1.0 0.4–2.8 34 26.5 1.3 0.4–4.2 ≥ 5 39 56.4 1.8 0.7–4.2 26 19.2 0.7 0.2–2.8 26 23.1 0.5 0.2–1.9 26 19.2 0.8 0.2–3.1 p for trend 0.25 0.73 0.38 0.81 CD4 count/mm ≥ 500 34 41.2 1 20 15.0 1 20 15.0 1 20 10.0 1 200–499 51 49.0 1.8 0.7–4.7 39 23.1 4.2 0.8–22.2 39 30.8 4.8 1.0–22.7 39 23.1 5.7 0.9–34.1 < 200 53 59.9 1.8 0.7–4.6 43 32.6 5.9 1.2–28.6 43 34.9 5.0 1.1–22.4 43 27.9 6.2 1.1–34.9 p for trend 0.24 0.03 0.06 0.06 Commercial sex worker Never 107 46.7 1 82 24.4 1 82 26.8 1 82 20.7 1 Ever 31 51.6 1.2 0.5–2.6 20 30.0 1.2 0.4–3.8 20 40.0 1.7 0.6–4.8 20 30.0 1.5 0.5–4.6 Lifetime number of sexual partners ≤ 2 34 41.2 1 26 26.9 1 26 30.8 1 26 26.9 1 3–5 44 52.3 1.5 0.6–3.8 35 25.7 0.9 0.3–2.9 35 25.7 0.7 0.2–2.3 35 17.1 0.5 0.1–1.8 ≥ 6 60 48.3 1.2 0.5–3.0 41 24.4 0.7 0.2–2.3 41 31.7 0.8 0.3–2.6 41 24.4 0.7 0.2–2.2 p for trend 0.63 0.32 0.85 0.53 Recent sexual partners 0 48 43.8 1 42 21.4 1 42 26.2 1 42 21.4 1 1 74 47.3 1.0 0.5–2.1 51 25.5 0.8 0.3–2.4 51 27.5 0.8 0.3–2.0 51 19.6 0.6 0.2–1.7 ≥ 2 13 76.9 3.5 0.8–15.0 9 44.4 2.2 0.5–10.7 9 55.6 2.6 0.5–12.0 9 44.4 2.0 0.4–9.5 p for trend 0.21 0.56 0.52 0.83 Condom use Yes 69 47.8 1 47 25.5 1 47 27.7 1 47 19.2 1 No 20 60.0 1.7 0.6–4.8 13 38.5 2.0 0.5–7.6 13 46.2 2.4 0.7–8.8 13 38.5 2.9 0.7–11.6 Anal intercourse Never 66 48.5 1 51 19.6 1 51 19.6 1 51 19.6 1 Ever 72 47.2 0.9 0.5–1.8 51 31.4 1.7 0.6–4.3 51 39.2 2.4 0.97–6.0 51 25.5 1.2 0.5–3.2 a b c d Some figures do not add up to the total due to missing values; Presented for 102 HIV-positive women; Adjusted for age. HPV = human papillomavirus; relative to the last 6 months preceding interview; HIV = human immunodeficiency virus; OR = odds ratio; CI = confidence intervals. Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 Page 5 of 7 (page number not for citation purposes) Infectious Agents and Cancer 2008, 3:5 http://www.infectagentscancer.com/content/3/1/5 9. Palefsky JM, Minkoff H, Kalish LA, Levine A, Sacks HS, Garcia P, Young also be detected in women who do not report anal inter- M, Melnick S, Miotti P, Burck R: Cervicovaginal human papillo- course, particularly if a concomitant infection occurs at a mavirus infection in human immunodeficiency virus-1 (HIV)- genital site [27,28]. The other factor that appeared more positive and high-risk HIV-negative women. J Natl Cancer Inst 1999, 91:226-236. strongly associated with anal than cervical or vaginal HPV 10. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, Brudney K, infection was low CD4 counts, thus suggesting that Wright TC: Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000, 283:1031-1037. immunosupression may particularly facilitate HPV infec- 11. Strickler HD, Palefsky JM, Shah KV, Anastos K, Klein RS, Minkoff H, tion and maybe persistence in the anal area. Duerr A, Massad LS, Celentano DD, Hall C, Fazzari M, Cu-Uvin S, Bacon M, Schuman P, Levine AM, Durante AG, Gange S, Melnick S, Burk RD: Human papillomavirus type 16 and immune status One of the limitations of this work is its small sample size. in human immunodeficiency virus-seropositive women. J As a consequence, many relatively strong associations did Natl Cancer Inst 2003, 95:1062-1071. not attain statistical significance. Furthermore, the cross- 12. 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