HPV genotype distribution and oncogene expression in HIV-positive adults and the underlying risk factors for anal, oral and genital malignancy : an Atlantic Canada prospective cohort study

Aslanova, Rana (2012) HPV genotype distribution and oncogene expression in HIV-positive adults and the underlying risk factors for anal, oral and genital malignancy : an Atlantic Canada prospective cohort study. Masters thesis, Memorial University of Newfoundland.

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Abstract

BACKGROUND: -- Human Papillomavirus (HPV) is the most common sexually transmitted agent. These small DNA viruses target the basal cells of the epithelium. While the HPV family is comprised of more than 100 genotypes, only about 40 or so types are associated with human anogenital infections. Infections with oncogenic HPV (probably high-risk 26,53,66,68,73,82 and high-risk HPV types 16,18,31,33,35,39,45,51,52,56,58,59) are causally linked to the development of cervical cancer (HPVI6 & 18 are related to about 99% of cervical malignancy) as well as a proportion of anal, oropharyngeal, vulvar, vaginal and penile cancers and their associated precancerous lesions. HPV is also the cause of genital warts (low-risk HPV types 06,11,34,40,42,44,53, & others). However, in most people HPV infection is transient and does not lead to disease. Immune suppression increases the likelihood of HPV-related diseases, and people with human immunodeficiency virus (HIV) infection or with HIV-positive partners are at a higher risk of pre-cancer lesions and cancers, as well as genital warts. The literature suggests HIV-HPV co-infection in women increases the risk of anal carcinoma by 30 times and the risk of HPV associated anal cancer is 163-fold greater in young men with HIV. A number of studies have recommended that all HIV-infected individuals be routinely screened for HPV-related disorders to facilitate early detection and treatment because of the heightened risk of persistent HPV infection with the risk of malignant transformation. -- OBJECTIVES: -- Primary: To determine the prevalence and distribution of high risk (HR) oncogenic HPV-types in HIV-positive adults in Atlantic Canada. -- Secondary: To correlate the prevalence of HR HPV genotypes with underlying pre-malignant lesions and malignancy through a cross-sectional study. -- To correlate pre-malignant lesions and malignancy with patients' demographics and underlying risk factors. -- METHODS: -- This thesis is part of a larger prospective cohort study designed to follow consenting persons with HIV infection in Atlantic Canada over a 3-year period subsequent to baseline screening in year one. The data in this thesis are limited to that obtained at baseline in all four Atlantic Provinces during the first year of the study. All HIV-positive adults treated through the participating infectious disease clinics were approached by the clinic physicians or nurses to request participation in the study. Atlantic Canada has approximately 800 routinely followed HIV-positive adults and we expected to enroll approximately 400 of them. This study was approved by ethic committees of all participating institutions as well as the Public Health Agency of Canada, the funding agency for the study. -- Recruitment commenced in June, 2009. All procedures were performed after obtaining informed consent. Consenting participants were required to complete a confidential questionnaire to obtain demographic and risk factor data. Participants' identifiers were retained to permit questionnaire data to be correlated with HPV related disease outcomes. SurePath (Becton Dickinson) liquid cytology medium was used in the collection of oropharyngeal and anal swab specimens from all males and females, and an additional cervical specimen was obtained from females. All specimens were tested for cytologic abnormalities, HPV DNA and genotyping. The study cohort will be followed up with the above protocol for a period of 3 years. These results will be subsequently used to assess any HPV related disease outcome and genotypic specific information. Consent also gives access to patients' medical files for information on viral load, CD4⁺ T cell count and treatment regimens in order to correlate these factors with disease outcome. -- RESULTS: -- The study analysis is based on a total of 300 patients; of these 91.7% were males. The population and gender distribution among the provinces were: Nova Scotia, Halifax (NSH) - total 150 patients, of these 142 (94.7%) were males; New Brunswick, Moncton (NBM) - total 90 patients, of these 85 (94.4%) were males; Newfoundland and Labrador, St. John's (NLSJ) - total 44 patients, of these 34 (77.3%) were males; and New Brunswick, Saint John (NBSJ) - total 16 patients, of these 14 (87.4%) were males. The mean (SD) age of the study population was 46.9 (9.36) years and its distribution by age categories was: 62 (20.7%) aged 25 to 39 years; 209 (69.7%) aged 40 to 59 years; and 29 (9.6%) aged 60 years and older. -- There was no significant difference in the association of cytologic results with CD4 cells count and plasma viral load levels. -- A total of 232 (77.3%) of the participants tested positive for any HPV infection with 125 (54.0%) showing multiple HPV types. Up to 46 HPV genotypes were detected, of which 39% were HR oncogenic types and 61% of low-risk (LR) types. The most frequently detected HR HPV types among all specimens were: HPV16 11.8%; HPV52 7.2%; HPV45 5.6%; HPV51 5.4% & HPV18/HPV59 4.6% each. Six HR HPV types: 16 (p<0.001); 45 (p=0.044); 51 (p=0.014); 52 (p<0.001); 53 (p=0.045); and 59 (p=0.006) were more frequently associated with anal lesions; from them atypical squamous cells of undetermined significance (ASC-US) were detected in 37 (12.3%) patients; atypical squamous cells of undetermined significance cannot exclude high-grade intraepithelial lesion (ASC-H) in 3 (0.5%) patients; low-grade squamous intraepithelial lesions (LSILs) were detected in 35 (11.6%) participants; and high-grade intraepithelial lesions (HSILs) in 3 (0.5%) of them. HPV51 was detected in one oropharyngeal specimen with ASC-US cytologic changes; and HPV35 was more frequently associated with cervical lesions (ASC-US in one female; LSIL in one patients also; and LSIL cannot exclude high-grade lesion (LSIL/HSIL) in one female participant). The highest number of cytologic abnormalities was reported in anal specimens (26%) as compared to cervical and oropharyngeal specimens (12% & 0.3%, respectively). Cytologic changes were significantly associated with patients' high risk behaviour such as unprotected anal and vaginal sex. All patients with detected lesions were referred to an appropriate specialist for further investigation. -- The overall prevalence rate of the cases with the high-risk (HR) HPV genotypes was 46.6% (108/232). The overall prevalence of the cytologic abnormalities caused by HR HPV types in the study population was 27.3% (82/300) during the screening year. -- CONCLUSION: -- In this study, 74% of 300 patients studied had normal anal cytology, with 26% having abnormal anal cytology, and with 15.3% (46/300) of patients having unsatisfactory anal specimens for evaluation. Abnormal cytology was reported mostly as ASC-US (12.3%) and LSIL (11.7%), with fewer samples showing HSIL (1.0%). All participants with detected anal, cervical and oropharyngeal precancerous lesions were referred to specialists to undergo a high-resolution anoscopy (HRA) and colposcopy with biopsy (the results of these tests will be analyzed as a part of the larger study). The results of the data presented here are comparable with the results from other studies. Follow-up analysis of anal, cervical and oropharyngeal biopsy results are required to draw conclusions about real prevalence of cytologic abnormalities in the study population; cytologic outcomes have to be correlated with histologic outcomes. -- KEY WORDS: -- Human papillomavirus infection; anal cancer; cervical cancer; head and neck cancer; HPV genotyping; HPV prevalence and incidence; HPV and malignancy; HPV risk factors; HIV-HPV co-infection.

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