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The prevalence of cervical cytology abnormalities and human papillomavirus in women infected with the human immunodeficiency virus

The prevalence of cervical cytology abnormalities and human papillomavirus in women infected with... Introduction: The human papillomavirus (HPV) is the major etiologic agent in the development of cervical cancer and its natural history of infection is altered in persons infected with the human immunodeficiency virus (HIV). The prevalence of HPV infection and cervical dysplasia in the HIV sero-positive females in the Bahamas is not known. Finding out the prevalence would allow for the establishment of protocols to optimize total care of this population and help prevent morbidity and mortality related to cervical cancer. Objective: The Objective of this study is to determine the prevalence of high risk HPV genotypes and the prevalence of cervical dysplasia in the HIV sero-positive females attending the Infectious Disease Clinic at the Princess Margaret Hospital, Nassau, Bahamas. Methods: One hundred consecutive, consenting, non-pregnant, HIV-sero-positive females from the Infectious Disease Clinic at the Princess Margaret Hospital in Nassau, Bahamas were screened for high-risk HPV infections and cervical cytology abnormalities using liquid-based pap smear and signal amplification nucleic acid method for HPV detection. A questionnaire was also utilized to gather demographic information and obtain information on known risk factors associated with HPV infections such numbers of partners. Results: The prevalence of high-risk HPV was 67% and cervical abnormalities were noted in 44% of the study population. High-risk HPV types were more likely to be present in women with CD4+ cell counts less than 400 -1 μl and in women with cervical cytology abnormalities (97%). The most common cervical abnormality was low- grade squamous intraepithelial lesions. Conclusion: Findings suggest that HIV-sero positive females should have HPV testing done as part of their normal gynecology evaluation and these patients should be encouraged and provisions be made for ease of access having regular PAP smears and HPV testing. Page 1 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 ics Committee of the Public Hospital Authority and the Background The human papillomavirus (HPV) is the major etiologic University of the West Indies – Bahamas Campus. agent in the development of cervical cancer [1] with known risk factors such an early age at first intercourse, Sample and data collection history of multiple sexual partners, oral contraceptive use, Each participant had a vaginal examination performed by high parity, lower socioeconomic status, and immuno- an Obstetrics and Gynaecology Resident. Cervical samples suppression. In immunocompetent subjects, HPV infec- were collected using a cytobrush (cytobroom) and stored tions normally clear in six to twenty-four months in 70% in Sure Path vials. A cytotechnologist screened the pre- of females [2]. The natural history of HPV infection is pared slides. All positive results and fifteen percent (15%) altered in persons infected with the human immunodefi- of all negatives results were reviewed by a board certified ciency virus (HIV) and there is an increased likelihood of cytopathologist. The cytology was reported as either nega- persistent HPV infections in this population [3]. This per- tive, atypical squamous cells of unknown significance sistent infection increases their risk of having cervical dys- (ASCUS), low-grade squamous intraepithelial lesion plasia and cervical intraepithelial neoplasms (CIN) [3,4]. (LGSIL) or high-grade squamous intraepithelial lesion HIV-positive women especially those with severe immu- (HGSIL). Additionally co-infections as well as presence of nosuppression are five times more likely than HIV sero- HPV changes were noted. The Obstetrics and Gynaecology negative women to have lower genital tract neoplasias Oncologist referred all patients with abnormal cytology [4,7]. High HPV load in HIV-positive women is associated results to Colposcopy Clinic for further evaluation, treat- with a 10-fold increase risk of CIN in severe immunosup- ment and follow-up as determined. pression [5]. Recent studies indicate that plasma HIV RNA levels and CD4+ cell counts are strong determinants of the Each patient was interviewed and a questionnaire com- ability to detect HPV suggesting that as the immune sys- pleted by the interviewer. Information on associated HPV tem weakens, it facilitates reactivation of the HPV thus risk factors such as parity, number of sexual partners, and helping to explain the increase rates of HPV infection in birth control method, risky behavior such as drug use, sex women with HIV [6,7]. Additionally, Highly Active Anti- under the influence of drugs and condom usage as well as Retroviral Therapy (HAART) does not seem to impact this demographic were obtained via the questionnaire. The increased rate or persistent of HPV infections in this pop- medical records were reviewed to obtain patient's date of ulation [8]. For many years the focus of care for HIV sero- HIV testing and confirm sero-positivity, most recent positive patients in the Bahamas was on immune system CD4+ lymphocyte counts and viral load, and use of high reconstitution using HAART. Patients receiving HAART active anti-retroviral therapy. die less frequently from opportunistic infections but more now face morbidity from chronic medical diseases and CD4+ and viral load other illnesses including malignancies. One such prevent- Samples collected from patients were stained with Flow- able disease is cervical cancer. There is no available data CARE PLG CD4 Reagent. CD4+ lymphocytes counts were from the Bahamas or the Caribbean that documents the determined by flow cytometry. White blood cell counts prevalence of cervical dysplasia or HPV infections in HIV were obtained with a COULTER STKS Instrument. The sero-positive females. values were expressed in terms of percentage (%) of total lymphocytes and absolute count (cells/μL). Study goal The goal of the study is to determine the prevalence of The DNA HIV viral load was tested using a quantiplex high-risk HPV infections and associated cervical abnor- HIV-1 RNA 3.0 Assay. This assay is a nucleic acid hydridi- malities in HIV sero-positive females in the Bahamas. zation procedure to directly quantify HIV-1 RNA in human plasma. The HIV-1 is concentrated from the plasma by centrifugation then the genomic RRNA is liber- Methods Study population ated from the virions and captured on a microwell by spe- One hundred (100) consecutive, consenting, non-preg- cific synthetic oligonucleotide capture probes. The probes nant, HIV sero-positive females (18) years or older were bind to different regions of the pol gene of the viral RNA recruited from the Infectious Disease Clinic at the Princess which is them amplified. Margaret Hospital in Nassau, Bahamas. The criteria for eli- gibility required all of the following: Females 18 years and Multiple copies of the alkaline phosphatase-labelled older, a positive HIV via ELISA and Western Blot methods probe are then hybridized to an immobilized complex to and HIV infectivity via sexual intercourse. All participants amplify the signal. Detection is achieved by incubating were interviewed, provided informed written consent and the complex with a chemiluminescent substrate. The light had a liquid based pap smeared performed after receiving emission generated by the bound alkaline phosphatase consent. The study received ethical approval from the Eth- reacting with the chemiluminescent substrate is recorded Page 2 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 1: Demographics and characteristics of the study as relative light units (RLUs). The light emission is directly population proportional to the amount of HIV-1 present in each sam- ple. A standard curve is defined by light emission from standards containing known concentrations of beta proiolactone (BPL)-treated virus. Concentrations of HIV- Marital Status 1 RNA in plasma specimens are determined form this Single 56 Married 24 standard curve. Divorced 9 Widowed 11 HPV testing Nationality HPV was detected using the HPV Hybrid Capture II assay Bahamians 94 which is a signal amplification nucleic acid method for Haitians 4 the qualitative detection of eighteen types of human pap- Jamaicans 2 illomavirus (HPV) DNA in cervical specimens. The assay Alcohol Use Never 52 differentiates between high risk and low risk groups. High Ever 48 HPV types detected are 16, 18, 31, 33, 35, 39, 45, 51, 52, Marijuana Use 56, 58, 59 and 68. Never 82 Ever 18 Statistical analysis Tobacco Use Clinical and laboratory risk factors for the study popula- Never 89 tion were imported to a statistical software package for Ever 11 HAART Therapy analysis. Statistical analyses were performed using the No 18 Intercooled STATA (version SE 10.0) software (StataCorp. Yes 81 LP, College Station TX). Factors associated with high-risk Cervical Cytology HPV status were selected based on cross-tabulations and Negative 56 univariate logistic regression analyses. Cross-tabulations ASCUS 7 were analyzed using the Fisher's exact test. Logistic regres- LGSIL 31 HGSIL 6 sion was used to perform the analyses of associations High Risk HPV between demographic, behavioral and clinical variables Negative 32 with high-risk HPV status. Crude odds ratios were first cal- Positive 67 culated. Potential confounders were identified based on Not available 1 p-values = 0.05. Logistic regression was used to calculate Total 100 the relative odds of high-risk HPV status after adjusting for the potential confounders (age (continuous), marital sta- tus, number of pregnancies, Tobacco use, duration of found to have abnormal cervical cytology with 95% test- HAART therapy, CD4 counts, viral load and cervical cytol- ing positive for high-risk HPV. Seven patients (7%) had ogy). ASCUS, LGSIL in 31 (31%) and HGSIL in six (6%) partic- ipants. Results Characteristics of the study population High-risk HPV infections and behavior One hundred females ranging from ages 20–71 years were Adjusting for potential confounders (Adjusted Odds Ratio interviewed and had a PAP smear performed. The mean [AdjOR] 27.0, 95% confidence interval [CI] 2.0–355.3), and median ages were 40.1 years and 39 years respec- one hundred percent of participants with HGSIL were tively. Fifty-six participants (56%) were single and twenty- high-risk HPV positive (Table 2). four (24%) were married (Table 1). Ninety-four partici- pants were Bahamians with only 6% accounting for other There were no statistically significant associations nationalities. Thirty-nine percent reported their age of first observed between high-risk HPV infections and alcohol sexual intercourse prior to age 16 years and seventy partic- use, marijuana use, tobacco use or cocaine use. There were ipants (70%) were sexually active before the age of 18 no associations between high-risk HPV infections and years. Sixty participants (60%) had five or more lifetime genital herpes, gonorrhea, syphilis, chancroid, trichomo- sexual partners. niasis or Chlamydia infections, (p > 0.1). Of note, partic- ipants with greater than ten lifetime sexual partners were Sixty-seven women (67%) tested positive for high-risk four times more likely to have high-risk HPV infections HPV genotypes. The proportion of high-risk HPV-positive than those with less than 10 lifetime sexual partners women was significantly higher than those who are HPV- (AdjOR 4.4, 95% CI 0.7 – 29.6). This finding was not sta- negative (p = 0.001). Forty-four women (44%) were tistically significant. Page 3 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 2: Association of high-risk HPV with behavioral variables High Risk HPV Infections Negative (32) Positive (67) Odds Ratio Adjusted Odds Ratio N N (95% CI) (95% CI)* Age <40 10 42 1.0 (ref) 1 (ref) 40+ 22 25 0.3 (0.1–0.7) 0.4 (0.1–1.5) Birth-control method None 5 7 0.6 (0.1 – 2.3) 0.3 (0.0 – 5.1) Barrier 10 24 1.0 (ref) 1.0 (ref) No barrier 2 12 2.5 (0.5–13.3) 6.8 (0.7 – 67.8) Abstinence 15 24 0.7 (0.3 – 1.8) 0.5 (0.1 – 2.5) Age at menarche <13 years 10 22 1.0 (ref) 1.0 (ref) 13+ years 22 45 0.9 (0.4 – 2.3) 2.3 (0.5–9.8) Number of pregnancies <3 6 31 1.0 (ref) 1.0 (ref) 3+ 26 36 0.3 (0.1 – 0.7) 0.2 (0.1 – 0.99) Age of first sexual intercourse <16 years 12 27 1.0 (ref) 1.0 (ref) 16+ years 20 40 0.9 (0.4 – 2.1) 1.0 (0.3 – 3.8) Lifetime number of sex partners <5 11 28 1.0 (ref) 1.0 (ref) 5 to 10 16 24 0.6 (0.2 – 1.5) 1.2 (0.3 – 5.4) >10 5 15 1.2 (0.3 – 4.0) 4.4 (0.7 – 29.6) Alcohol Never 18 34 1.0 (ref) 1.0 (ref) Ever 14 33 1.3 (0.5 – 2.9) 1.7 (0.4 – 6.8) Marijuana Never 27 54 1.0 (ref) 1.0 (ref) Ever 5 13 1.3 (0.4 – 4.0) 7.0 (0.5 – 91.2) Tobacco Never 27 63 1.0 (ref) 1.0 (ref) Ever 7 4 0.2 (0.1 – 0.8) 0.2 (0.04 – 1.6) ref = reference; *Adjusted for age (continuous), marital status, number of pregnancies, Tobacco use, duration of HAART therapy, CD4 counts, viral load and cervical cytology; Birth control method: Barrier = male condom, No barrier = birth control pill or Depo-Provera High-risk HPV infection and clinical correlates of HIV 12]. The increased risk of HPV infections in sero-positive infection women with multiple partners and early onset of sexual The mean and median CD4+ lymphocyte counts were activities only confirm what multiple studies have dem- 339.15 and 260 respectively. Twenty-three participants onstrated previously. There is a strong correlation -1 (23%) had CD4+ counts ≥ 500 μl , 38 (38%) had CD4+ between the presence of high-risk HPV and cervical cytol- -1 counts between 200 and 499 μl , and 39 (39%) had ogy abnormalities. Forty-one of the forty-four patients -1 CD4+ counts less that 200 μl . After adjusting for poten- with cervical cytology abnormalities were high-risk HPV tial confounders, subjects with CD4+ counts greater than positive demonstrating the role of high-risk HPV in cervi- -1 400 μl were less likely to test positive for high-risk HPV cal dysplasia. Participants were not tested for low-risk (AdjOR 0.2, 95% CI: 0.05 – 0.8, p = 0.019) (Table 3). HPV genotypes. HIV sero-positive women tend to be infected with multiple genotypes of HPV [10,11]. Three Discussion participants with cervical abnormalities were not high- High-risk HPV is prevalent in the HIV sero-positive risk HPV positive and may have infections with low risk females attending the Infectious Disease Clinic at the HPV genotypes. There is a lack of evidence to suggest that Princess Margaret Hospital. Unfortunately, a comparison low-risk HPV genotypes do not play a role in the increase with the HIV sero-negative population could not be done level of cervical abnormalities and cervical intraepithelial as there is no published HPV prevalence study for the gen- lesions in this immune-compromised population. eral population. The high prevalence reported in this study is not unusual with HPV infections being quoted as Subjects living with HIV infection for two to six years were anywhere from 33–47% in other published studies [9- three times more likely to carry high-risk HPV infections Page 4 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 3: Association of high-risk HPV infection with variables associated with HIV infection High Risk HPV Infections Negative (32) Positive (67) Odds Ratio Adjusted Odds Ratio N N (95% CI) (95% CI)* Years living with HIV <2 8 21 1 (ref) 1 (ref) 2 to 6) 12 13 2.4 (0.8 – 7.5) 3.0 (0.5 – 18.5) 6+ 12 33 2.5 (0.9 – 7.1) 1.7 (0.3 – 9.2) Duration of HAART therapy <3 12 42 1 (ref) 1 (ref) 3+ 20 25 0.4 (0.1 – 0.9) 0.4 (0.1 – 1.4) CD4 count <400 11 57 1 (ref) 1 (ref) 400+ 21 10 0.1 (0.03 – 0.2) 0.2 (0.05 – 0.8) HIV viral load <50 23 22 1 (ref) 1 (ref) 50 – 28,000 8 26 3.4 (1.3 – 9.1) 1.9 (0.5 – 7.2) >28,000 1 19 19.9 (2.4 – 161.3) 2.2 (0.2 – 25.9) Cervical cytology Negative 29 25 1 (ref) 1 (ref) ASCUS 1 6 LGSIL 2 29 HGSIL 0 6 ref = reference; *Adjusted for age (continuous), marital status, number of pregnancies, Tobacco use, duration of HAART therapy, CD4 counts, viral load and cervical cytology than those infected for less than two years, however this sero-positive females should be an integral component of association was not significant (p > 0.1). Similarly, their routine gynaecological evaluation and these patients women who lived with HIV infections for more than 6 should be encouraged and provisions be made for ease of years were almost two times more likely to carry high-risk access to having regular PAP smears and HPV testing. HPV infections however; this also was not significant. Competing interests Individuals with a CD4+ lymphocyte count of less than The authors declare that they have no competing interests. 400 μl- were more likely to test positive for high-risk HPV genotypes. As CD4+ count is a reflection of the state of the Authors' contributions immune system, it reasonable to assume that the immune DND conceived of the study, participated in its design and dysfunction noted at lower CD4+ levels is responsible for coordination and drafted the manuscript. CR performed the increased detection of high-risk HPV in these women. the statistical analysis and reviewed the manuscript. AGB performed the Pap smears and cervical examination. RB An increased number of lifetime sexual partners was asso- sourced the funding, helped with coordination of the ciated with an increased likelihood of testing positive for study, provided further management for patients with high-risk HPV. Other behavioral variables such as cocaine detected abnormalities and reviewed the manuscript. use, alcohol use and non-barrier method did not show the expected increased risk. This lack of increased risk could Acknowledgements Special thanks to the staff of the Infectious Diseases division, the Depart- be the result of a relatively small study population. ment of Pathology, and Laboratory Services at the Princess Margaret Hos- pital as well as the staff of Premier Clinical Laboratory. Conclusion The high prevalence of high-risk HPV genotypes and cer- This article has been published as part of Infectious Agents and Cancer. Vol- vical cytology abnormalities demonstrates the need to ume 4 Supplement 1, 2009: Second Annual International African-Caribbean screen and monitor HIV sero-positive women and to Cancer Consortium Conference. The full contents of the supplement are implement preventative measures to decrease the num- available online at http://www.infectagentscancer.com/supplements/4/S1. bers of females with high risk HPV infections. Most partic- ipants reported not having yearly PAP smears and References 1. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC: unfortunately, routine HPV screening is not conducted at Human Papillomavirus Infection in Women Infected with the public facilities where most of these patients receive the Human Immunodeficiency Virus. NEJM 1997, their PAP smears. Screening for HPV infections in HIV 337:1343-1349. Page 5 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 2. Kanowitz S, Miller SB, Stone J, Hanson E: The Natural History of Human Papillomavirus Infection as Measured by Repeated DNA testing in Adolescent and Young Women. J Pediatr 1998, 132(2):277-84. 3. Strickler HD, Burk RD, Fazzari M, nastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Sch- lecht NF, Melnick S, Palefsky JM: Natural History and Possible Reactivation of Human Paillomavirus in Human Immunode- ficiency Virus-Positive Women. J Natl Cancer Inst 2005, 97:577-586. 4. Sun XW, Ellerbrock TV, Lungu O, Chiasson MA, Bush TJ, Wright TC Jr: Human papillomavirus infection in human immunodefi- ciency virus-seropositive women. Obstet Gynecol 1995, 85:680-686. 5. Vermund SH, Kelley KF, Klein RS, et al.: High risk of human papil- lomavirus infection and cervical squamous intraepithelial lesions among woman with symptomatic human immunode- ficiency virus infection. Am J Obstet Gynecol 1991, 165:392-400. 6. Ferenczy Alex, Coutlee Francois, Franco Eduardo, et al.: Human papillomavirus coinfection and the risk of neoplasia of the lower genital tract: a review of recent developments. Cana- dian Medical Association Journal 2003, 169:431-434. 7. Harris TG, Burk RD, Palesky JM, Massad LS, Bang JY, Anastos K, Minkoff H, Hall CB, Bacon MC, Levine AM, Watts H, Silverberg MJ, Xue X, Melick SL, Strickler HD: Incidence of cervical intraepithe- lial lesions associated with HIV serostatus, CD4 cell counts and human paillomavirus test results. JAMA 2005, 293:1471-1476. 8. de Sanjose S, Palefsky J: Cervical and anal HIV infections in HIV positive women and men. Virus Research 89(2):201-211. 9. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, BRudney K, Wright TC Jr: Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000, 283:1031-1037. 10. Langley CL, Benga-De E, Critchlow CW, Ndoye I, Mbengue Ly, Kuy- pers J, Woto-Gaye G, Myboup S, Bergeron C, Holmes KK, Kiviat NB: HIV-1, HIV-2, human papillomavirus infection and cervical neoplasia in high-risk African women. AIDS 1996, 10(4):413-417. 11. Blossom DB, Beigi RH, Farrell JJ, et al.: Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women. J Med Virol 2007, 79(6):758-65. 12. Joshi SN, Gopalkrishna , Kumar BK, Dutta S, Hyaynirgune P, Thankar M, Tripathy S, Mehendale S, Paranjape R: Cervical squamous intra- epithelial changes and human papillomavirus infection in women infected with human immunodeficiency virus in Pune, India. J Med Virol 2005, 76(4):470-5. 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 6 of 6 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Infectious Agents and Cancer Springer Journals

The prevalence of cervical cytology abnormalities and human papillomavirus in women infected with the human immunodeficiency virus

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Publisher
Springer Journals
Copyright
Copyright © 2009 by Dames et al; licensee BioMed Central Ltd.
Subject
Biomedicine; Cancer Research; Infectious Diseases; Oncology
eISSN
1750-9378
DOI
10.1186/1750-9378-4-S1-S8
pmid
19208213
Publisher site
See Article on Publisher Site

Abstract

Introduction: The human papillomavirus (HPV) is the major etiologic agent in the development of cervical cancer and its natural history of infection is altered in persons infected with the human immunodeficiency virus (HIV). The prevalence of HPV infection and cervical dysplasia in the HIV sero-positive females in the Bahamas is not known. Finding out the prevalence would allow for the establishment of protocols to optimize total care of this population and help prevent morbidity and mortality related to cervical cancer. Objective: The Objective of this study is to determine the prevalence of high risk HPV genotypes and the prevalence of cervical dysplasia in the HIV sero-positive females attending the Infectious Disease Clinic at the Princess Margaret Hospital, Nassau, Bahamas. Methods: One hundred consecutive, consenting, non-pregnant, HIV-sero-positive females from the Infectious Disease Clinic at the Princess Margaret Hospital in Nassau, Bahamas were screened for high-risk HPV infections and cervical cytology abnormalities using liquid-based pap smear and signal amplification nucleic acid method for HPV detection. A questionnaire was also utilized to gather demographic information and obtain information on known risk factors associated with HPV infections such numbers of partners. Results: The prevalence of high-risk HPV was 67% and cervical abnormalities were noted in 44% of the study population. High-risk HPV types were more likely to be present in women with CD4+ cell counts less than 400 -1 μl and in women with cervical cytology abnormalities (97%). The most common cervical abnormality was low- grade squamous intraepithelial lesions. Conclusion: Findings suggest that HIV-sero positive females should have HPV testing done as part of their normal gynecology evaluation and these patients should be encouraged and provisions be made for ease of access having regular PAP smears and HPV testing. Page 1 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 ics Committee of the Public Hospital Authority and the Background The human papillomavirus (HPV) is the major etiologic University of the West Indies – Bahamas Campus. agent in the development of cervical cancer [1] with known risk factors such an early age at first intercourse, Sample and data collection history of multiple sexual partners, oral contraceptive use, Each participant had a vaginal examination performed by high parity, lower socioeconomic status, and immuno- an Obstetrics and Gynaecology Resident. Cervical samples suppression. In immunocompetent subjects, HPV infec- were collected using a cytobrush (cytobroom) and stored tions normally clear in six to twenty-four months in 70% in Sure Path vials. A cytotechnologist screened the pre- of females [2]. The natural history of HPV infection is pared slides. All positive results and fifteen percent (15%) altered in persons infected with the human immunodefi- of all negatives results were reviewed by a board certified ciency virus (HIV) and there is an increased likelihood of cytopathologist. The cytology was reported as either nega- persistent HPV infections in this population [3]. This per- tive, atypical squamous cells of unknown significance sistent infection increases their risk of having cervical dys- (ASCUS), low-grade squamous intraepithelial lesion plasia and cervical intraepithelial neoplasms (CIN) [3,4]. (LGSIL) or high-grade squamous intraepithelial lesion HIV-positive women especially those with severe immu- (HGSIL). Additionally co-infections as well as presence of nosuppression are five times more likely than HIV sero- HPV changes were noted. The Obstetrics and Gynaecology negative women to have lower genital tract neoplasias Oncologist referred all patients with abnormal cytology [4,7]. High HPV load in HIV-positive women is associated results to Colposcopy Clinic for further evaluation, treat- with a 10-fold increase risk of CIN in severe immunosup- ment and follow-up as determined. pression [5]. Recent studies indicate that plasma HIV RNA levels and CD4+ cell counts are strong determinants of the Each patient was interviewed and a questionnaire com- ability to detect HPV suggesting that as the immune sys- pleted by the interviewer. Information on associated HPV tem weakens, it facilitates reactivation of the HPV thus risk factors such as parity, number of sexual partners, and helping to explain the increase rates of HPV infection in birth control method, risky behavior such as drug use, sex women with HIV [6,7]. Additionally, Highly Active Anti- under the influence of drugs and condom usage as well as Retroviral Therapy (HAART) does not seem to impact this demographic were obtained via the questionnaire. The increased rate or persistent of HPV infections in this pop- medical records were reviewed to obtain patient's date of ulation [8]. For many years the focus of care for HIV sero- HIV testing and confirm sero-positivity, most recent positive patients in the Bahamas was on immune system CD4+ lymphocyte counts and viral load, and use of high reconstitution using HAART. Patients receiving HAART active anti-retroviral therapy. die less frequently from opportunistic infections but more now face morbidity from chronic medical diseases and CD4+ and viral load other illnesses including malignancies. One such prevent- Samples collected from patients were stained with Flow- able disease is cervical cancer. There is no available data CARE PLG CD4 Reagent. CD4+ lymphocytes counts were from the Bahamas or the Caribbean that documents the determined by flow cytometry. White blood cell counts prevalence of cervical dysplasia or HPV infections in HIV were obtained with a COULTER STKS Instrument. The sero-positive females. values were expressed in terms of percentage (%) of total lymphocytes and absolute count (cells/μL). Study goal The goal of the study is to determine the prevalence of The DNA HIV viral load was tested using a quantiplex high-risk HPV infections and associated cervical abnor- HIV-1 RNA 3.0 Assay. This assay is a nucleic acid hydridi- malities in HIV sero-positive females in the Bahamas. zation procedure to directly quantify HIV-1 RNA in human plasma. The HIV-1 is concentrated from the plasma by centrifugation then the genomic RRNA is liber- Methods Study population ated from the virions and captured on a microwell by spe- One hundred (100) consecutive, consenting, non-preg- cific synthetic oligonucleotide capture probes. The probes nant, HIV sero-positive females (18) years or older were bind to different regions of the pol gene of the viral RNA recruited from the Infectious Disease Clinic at the Princess which is them amplified. Margaret Hospital in Nassau, Bahamas. The criteria for eli- gibility required all of the following: Females 18 years and Multiple copies of the alkaline phosphatase-labelled older, a positive HIV via ELISA and Western Blot methods probe are then hybridized to an immobilized complex to and HIV infectivity via sexual intercourse. All participants amplify the signal. Detection is achieved by incubating were interviewed, provided informed written consent and the complex with a chemiluminescent substrate. The light had a liquid based pap smeared performed after receiving emission generated by the bound alkaline phosphatase consent. The study received ethical approval from the Eth- reacting with the chemiluminescent substrate is recorded Page 2 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 1: Demographics and characteristics of the study as relative light units (RLUs). The light emission is directly population proportional to the amount of HIV-1 present in each sam- ple. A standard curve is defined by light emission from standards containing known concentrations of beta proiolactone (BPL)-treated virus. Concentrations of HIV- Marital Status 1 RNA in plasma specimens are determined form this Single 56 Married 24 standard curve. Divorced 9 Widowed 11 HPV testing Nationality HPV was detected using the HPV Hybrid Capture II assay Bahamians 94 which is a signal amplification nucleic acid method for Haitians 4 the qualitative detection of eighteen types of human pap- Jamaicans 2 illomavirus (HPV) DNA in cervical specimens. The assay Alcohol Use Never 52 differentiates between high risk and low risk groups. High Ever 48 HPV types detected are 16, 18, 31, 33, 35, 39, 45, 51, 52, Marijuana Use 56, 58, 59 and 68. Never 82 Ever 18 Statistical analysis Tobacco Use Clinical and laboratory risk factors for the study popula- Never 89 tion were imported to a statistical software package for Ever 11 HAART Therapy analysis. Statistical analyses were performed using the No 18 Intercooled STATA (version SE 10.0) software (StataCorp. Yes 81 LP, College Station TX). Factors associated with high-risk Cervical Cytology HPV status were selected based on cross-tabulations and Negative 56 univariate logistic regression analyses. Cross-tabulations ASCUS 7 were analyzed using the Fisher's exact test. Logistic regres- LGSIL 31 HGSIL 6 sion was used to perform the analyses of associations High Risk HPV between demographic, behavioral and clinical variables Negative 32 with high-risk HPV status. Crude odds ratios were first cal- Positive 67 culated. Potential confounders were identified based on Not available 1 p-values = 0.05. Logistic regression was used to calculate Total 100 the relative odds of high-risk HPV status after adjusting for the potential confounders (age (continuous), marital sta- tus, number of pregnancies, Tobacco use, duration of found to have abnormal cervical cytology with 95% test- HAART therapy, CD4 counts, viral load and cervical cytol- ing positive for high-risk HPV. Seven patients (7%) had ogy). ASCUS, LGSIL in 31 (31%) and HGSIL in six (6%) partic- ipants. Results Characteristics of the study population High-risk HPV infections and behavior One hundred females ranging from ages 20–71 years were Adjusting for potential confounders (Adjusted Odds Ratio interviewed and had a PAP smear performed. The mean [AdjOR] 27.0, 95% confidence interval [CI] 2.0–355.3), and median ages were 40.1 years and 39 years respec- one hundred percent of participants with HGSIL were tively. Fifty-six participants (56%) were single and twenty- high-risk HPV positive (Table 2). four (24%) were married (Table 1). Ninety-four partici- pants were Bahamians with only 6% accounting for other There were no statistically significant associations nationalities. Thirty-nine percent reported their age of first observed between high-risk HPV infections and alcohol sexual intercourse prior to age 16 years and seventy partic- use, marijuana use, tobacco use or cocaine use. There were ipants (70%) were sexually active before the age of 18 no associations between high-risk HPV infections and years. Sixty participants (60%) had five or more lifetime genital herpes, gonorrhea, syphilis, chancroid, trichomo- sexual partners. niasis or Chlamydia infections, (p > 0.1). Of note, partic- ipants with greater than ten lifetime sexual partners were Sixty-seven women (67%) tested positive for high-risk four times more likely to have high-risk HPV infections HPV genotypes. The proportion of high-risk HPV-positive than those with less than 10 lifetime sexual partners women was significantly higher than those who are HPV- (AdjOR 4.4, 95% CI 0.7 – 29.6). This finding was not sta- negative (p = 0.001). Forty-four women (44%) were tistically significant. Page 3 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 2: Association of high-risk HPV with behavioral variables High Risk HPV Infections Negative (32) Positive (67) Odds Ratio Adjusted Odds Ratio N N (95% CI) (95% CI)* Age <40 10 42 1.0 (ref) 1 (ref) 40+ 22 25 0.3 (0.1–0.7) 0.4 (0.1–1.5) Birth-control method None 5 7 0.6 (0.1 – 2.3) 0.3 (0.0 – 5.1) Barrier 10 24 1.0 (ref) 1.0 (ref) No barrier 2 12 2.5 (0.5–13.3) 6.8 (0.7 – 67.8) Abstinence 15 24 0.7 (0.3 – 1.8) 0.5 (0.1 – 2.5) Age at menarche <13 years 10 22 1.0 (ref) 1.0 (ref) 13+ years 22 45 0.9 (0.4 – 2.3) 2.3 (0.5–9.8) Number of pregnancies <3 6 31 1.0 (ref) 1.0 (ref) 3+ 26 36 0.3 (0.1 – 0.7) 0.2 (0.1 – 0.99) Age of first sexual intercourse <16 years 12 27 1.0 (ref) 1.0 (ref) 16+ years 20 40 0.9 (0.4 – 2.1) 1.0 (0.3 – 3.8) Lifetime number of sex partners <5 11 28 1.0 (ref) 1.0 (ref) 5 to 10 16 24 0.6 (0.2 – 1.5) 1.2 (0.3 – 5.4) >10 5 15 1.2 (0.3 – 4.0) 4.4 (0.7 – 29.6) Alcohol Never 18 34 1.0 (ref) 1.0 (ref) Ever 14 33 1.3 (0.5 – 2.9) 1.7 (0.4 – 6.8) Marijuana Never 27 54 1.0 (ref) 1.0 (ref) Ever 5 13 1.3 (0.4 – 4.0) 7.0 (0.5 – 91.2) Tobacco Never 27 63 1.0 (ref) 1.0 (ref) Ever 7 4 0.2 (0.1 – 0.8) 0.2 (0.04 – 1.6) ref = reference; *Adjusted for age (continuous), marital status, number of pregnancies, Tobacco use, duration of HAART therapy, CD4 counts, viral load and cervical cytology; Birth control method: Barrier = male condom, No barrier = birth control pill or Depo-Provera High-risk HPV infection and clinical correlates of HIV 12]. The increased risk of HPV infections in sero-positive infection women with multiple partners and early onset of sexual The mean and median CD4+ lymphocyte counts were activities only confirm what multiple studies have dem- 339.15 and 260 respectively. Twenty-three participants onstrated previously. There is a strong correlation -1 (23%) had CD4+ counts ≥ 500 μl , 38 (38%) had CD4+ between the presence of high-risk HPV and cervical cytol- -1 counts between 200 and 499 μl , and 39 (39%) had ogy abnormalities. Forty-one of the forty-four patients -1 CD4+ counts less that 200 μl . After adjusting for poten- with cervical cytology abnormalities were high-risk HPV tial confounders, subjects with CD4+ counts greater than positive demonstrating the role of high-risk HPV in cervi- -1 400 μl were less likely to test positive for high-risk HPV cal dysplasia. Participants were not tested for low-risk (AdjOR 0.2, 95% CI: 0.05 – 0.8, p = 0.019) (Table 3). HPV genotypes. HIV sero-positive women tend to be infected with multiple genotypes of HPV [10,11]. Three Discussion participants with cervical abnormalities were not high- High-risk HPV is prevalent in the HIV sero-positive risk HPV positive and may have infections with low risk females attending the Infectious Disease Clinic at the HPV genotypes. There is a lack of evidence to suggest that Princess Margaret Hospital. Unfortunately, a comparison low-risk HPV genotypes do not play a role in the increase with the HIV sero-negative population could not be done level of cervical abnormalities and cervical intraepithelial as there is no published HPV prevalence study for the gen- lesions in this immune-compromised population. eral population. The high prevalence reported in this study is not unusual with HPV infections being quoted as Subjects living with HIV infection for two to six years were anywhere from 33–47% in other published studies [9- three times more likely to carry high-risk HPV infections Page 4 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 Table 3: Association of high-risk HPV infection with variables associated with HIV infection High Risk HPV Infections Negative (32) Positive (67) Odds Ratio Adjusted Odds Ratio N N (95% CI) (95% CI)* Years living with HIV <2 8 21 1 (ref) 1 (ref) 2 to 6) 12 13 2.4 (0.8 – 7.5) 3.0 (0.5 – 18.5) 6+ 12 33 2.5 (0.9 – 7.1) 1.7 (0.3 – 9.2) Duration of HAART therapy <3 12 42 1 (ref) 1 (ref) 3+ 20 25 0.4 (0.1 – 0.9) 0.4 (0.1 – 1.4) CD4 count <400 11 57 1 (ref) 1 (ref) 400+ 21 10 0.1 (0.03 – 0.2) 0.2 (0.05 – 0.8) HIV viral load <50 23 22 1 (ref) 1 (ref) 50 – 28,000 8 26 3.4 (1.3 – 9.1) 1.9 (0.5 – 7.2) >28,000 1 19 19.9 (2.4 – 161.3) 2.2 (0.2 – 25.9) Cervical cytology Negative 29 25 1 (ref) 1 (ref) ASCUS 1 6 LGSIL 2 29 HGSIL 0 6 ref = reference; *Adjusted for age (continuous), marital status, number of pregnancies, Tobacco use, duration of HAART therapy, CD4 counts, viral load and cervical cytology than those infected for less than two years, however this sero-positive females should be an integral component of association was not significant (p > 0.1). Similarly, their routine gynaecological evaluation and these patients women who lived with HIV infections for more than 6 should be encouraged and provisions be made for ease of years were almost two times more likely to carry high-risk access to having regular PAP smears and HPV testing. HPV infections however; this also was not significant. Competing interests Individuals with a CD4+ lymphocyte count of less than The authors declare that they have no competing interests. 400 μl- were more likely to test positive for high-risk HPV genotypes. As CD4+ count is a reflection of the state of the Authors' contributions immune system, it reasonable to assume that the immune DND conceived of the study, participated in its design and dysfunction noted at lower CD4+ levels is responsible for coordination and drafted the manuscript. CR performed the increased detection of high-risk HPV in these women. the statistical analysis and reviewed the manuscript. AGB performed the Pap smears and cervical examination. RB An increased number of lifetime sexual partners was asso- sourced the funding, helped with coordination of the ciated with an increased likelihood of testing positive for study, provided further management for patients with high-risk HPV. Other behavioral variables such as cocaine detected abnormalities and reviewed the manuscript. use, alcohol use and non-barrier method did not show the expected increased risk. This lack of increased risk could Acknowledgements Special thanks to the staff of the Infectious Diseases division, the Depart- be the result of a relatively small study population. ment of Pathology, and Laboratory Services at the Princess Margaret Hos- pital as well as the staff of Premier Clinical Laboratory. Conclusion The high prevalence of high-risk HPV genotypes and cer- This article has been published as part of Infectious Agents and Cancer. Vol- vical cytology abnormalities demonstrates the need to ume 4 Supplement 1, 2009: Second Annual International African-Caribbean screen and monitor HIV sero-positive women and to Cancer Consortium Conference. The full contents of the supplement are implement preventative measures to decrease the num- available online at http://www.infectagentscancer.com/supplements/4/S1. bers of females with high risk HPV infections. Most partic- ipants reported not having yearly PAP smears and References 1. Sun XW, Kuhn L, Ellerbrock TV, Chiasson MA, Bush TJ, Wright TC: unfortunately, routine HPV screening is not conducted at Human Papillomavirus Infection in Women Infected with the public facilities where most of these patients receive the Human Immunodeficiency Virus. NEJM 1997, their PAP smears. Screening for HPV infections in HIV 337:1343-1349. Page 5 of 6 (page number not for citation purposes) Infectious Agents and Cancer 2009, 4(Suppl 1):S8 http://www.infectagentscancer.com/content/4/S1/S8 2. Kanowitz S, Miller SB, Stone J, Hanson E: The Natural History of Human Papillomavirus Infection as Measured by Repeated DNA testing in Adolescent and Young Women. J Pediatr 1998, 132(2):277-84. 3. Strickler HD, Burk RD, Fazzari M, nastos K, Minkoff H, Massad LS, Hall C, Bacon M, Levine AM, Watts DH, Silverberg MJ, Xue X, Sch- lecht NF, Melnick S, Palefsky JM: Natural History and Possible Reactivation of Human Paillomavirus in Human Immunode- ficiency Virus-Positive Women. J Natl Cancer Inst 2005, 97:577-586. 4. Sun XW, Ellerbrock TV, Lungu O, Chiasson MA, Bush TJ, Wright TC Jr: Human papillomavirus infection in human immunodefi- ciency virus-seropositive women. Obstet Gynecol 1995, 85:680-686. 5. Vermund SH, Kelley KF, Klein RS, et al.: High risk of human papil- lomavirus infection and cervical squamous intraepithelial lesions among woman with symptomatic human immunode- ficiency virus infection. Am J Obstet Gynecol 1991, 165:392-400. 6. Ferenczy Alex, Coutlee Francois, Franco Eduardo, et al.: Human papillomavirus coinfection and the risk of neoplasia of the lower genital tract: a review of recent developments. Cana- dian Medical Association Journal 2003, 169:431-434. 7. Harris TG, Burk RD, Palesky JM, Massad LS, Bang JY, Anastos K, Minkoff H, Hall CB, Bacon MC, Levine AM, Watts H, Silverberg MJ, Xue X, Melick SL, Strickler HD: Incidence of cervical intraepithe- lial lesions associated with HIV serostatus, CD4 cell counts and human paillomavirus test results. JAMA 2005, 293:1471-1476. 8. de Sanjose S, Palefsky J: Cervical and anal HIV infections in HIV positive women and men. Virus Research 89(2):201-211. 9. Ellerbrock TV, Chiasson MA, Bush TJ, Sun XW, Sawo D, BRudney K, Wright TC Jr: Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000, 283:1031-1037. 10. Langley CL, Benga-De E, Critchlow CW, Ndoye I, Mbengue Ly, Kuy- pers J, Woto-Gaye G, Myboup S, Bergeron C, Holmes KK, Kiviat NB: HIV-1, HIV-2, human papillomavirus infection and cervical neoplasia in high-risk African women. AIDS 1996, 10(4):413-417. 11. Blossom DB, Beigi RH, Farrell JJ, et al.: Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women. J Med Virol 2007, 79(6):758-65. 12. Joshi SN, Gopalkrishna , Kumar BK, Dutta S, Hyaynirgune P, Thankar M, Tripathy S, Mehendale S, Paranjape R: Cervical squamous intra- epithelial changes and human papillomavirus infection in women infected with human immunodeficiency virus in Pune, India. J Med Virol 2005, 76(4):470-5. 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