Background: Women living with HIV/AIDS present with a higher prevalence of human papillomavirus (HPV) infection, higher rates of squamous intraepithelial lesions, and are more susceptible to invasive cervical carcinoma progression.
Objective: We assessed the frequency of precursory cervical lesions of cancer and its risk factors for women living with HIV/AIDS.
Methods: Sociodemographic, clinical, behavioral, and laboratory data were collected from medical records from 2008 to 2009 and analyzed using forward stepwise logistic regression.
Results: Medical records of 631 women were reviewed; mean age at AIDS diagnosis was 34 years old (interquartile range = 29-40 years old), 32% were <16 years old at first sexual intercourse; 61% had ≤5 sexual partners during life; 43% had been living with AIDS for ≥9 years; 47% reported previous sexually transmitted infections; 44% presented with HPV infection; and 10% presented with high squamous intraepithelial lesions. Presenting high squamous intraepithelial lesions was significantly associated with home district Human Development Index, age at AIDS diagnosis (>40 years old), time of AIDS diagnosis (>8 years), CD4+ cell count <350/mm3, and HPV infection.
Conclusions: Frequent squamous intraepithelial neoplasia in these women shows the importance of gynecologic examinations in routine care and follow-up required by those who present with cervical lesions.
From the *Departamento de DST, AIDS e Hepatites virais, Secretaria de Vigilância em Saúde, Ministério da Saúde, Brazil; †Division of Infectious Diseases, Bloomberg School of Public Health, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, ‡Programa Estadual de DST e Aids de São Paulo, Secretaria de Estado da Saúde de São Paulo, São Paulo, Brazil; and §Departamento de Medicina Social, Núcleo de Doenças Infecciosas, Universidade Federal do Espírito Santo (UFES), Vitória, Brazil.
Supported by the National Institute of Health grant number 3D43TW000010-21S1 and National Institutes of Health grant AI06699 (JEG).
The authors have no conflicts of interest to disclose.
Correspondence to: Valdir Monteiro Pinto, MD, MSc, Rua Santos Dumont, 136. São Paulo, SP 04638-000, Brazil (e-mail: firstname.lastname@example.org; email@example.com).
Women who live with HIV/AIDS present significantly high rates of squamous intraepithelial lesions (SIL) and are more susceptible to invasive cervical carcinoma progression than HIV-negative women.1,2 The prevalence of human papillomavirus infection (HPV) is usually greater among HIV-infected women3,4 than among HIV-uninfected women; this may be explained by the persistence of HIV viral load, which increases the risk of developing SIL.5,6
There is no HIV infection surveillance in Brazil, thus only AIDS is a reportable disease. The AIDS prevalence rate in the country is 0.6%; 0.8% among men and 0.4% among women with a significant impact on reproductive health. From 1980 to June 2009, 544,846 cases of AIDS were reported in Brazil and among these 201,333 cases (36,9%) were reported in Sao Paulo state.7 The male to female ratio in Brazil has decreased from 26.7 in 1985 to 1.5 in 2009.7
The combination of a systematic antiretroviral therapy (ART) program since 1996, strong efforts to prevent opportunistic infections, and the referral of HIV-infected patients for specialized care has resulted in longer survival among people living with AIDS in Brazil. Long-term survival has led to increased efforts to diagnose and treat chronic diseases including precursory diseases of cervical cancer that may threaten the quality of life and survival of women living with AIDS.8 The importance of SIL is reflected by the inclusion of cervical cancer as an AIDS-defining illness in 1993 by the Centers for Diseases Control and Prevention9 in the United States.
The goals of this study were to describe the frequency of cervical cancer precursor lesions and risk factors for these lesions in women living with AIDS in Brazil.
This is a cross-sectional study carried out in the Reference and Training Center for Sexually Transmitted Diseases and AIDS in the city of Sao Paulo, Brazil. This center has about 1800 women in follow-up for HIV/AIDS. Data were collected from medical records of women living with AIDS, under ART. Women scheduled for a gynecological appointment in the outpatient gynecological clinics of reference center for sexually transmitted disease (STD)/AIDS between July 1, 2008 and May 31, 2009 were included in the study. Women living with AIDS but not receiving ART were excluded from the study as were those with no CD4+ results or those with no gynecological consultation described in medical records.
Independent variables were grouped as sociodemographic, behavioral, or clinical. Sociodemographic variables included age at AIDS diagnosis, education, race, and Human Development Index (HDI) of home district. HDI is a composite statistic used to rank countries by level of “human development.”. The statistic is composed from data on life expectancy, education, and per capita rate. Education and HDI were used as indicators for socioeconomic level. Data were collected from medical records and linked to the HDI database of the city of Sao Paulo. Behavioral variables included age at first sexual intercourse and number of lifetime sexual partners. Clinical variables included previous sexually transmitted infection (STI) (Chlamydia, Gonorrhea, Trichomonas, hepatitis B and Cvirus, syphilis, HPV, herpes simplex virus 2), time since AIDS diagnosis, and CD4+ cell count.
Papanicolaou smear of endocervic and ectocervix for cervical cytology were classified according to the Bethesda classification for changes characteristic of HPV infection. HPV cytological changes were diagnosed by the presence of koilocytotic atypia and SIL of the cervix. The outcome of interest was the presence of high SIL, including carcinoma or previous cervical conization surgery.
A bivariate analysis was conducted to investigate associations between dependent and independent variables and as a strategy to select variables to adjust for the logistic regression model. χ2 test was used for comparing proportions and Student t test for comparing means. Odds ratios were calculated for each independent variable. Forward stepwise logistic regression was conducted to develop a final model. STATA SE 10.1 (STATACORP STATA Statisitical Software: release 10.1; Stata Corporation, College Station, TX) was used for data analysis.
Ethical and Research Committee of Reference and Training Center of STD/AIDS of the city of Sao Paulo, Brazil, approved this project.
There were 710 women with clinic visits during the study period, though 79 (11%) of them were excluded for the following reasons: 29 had no early gynecologic follow-up, 23 did not receive ART, 18 were HIV negative, and 9 had HIV infection acquired by vertical transmission and did not report sexual activity.
Among 631 women included in our analysis, 64 were diagnosed with high SIL, a prevalence of 10.1% [95% confidence interval (CI): 7.7% to 12.5%]. Socioeconomic characteristics are presented in Table 1. Patients with high SIL were more likely to be older than 40 years old (52% vs. 25%, P < 0.001) and have a lower HDI (88% vs. 25%, P < 0.001) than those who did not present with high SIL.
Table 2 presents behavioral and clinical characteristics of women living with AIDS with and without high SIL. More than half of these women (57%) started their sexual life at 16 years of age or above, and 61% had ≤5 sexual partners during their lives. Women with high SIL had AIDS diagnosis for more than 9 years (76% vs. 39%, P < 0.001) and present CD4+ count <350 cell/mm3 (83% vs. 37%, P < 0.001) more frequently than those women without high SIL. Previous STI were reported by 47% of women; 44% reported HPV, 20% reported herpes simplex virus 2, and 18% had a history of ≥2 STI.
The last Pap smear test was done within 1 year in 80% of cases, 13% from 1 to 3 years, and 7% >3 years. The time interval between last two Pap tests was <1 year in 36%, 1-3 years in 46%, and >3years in 10%. The last Pap smear results were normal for 90%, 9% low-grade lesions and 2% high-grade lesions. Colposcopy was performed in 35% of cases.
Associated risk factors for high SIL in multivariate analysis were HPV cytological changes [odds ratio (OR)aj = 68.6 (95% CI: 11.6 to 404.6)], CD4+ T-lymphocyte cells counting <350 cells/mm3 [ORaj = 24.5 (95% CI: 2.7 to 224.9)], HDI of home district <0.50 [ORaj = 3.3 (95% CI: 1.1 to 10.8)], time since AIDS diagnosis >8 years [ORaj = 2.9 (95% CI: 1.3 to 6.5)], age at AIDS diagnosis (>40 years old) [ORaj = 2.7 (95% CI: 1.2 to 6.0)] (Table 3).
We found a prevalence rate of 10.1% for high SIL among women living with AIDS attending a reference center for HIV/AIDS in Brazil. High SIL was frequent in this population, and it shows the importance of routine monitoring for these women through Pap smear tests and follow-up of those with cervical abnormalities. Other studies also described SIL as frequent lesions in HIV-infected women.1,10-12
A low human development index increases risk of high SIL. Indicators such as low personal/household income, unemployment, lack of health insurance, and low HDI may all be associated with decreased accessibility to health services and low adherence to antiretroviral treatment,13 despite free access and distribution of ART in Brazil. Kalichman et al14 reported educational level as a marker for social inclusion and for patient relationship with health services in Brazil.
HPV is one of the most important risk factors for cervical cancer.15,16 In our study, HPV cytological changes were frequent (44%) and were associated with high SIL. HPV infection and SIL are common in this population.1,3,12 Women living with HIV may be asymptomatic; however, women with fast progressing SIL must be tested for HIV as SIL may be a sign of immunosuppression. On the 70's, a hypothesis that HPV infection was involved in cervical carcinogenesis was suggested,17,18 and subsequent studies showed that nearly all cervical neoplasias occur in HPV-positive patients and only specific types of virus are associated with invasive carcinoma.3
Other clinical variables associated with high SIL in this study were CD4+ cell counts <350 cells/mm3. Other studies have suggested that the frequency of HPV persistence varies inversely with CD4+ count and that higher HPV prevalence and incidence of oncogenic HPV types are found in HIV-infected patients, especially those with lower CD4+ counts.11,19,20 These data suggest that the level of CD4+ is important in the pathogenesis of HPV infection in HIV patients.
Being older than 40 years at AIDS diagnosis and living with AIDS for more than 8 years were associated with high SIL. These findings can be explained by the fact that women older than 45 years have higher risk of developing cancer and, individuals who survive several years after an AIDS diagnosis have persistent excess risk for both AIDS-defining and non-AIDS-related malignancies.21
The present study had some limitations. First, we used secondary data. Furthermore, the results cannot be extrapolated to other populations of women living with AIDS because we used a convenient sample in one reference center for STD/AIDS in Brazil that only included women who sought care. Moreover, we cannot establish that the risk factors associated with high SIL were causally related because of the retrospective design of the study. The possibility of response bias also cannot be discarded due to the tendency of individuals to give socially acceptable self-reported responses during medical appointments. Also, lack of accuracy in the women's responses with respect to age at first sexual intercourse, number of sexual partners, and drug use, among others, cannot be excluded. The study population was composed entirely of women living with AIDS receiving care and ART within the Brazilian National Health Service, thus excluding all consultations in the private sector. Despite these limitations, data registered in the medical records was satisfactory and it showed that secondary data could be used to monitor the implementation of STI prevention and cervical cancer programs. Nevertheless, the high quality of data from the primary public outpatient clinic in the city attending AIDS patients strengthens the study.
Performing routinely cervical cytological examinations is recommended and any degree of abnormality in this test should be referred to colposcopy assessment.22 HIV-positive women with cervical invasive carcinoma normally present faster evolution and greater risk of disease recurrence.1 Cervical cancer incidence in HIV-positive women is not changed with use of ARV therapy.23 Therapeutic management is the same for any woman, independently of her HIV serology, but with poorer prognosis in women with AIDS.1,12
Despite Pap smear test availability for universal screening for cervical cancer in Brazil, the prevalence and incidence rates of this disease did not decrease consistently, characterizing a significant public health problem.24,25 In addition, regardless of the fact that the Pap smear is a low-cost test and easily available for women with AIDS in Brazil, there is a need to identify innovative interventions that reduce social, cultural, and environmental influences on HPV infection and cervical cancer in this population.
Screening, treatment, and prevention counseling and support in health facilities should be considered and evaluated as a core component of cervical cancer prevention efforts in gynecological outpatients clinics for HIV patients. Our results reinforce the importance to perform routine gynecologic examinations for women with CD4+ cells count <350 cells/mm3.
The authors would like to acknowledge the expert assistance and suggestions of Dr Ivan França Junior and Dr Cassia Maria Buchalla, Faculdade de Saúde Pública - University of Sao Paulo.
1. Clarke B, Chetty R. Postmodern cancer: the role of human immunodeficiency virus in uterine cervical cancer. Mol Pathol
2. Ng'andwe C, Lowe JL, Richards PJ, et al. The distribution of sexually-transmitted human papillomaviruses in HIV positive and negative patients in Zambia, Africa. BMC Infect Dis
3. Ellerbrock TV, Chiasson MA, Bush TJ, et al. Wright. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA
4. Palefsky J. Human papillomavirus-related disease in people with HIV. Curr Opin HIV AIDS
5. Delmas MC, Larsen C, van Benthem B, et al. Cervical squamous intraepithelial lesions in HIV-infected women: prevalence, incidence and regression. AIDS
6. Davis AT, Chakraborty H, Flowers L, et al. Cervical dysplasia in women infected with the human immunodeficiency virus (HIV): a correlation with HIV viral load and CD4+ count. Gynecol Oncol
7. Ministério da Saúde. Secretaria de Vigilância em Saúde. Departamento de DST, Aids e Hepatites virais. Boletim Epidemiológico Aids e DST
. Brasília; Ministério da Saúde; 2009.
8. Schuman P, Ohmit SE, Klein RS, et al. Longitudinal study of cervical squamous intraepithelial lesions in human immunodeficiency virus (HIV)-seropositive and at-risk HIV-seronegative women. J Infect Dis
9. CDC. Centers for Disease Control and Prevention. Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. Morb Mortal Wkly Rep
10. Coelho Lima BM, Golub JE, Tonani Mattos A, et al. Human papillomavirus in women with and without HIV-1 infection attending an STI clinic in Vitoria, Brazil. J Int Assoc Physicians AIDS Care
11. Calore EE, Pereira SM, Cavaliere MJ. Progression of cervical lesions in HIV-seropositive women: a cytological study. Diagn Cytopathol
12. Mayaud P, Gill DK, Weiss HA, et al. The interrelation of HIV, cervical human papillomavirus, and neoplasia among antenatal clinic attenders in Tanzania. Sex Transm Infect
13. Muñoz A, Palacio H, Li X, et al. Healthcare use by varied highly active antiretroviral therapy (HAART) strata: HAART use, discontinuation and naivety. AIDS
14. Kalichman AO. Access to HAART for injection drug users. Cad. Saude Publica
15. Weaver BA. Epidemiology and natural history of genital human papillomavirus infection. J Am Osteopath Assoc
. 2006;106(suppl 1):S2-S8.
16. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst
17. Arends MJ, Buckley CH, Wells M. Aetiology, pathogenesis, and pathology of cervical neoplasia. J Clin Pathol
18. Schneider A, Koutsky LA. Natural history and epidemiological features of genital HPV infection. IARC Sci Publ
19. Micheletti AM, Dutra Vde F, Murta EF, et al. Cervicovaginal cytological abnormalities in patients with human immunodeficiency virus infection, in relation to disease stage, CD4 cell count and viral load. Diagn Cytopathol
20. Mangclaviraj S, Kerr SJ, Chaithongwongwatthana S, et al. Nadir CD4 count and monthly income predict cervical squamous cell abnormalities in HIV-positive women in a resource-limited setting. Int J STD AIDS
21. Zucchetto A, Suligoi B, De Paoli A, et al. Excess mortality for non-AIDS-defining cancers among people with AIDS. Clin Infect Dis
23. Massad LS, Seaberg EC, Watts DH, et al. Long-term incidence of cervical cancer in women with human immunodeficiency virus. Cancer
24. Arcuri RA, Cunha KCF, Alves EC et al. Controle interno da qualidade em citopatologia ginecológica: um estudo de 48.355 casos. J Bras Patol Med Lab
25. Ministério da Saúde. Secretaria de Assistência a Saúde. Instituto Nacional de Câncer. Estimativa 2008: incidência de câncer no Brasil
. Rio de Janeiro: INCA; 2007.