Cervical cytological abnormalities and factors associated with high-grade squamous intraepithelial lesions among HIV-infected women from Rio de Janeiro,Brazil

Abstract

Although cervical cancer remains a major public health problem in Brazil, knowledge of cervical cytological abnormalities among HIV-infected women remains scarce. At baseline evaluation of a cohort followed in Rio de Janeiro, Brazil, 703 HIV-infected women underwent cytology-based cervical cancer screening and human papillomavirus (HPV) DNA testing. Poisson regression analysis was used to evaluate the association of factors with the presence of high-grade squamous intraepithelial lesions (HSIL). Cervical cytology was abnormal in 24.3% of the women; 4.1% had HSIL. Beyond HPV infection, factors independently associated with the presence of HSIL was age (≥25 and ≤40 years, prevalence ratio [PR] 2.60, 95% confidence interval [CI] 1.11–6.10), and more than three pregnancies was protective (PR 0.33, 95% CI 0.11–0.94). High coverage of cervical cancer screening is warranted to prevent morbidity and mortality from cervical cancer in this population.

Keywords

HIV women HPV HSIL high-grade squamous intraepithelial lesions prevalence Brazil

INTRODUCTION

Worldwide, cervical cancer is the second most common cancer in women.¹ In 2002, there were about 500,000 incident cervical cancer cases and 275,000 cervical cancer deaths, which amount to approximately 10% of all cancer deaths in women.² Any of the 15 specific types of the human papillomavirus (HPV), in particular, types 16 and 18, are necessary causal agents of cervical cancer.^3–6 Non-viral factors that influence the risk of cervical cancer among women with persistent HPV infection include smoking, parity and oral contraceptive use.^5,7,8

Among HIV-infected women, cervical cancer is a growing concern. The incidence and persistence of HPV infection are increased in this population.⁹ Also, HIV-infected women are at increased risk of high-grade squamous intraepithelial lesion (HSIL) and invasive cervical cancer.^10,11 Highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected individuals which can lead to complex scenarios. The immunological reconstitution derived from HAART could change the course of HSIL progression.^12,13 On the other hand, the increased survival of HIV-infected women could lead to an increased incidence of HSIL and invasive cervical cancer, particularly in settings where screening coverage is low.¹⁴ Indeed, in the past, cervical cancer was not an important cause of mortality among HIV-infected women in resource-limited settings because of their short survival.¹⁵

Screening for cervical cancer and its precursor lesions represents an opportunity for preventing cervical cancer. However, in resource-limited settings screening is of limited impact for several reasons, including limited coverage, poor sample collection, laboratories with deficient infrastructure, personnel with inadequate training or supervision and lack of follow-up of abnormal findings.¹⁶ Additionally, in these same settings, the HIV/AIDS pandemic has overwhelmed the health-care systems imposing an enormous impact on women, particularly those of reproductive age.¹⁷

In Brazil, cervical cancer is a major public health issue, being the third most common form of cancer and the fourth cause of death by cancer.¹⁸ There is pronounced inequality in the access to cervical cancer screening within the country.¹⁹ The burden of HIV infection among young women under the age of 30 years is increasing.²⁰ In Brazil, individuals living with HIV/AIDS have universal access to HAART, a policy that has lead to survival rates of the same order of magnitude as in developed countries.^20,21 As such, HIV-infected women in Brazil may be at heightened risk for the development and progression of HPV-induced disease. Among HIV-infected women, studies from Brazil have evidenced a high prevalence of HPV infection²² and increased risk to progression from HSIL to invasive cervical cancer.²³ Thus, it is necessary to provide consistent cervical cancer screening and to link screening and care in such a manner that it ensures effective treatment. To better programme such necessities, studies that characterize the gynaecological manifestations of HIV-infected women are warranted.

The purpose of this study was to assess the prevalence of cervical cytology abnormalities and to measure the association of factors with HSIL in the baseline assessment of the cohort of HIV-infected women followed at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, located in Rio de Janeiro, Brazil.

METHODS

To study the natural history of HIV infection in women, we established a cohort at the Evandro Chagas Clinical Research Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. From May 1996 through December 2007, 732 HIV-infected women enrolled into the cohort after signing an informed consent that enquired on willingness to participate and attend all medical appointments. The study was reviewed and approved by the institution ethics review board. The present analysis reports on the subset of 703 women that neither had a hysterectomy (26 women) nor were virgins (3 women). The women were submitted to cytology-based cervical cancer screening, i.e. conventional Papanicolaou (Pap) smears and HPV DNA testing, and were referred to colposcopy. Cohort procedures have been described elsewhere.²⁴

Conventional Pap smears were performed with an Ayre's wooden spatula and an endocervical brush, and were classified according to the Bethesda 2001 classification system. Hybrid Capture II (Digene Inc, Gaithersburg, MD, USA) was used to diagnose HPV infection. Specimens were obtained with a sterile swab or cervical brush and stored in frozen conservative media until processing. HPV types classified as low risk were: 6, 11, 42, 43 and 44; those classified as high risk were: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68.

CD4+ T-cell counts (FACScan; Becton Dickinson and Co, Sparks, MD, USA) were obtained from the participant's medical record. Nadir CD4+ T-cell count was defined as the lowest level of immunosuppression since HIV diagnosis up to 90 days of cohort entry. Baseline CD4+ T-cell count was defined as the measured level of immunosuppression observed within 90 days of entry into the cohort. Individuals were considered under antiretroviral therapy (ART) if under treatment for at least two months before enrolment.

Prevalence of cervical cytological abnormalities was determined. The outcome of interest was HSIL, as diagnosed by a blinded cytopathologist. Poisson regression analysis was used to estimate associations of factors with HSIL presence, using women without HSIL as the reference category. Bivariate analysis was first conducted to determine which factors would enter the initial multivariate Poisson regression model. Factors associated with HSIL presence assuming a significance threshold of 25% were included in the initial multivariate model. The final model was reached by removing variables with less than 5% significance. Variables with borderline significance, known to be associated with HSIL, were kept in the final model.

RESULTS

Of the 703 HIV-infected women, 56.7% were aged between 25 and 40 years and 56.2% were non-white (Table 1). Most women were not married/living with a partner (59.3%), 75.6% had five or more years of formal education and 77.2% had neither ever smoked nor were current smokers. The age of first sexual intercourse was 17 years or less for 56.9% of the women. The number of lifetime sexual partners was five or more for almost half of the women. The great majority of the women were not making use of any type of hormonal contraceptive method. Sixty-eight percent of the women had three or fewer pregnancies during their lifetime. The last gynaecological examination of half of the women had occurred within one year of their current evaluation.

Table 1

Sociodemographic and behavioural characteristics of the 703 HIV-infected women from Rio de Janeiro, Brazil

Characteristic	n* (%)
Age (years)
<25	82 (11.8)
25–40	394 (56.7)
>40	219 (31.5)
Race/ethnicity
White	304 (43.8)
Non-white	390 (56.2)
Married/living with partner
Yes	283 (40.7)
No	412 (59.3)
Years of formal education
<5	168 (24.4)
5–8	234 (34.0)
>8	286 (41.6)
Monthly income (US$) ^†
<75	95 (13.5)
75–300	552 (78.5)
>300	56 (8.0)
Smoking
Yes, current smoker	160 (22.8)
Yes, not current smoker	166 (23.6)
No	377 (53.6)
Ever used drugs
No	497 (71.6)
Yes	197 (28.4)
Age at first sexual intercourse (years)
>17	302 (43.1)
≤17	398 (56.9)
Number of lifetime sexual partners
Up to 4	349 (51.1)
5 or more	334 (48.9)
Use of contraceptive hormones (oral or injectable)
Yes	62 (8.9)
No	634 (91.1)
Number of pregnancies
≤3	473 (68.0)
4 or more	222 (32.0)
Time since last gynaecological examination
≤1 year	345 (50.7)
>1 year	335 (49.3)
Self-reported history of STI
Yes, HPV	121 (18.0)
Yes, not HPV	135 (20.1)
No	416 (61.9)
Nadir CD4+ T-cell count (cells/mm ³ )
<100	125 (19.3)
100–199	119 (18.4)
≥200	403 (62.3)
Baseline CD4+ T-cell count (cells/mm ³ )
<200	295 (42.0)
200–499	256 (36.4)
≥500	152 (21.6)
HPV infection ^‡
Yes, high-risk	304 (45.9)
Yes, low-risk	020 (3.0)
No	338 (51.1)
Use of antiretroviral therapy
Yes, HAART	206 (29.9)
Yes, not HAART	135 (19.5)
No	349 (50.6)

STI = sexually transmitted infection; HPV = human papillomavirus; HAART = highly active antiretroviral therapy

*Percentages are given within the valid responses of each variable

^†Conversion: US$ 1.00 = R$ 2.00

^‡High-risk HPV infection is defined as an infection with at least one high-risk HPV, and low-risk HPV infection is defined as an infection with only low-risk HPV

HPV infection was detected in 324 (48.9%) of the women. Of these women, 304 had high-risk HPV (HR HPV; Table 1). Forty-two percent of the women had CD4+ T-cell counts ≤200 cells/mm³ at their baseline evaluation; and 19% had a nadir CD4+ T-cell count of ≤100 cells/mm³. Half of the women were already making use of ART at cohort entry and, among these, 60.4% were taking HAART.

Cervical cytology was abnormal in 24.3% of the HIV-infected women (Table 2). Atypical squamous and glandular cells of undetermined significance (ASCUS and AGUS, respectively) were detected in 6.7% and 0.3% of the women, respectively. Squamous intraepithelial lesions (SILs) were detected in 17.2% of the participants: low-grade squamous intraepithelial lesion (LSIL): 13.1% and HSIL: 4.1%. One patient presented with invasive cervical cancer (0.1%). SILs were much more frequent among those women co-infected with HR HPV (Table 2). In particular, 25 of the 29 HSIL results were detected in women co-infected with HR HPV . Also, the only case of invasive cervical cancer occurred in a woman with HR HPV infection.

Table 2

Prevalence of cervical cytological abnormalities among HIV-infected women and women co-infected with HIV and high-risk human papillomavirus (HPV)

	All women			High-risk HPV
Pap smear result	n	%	95% CI	n	%	95% CI
Normal	532	75.7	72.3–78.8	177	58.2	[52.5–64.0]
ASCUS	47	6.7	5.0–8.9	29	9.5	[6.5–12.5]
AGUS	2	0.3	0.1–1.1	1	0.3	[0.2–2.1]
LSIL	92	13.1	10.7–15.9	71	23.4	[18.8–28.6]
HSIL	29	4.1	2.8–5.9	25	8.2	[5.5–12.0]
Invasive cervical cancer	1	0.1	0.0–0.9	1	0.3	[0.2–2.1]
Total	703	100.0	–	304	100.0	–

ASCUS = atypical squamous cells of undetermined significance; AGUS = atypical glandular cells of undetermined significance; LSIL = low-grade squamous intraepithelial lesion; HSIL = high-grade squamous intra-epithelial lesion; CI = confidence interval

In the bivariate analysis, women infected with an HR HPV had seven times the prevalence of HSIL compared with those without an HR HPV infection (prevalence ratio [PR] 7.36, 95% confidence interval [CI] 2.56–21.1, Table 3). Age between 25 and 40 years was associated with a 143% increase in the prevalence of HSIL (PR 2.43, 95% CI 0.97–6.08). Not being married/living with a partner and drug use also trended towards increased HSIL prevalence (PR 1.80, 95% CI 0.80–4.07 and PR 1.78, 95% CI 0.85–3.73, respectively). Women having four of more pregnancies had a significantly lower prevalence of HSIL (PR 0.34, 95% CI 0.12–0.98). More than one year since the last gynaecological examination and self-reported history of HPV were both associated with higher HSIL prevalence (PR 1.68, 95% CI 0.80–3.57 and PR 2.05, 95% CI 0.93–4.50, respectively), though non-significant. Increased immunosuppression, as evidenced in the nadir or baseline CD4+ T-cell counts, were both associated with heightened prevalence of HSIL (Table 3).

Table 3

Unadjusted and adjusted prevalence ratios (PR) for the association of factors with the presence of high-grade squamous intra-epithelial lesions among HIV-infected women from Rio de Janeiro, Brazil

	Unadjusted		Adjusted
Variable	PR	95% Cl	PR	95%Cl
Age (years)
<25 or >40	1.00		1.00
25–40	2.43	0.97–6.08*	2.60	1.11–6.10**
Race/ethnicity
White	1.00
Non-white	0.55	0.26–1.15*
Married/living with partner
Yes	1.00
No	1.80	0.80–4.07*
Years of formal education
<5	0.78	0.29–2.06
5–8	0.94	0.41–1.14
>8	1.00
Monthly income (US$)***
<75	1.00
75–300	1.98	0.47–8.40
>300	3.39	0.63–18.5*
Ever smoked
No	1.00
Yes	1.27	0.61–2.64
Current smoker
No	1.00
Yes	1.27	0.56–2.87
Ever used drugs
No	1.00
Yes	1.78	0.85–3.73*
Age at first sexual intercourse (years)
>17	1.00
≤17	1.44	0.67–3.10
Number of lifetime sexual partners
Up to 4	1.00
5 or more	0.95	0.45–2.00
Use of contraceptive hormones
Yes	0.76	0.18–3.18
No	1.00
Number of pregnancies
≤3	1.00		1.00
4 or more	0.34	0.12–0.98**	0.33	0.11–0.94**
Time since last gynaecological examination
≤1 year	1.00		1.00
>1 year	1.68	0.80–3.57*	1.83	0.86–3.87*
Self-reported history of HPV
No	1.00
Yes	2.05	0.93–4.50*
Nadir CD4+ T-cell count (cells/mm ³ )
<100	2.23	0.95–5.22*
100–199	1.30	0.46–3.65
≥200	1.00
Baseline CD4+ T-cell count (cells/mm ³ )
<200	2.06	0.69–6.16*
200–499	1.34	0.41–4.34
≥500	1.00
High-risk HPV****
No	1.00		1.00
Yes	7.36	2.56–21.1**	7.12	2.48–20.5**
Use of HAART
No	1.00
Yes	1.20	0.44–2.25

HPV = human papillomavirus; HAART = highly active antiretroviral therapy; CI = confidence interval

*P value < 0.25 **P value < 0.05 ***Conversion: US$ 1 = R$ 2 ****High-risk HPV infection is defined as an infection with at least one high-risk HPV

Years of formal education, smoking (current or past), age at first sexual intercourse, number of lifetime sexual partners, use of contraceptive hormones (oral or injectable) and use of ART did not show an association with HSIL prevalence (Table 3). Factors that entered the initial multivariate Poisson model included ethnicity, marriage status, income, ever drug use, number of pregnancies, time since last gynaecological examination, self-reported history of HPV, baseline and nadir CD4+ T-cell counts and infection with HR HPV .

In multivariate analyses, HR HPV infection remained the most important determinant of HSIL prevalence, i.e. with the greatest adjusted prevalence ratio ([APR] 7.12, 95% CI: 2.48–20.5). Other factors independently associated with HSIL prevalence were: age (≥25 and ≤40 years; APR 2.60, 95% CI: 1.11–6.10); more than one year since the last gynaecological examination (APR 1.83, 95% CI: 0.86–3.87); and four or more pregnancies (APR 0.33, 95% CI: 0.11–0.94).

DISCUSSION

We estimated the prevalence of cervical cytological abnormalities and the factors associated with HSIL among HIV-infected women from Rio de Janeiro, Brazil. We found that a quarter of the women had abnormal conventional Pap smear results; prevalences of LSIL and HSIL were 13.1% and 4.1%, respectively. Studies conducted in resource-limited settings have shown similar prevalence of SIL among HIV-infected women. In São Paulo, Brazil, 12.6% of the HIV-infected women had a diagnosis of SIL or invasive cervical cancer.²³ In Thailand, the prevalence of LSIL and HSIL was 11.2% and 4.7%, respectively.¹⁴ Studies conducted in Africa, on the other hand, have reported higher prevalences; in Zambia, 34% of the HIV-infected women had HSIL detected on their cervical smears,²⁵ while in Uganda, 39% of the HIV-infected women had HSIL detected on their cervical smears.²⁶ Prevalence of SIL reported from developed countries, such as USA and Canada, varies between 6% and 38.3%.^11,27–29 Our findings corroborate the fact that HSIL is a condition of significant relevance among HIV-infected women, which needs to be properly addressed.

We found that a significant proportion of the HIV-infected women who were diagnosed with an abnormal conventional Pap smear result were also infected with an HR HPV. These infections progress to HSIL both more frequently and rapidly in HIV-infected women,^11,30 thus careful surveillance is warranted for this population. Moreover, since conventional Pap smears can give false-negatives results, repeated testing is recommended. On average, it takes 10 years for HSIL to progress to invasive cervical cancer, which is the reason why Pap smear screening implemented with high coverage has led to a decreased incidence and mortality of cervical cancer.⁶ Thus, high coverage of screening and proper follow-up are both needed in order to reduce the incidence and mortality rates of cervical cancer. Also, colposcopy should be recommended for all women with HR HPV infection and an abnormal Pap smear result.

Women with an HR HPV infection had seven times the prevalence of HSIL compared with those without HR HPV infection. This finding is expected given that HR HPV infection is a necessary cause of cervical cancer.^5,31 Beyond HR HPV infection, we found that HPV infection and self-reported history of HPV were both associated with a higher prevalence of HSIL. Others have reported that HPV infection, multiple HPV types and a history of genital warts interact to increase the risk of abnormal cytology among women participating in the Women's Interagency HIV Study.²⁹ We also found that the prevalence of HSIL was increased among women who had not had a gynaecological examination within the previous year from the current evaluation. In settings with limited access to care, our findings indicate that women with a history of HPV or absence of previous gynaecological examination should be prioritized.

In a previous analysis of the present cohort of HIV-infected women, we found that young age (<30 years) was associated with HPV infection.²² In agreement with the natural history of cervical cancer, we now found that women aged 25–40 years had two times the prevalence of HSIL when compared with those younger than 25 or older than 40 years of age. Following the natural history of cervical cancer, these results also agree with the fact that women of age 40 years or older are most affected by cervical cancer.^32,33

We found a strong protective effect of increasing number of pregnancies with respect to a HSIL Pap smear result. We hypothesize that the reason is the access to health care through the prenatal care offered by the national health system. Studies show that the coverage of prenatal care is greater than 80% in most urban settings of the south-east of Brazil, including the city of Rio de Janeiro,^34,35 and Pap smear is a routine procedure of prenatal care. Indeed, Pap smear test coverage is higher among women who have already given birth^36,37 possibly indicating that pregnancy allowed for a Pap smear test and entry into the national health system. Also, it is possible that young asymptomatic women might not seek care, while pregnancy stands as an important reason for attending the doctor's appointment, and, consequently, having the Pap smear performed. Thus, we argue that the number of pregnancies represents a proxy for access to Pap smear in our setting.

In the present study, we found that increasing levels of immunosuppression, as measured by the nadir and baseline CD4+ T-cell count, were associated with higher HSIL prevalence. However, neither of these measurements was significant when other factors were considered in the multivariate analysis. The absence of an association might be related to our study design not being optimal for the detection of causal relations. In a previous study, we found that nadir CD4+ T-cell count was associated with HR HPV infection.²² Although the degree of immunosuppression is said to influence the incidence and progression of HSIL among HIV-infected women,^11,38 many observational studies have not been able to detect an association. When considering the literature from our setting, other studies conducted among HIV-infected women also failed to find an association.^39,40 Similar to our study, the latter were of a cross-sectional design but different from ours, they had a limited sample size. A recent longitudinal study from Finland also did not find an increased risk of HSIL as a result of immunosuppression.⁴¹

HAART increases the survival of HIV-infected women and thus, theoretically, can allow for progression of HR HPV infection to HSIL/invasive cervical cancer. However, to date, there is no conclusive evidence on whether HAART independently influences the natural history of HR HPV infection or reduces the risk of HSIL/invasive cervical cancer. Indeed, contrasting results relating to the impact of HAART on HSIL regression have recently been reported.^12,13,42,43 These contrasting findings might be explained by the increased survival resulting from HAART leading to a confounded relationship between HAART and HPV/HSIL risk. That is, the longer survival allows for prolonged exposure of the cervix to HR HPV infection while in the presence of immunosuppression.⁵ In our study, we found no evidence of an association of HAART with HSIL prevalence.

Smoking and use of hormonal contraceptive methods were not found to be associated with increased HSIL prevalence. Both factors have been shown to be risk factors for cervical cancer among women in general.^8,17 Of note is the small fraction of women who reported use of hormonal contraceptive methods (9%) or current use of tobacco (23%).

Another finding worth mentioning is that four out of 29 women diagnosed with HSIL were not found to be infected with HR HPV. Since HR HPV is a necessary cause of HSIL, we can think of two reasons that might explain this finding. First, conventional Pap smear can lead to false-positive results thus implying that these women were correctly found not to be infected with HR HPV and incorrectly diagnosed with HSIL. Second, Hybrid Capture II could have failed to show HPV DNA as a result of a limitation related to the method, such as the cut-off point used, specimen collection and/or storage problems. Also, an infection with an HPV type not included in the spectrum of the Hybrid Capture II test could lead to a false-negative HPV result.

We found that HSIL is a significant problem in this cohort of HIV-infected women from Rio de Janeiro, Brazil, for whom HAART has been available for more than a decade. Despite HAART-induced immune reconstitution,⁴⁴ it is possible that the increased survival may lead to higher incidence and mortality from cervical cancer. Clinicians must be aware of the need for recurrent cervical cancer screening in this population. A multitude of factors influence the effectiveness of a screening strategy. While cytology-based screening has been shown effective in the developing world, other screening strategies such as HPV DNA testing and visual inspection with acetic acid might offer increased benefit, especially in resource-limited settings.^16,45,46 The most cost-effective cervical cancer screening protocol for HIV-infected women in a particular setting needs to be determined.

Footnotes

ACKNOWLEDGEMENTS

BG acknowledges funding from the National Counsel of Technological and Scientific Development (CNPq) and the Research Funding Agency of the State of Rio de Janeiro (FAPERJ). This study was funded by Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz and the Brazilian National STD/AIDS Program of the Ministry of Health.

References

Snijders

, Steenbergen

, Heideman

, Meijer

. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006;208:152–64

Parkin

, Bray

. Chapter 2: the burden of HPV-related cancers. Vaccine 2006;24(Suppl 3):S11–25

Bosch

, de Sanjose

. The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers 2007;23:213–27

Bosch

, Lorincz

, Munoz

, The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244–65

Schiffman

, Castle

, Jeronimo

, Human papillomavirus and cervical cancer. Lancet 2007;370:890–907

Wright

Jr . Cervical cancer screening in the 21^st century: is it time to retire the PAP smear? Clin Obstet Gynecol 2007;50:313–23

Franco

, Duarte-Franco

, Ferenczy

. Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection. CMAJ 2001;164:1017–25

Smith

, Green

, Berrington de Gonzalez

, Cervical cancer and use of hormonal contraceptives: a systematic review. Lancet 2003;361:1159–67

Strickler

, Burk

, Fazzari

, Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 2005;97:577–86

10.

Clifford

, Polesel

, Rickenbach

, Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J Natl Cancer Inst 2005;97:425–32

11.

Palefsky

. Cervical human papillomavirus infection and cervical intraepithelial neoplasia in women positive for human immunodeficiency virus in the era of highly active antiretroviral therapy. Curr Opin Oncol 2003;15:382–88

12.

Heard

, Tassie

, Kazatchkine

, Orth

. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS 2002;16:1799–802

13.

, Kiviat

. Cervical neoplasia and highly active antiretroviral therapy. J Natl Cancer Inst 2004;96:1051–53

14.

Mangclaviraj

, Kerr

, Chaithongwongwatthana

, Nadir CD4 count and monthly income predict cervical squamous cell abnormalities in HIV-positive women in a resource-limited setting. Int J STD AIDS 2008;19:529–32

15.

Bollen

, Chuachoowong

, Kilmarx

, Human papillomavirus (HPV) detection among human immunodeficiency virus-infected pregnant Thai women: implications for future HPV immunization. Sex Transm Dis 2006;33:259–64

16.

Franceschi

, Jaffe

. Cervical cancer screening of women living with HIV infection: a must in the era of antiretroviral therapy. Clin Infect Dis 2007;45:510–13

17.

Simon

, Ho

, Abdool Karim

. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 2006;368:489–504

18.

Ministry of Health. Cancer Estimates for the Year 2006 in Brazil. Rio de Janeiro, Brazil: National Cancer Institute, 2005

19.

Gakidou

, Nordhagen

, Obermeyer

. Coverage of cervical cancer screening in 57 countries: low average levels and large inequalities. PLoS Med 2008;5:e132

20.

Fonseca

, Bastos

. Twenty-five years of the AIDS epidemic in Brazil: principal epidemiological findings, 1980–2005. Cad Saude Publica 2007;23(Suppl 3):S333–44

21.

Campos

, Ribeiro

, Grinsztejn

, Survival of AIDS patients using two case definitions, Rio de Janeiro, Brazil, 1986–2003. AIDS 2005;19(Suppl 4):S22–26

22.

Grinsztejn

, Veloso

, Levi

, Factors associated with increased prevalence of human papillomavirus infection in a cohort of HIV-infected Brazilian women. Int J Infect Dis 2009;13:72–80

23.

Calore

, Pereira

, Cavaliere

. Progression of cervical lesions in HIV-seropositive women: a cytological study. Diagn Cytopathol 2001;24:117–19

24.

Grinsztejn

, Bastos

, Veloso

, Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil. Int J STD AIDS 2006;17:473–78

25.

Sahasrabuddhe

, Mwanahamuntu

, Vermund

, Prevalence and distribution of HPV genotypes among HIV-infected women in Zambia. Br J Cancer 2007;96:1480–83

26.

Blossom

, Beigi

, Farrell

, Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women. J Med Virol 2007;79:758–65

27.

Hankins

, Coutlee

, Lapointe

, Prevalence of risk factors associated with human papillomavirus infection in women living with HIV. Canadian Women's HIV Study Group. CMAJ 1999;160:185–91

28.

Luque

, Jabeen

, Messing

, Prevalence of human papillomavirus genotypes and related abnormalities of cervical cytological results among HIV-1-infected women in Rochester, New York. J Infect Dis 2006;194:428–34

29.

Massad

, Riester

, Anastos

, Prevalence and predictors of squamous cell abnormalities in Papanicolaou smears from women infected with HIV-1. Women's Interagency HIV Study Group. J Acquir Immune Defic Syndr 1999;21:33–41

30.

Nappi

, Carriero

, Bettocchi

, Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women. Eur J Obstet Gynecol Reprod Biol 2005;121:226–32

31.

Almonte

, Albero

, Molano

, Risk factors for human papillomavirus exposure and co-factors for cervical cancer in Latin America and the Caribbean. Vaccine 2008;26(Suppl 11):L16–36

32.

Fonseca

, Ramacciotti Ade

, Eluf Neto

. Mortality trends from uterine cervical cancer in the city of Sao Paulo from 1980 to 1999. Cad Saude Publica 2004;20:136–42

33.

Kalakun

, Bozzetti

. Evolution of uterine cervical cancer mortality from 1979 to 1998 in the State of Rio Grande do Sul, Brazil. Cad Saude Publica 2005;21:299–309

34.

Leal

, Gama

, Campos

, Factors associated with perinatal morbidity and mortality in a sample of public and private maternity centers in the City of Rio de Janeiro, 1999–2001. Cad Saude Publica 2004;20(Suppl 1):S20–33

35.

Rama

, Roteli-Martins

, Derchain

, Previous screening for cervical cancer among women with cytological and histological abnormalities. Rev Saude Publica 2008;42:411–19

36.

Leal

, Gama

, Frias

, Szwarcwald

. Healthy lifestyles and access to periodic health exams among Brazilian women. Cad Saude Publica 2005;21(Suppl):78–88

37.

de Albuquerque

, Frias

, de Andrade

, Pap smear coverage and factors associated with non-participation in cervical cancer screening: an analysis of the Cervical Cancer Prevention Program in Pernambuco State, Brazil. Cad Saude Publica 2009;25(Suppl 2):S301–09

38.

de Sanjose

, Palefsky

. Cervical and anal HPV infections in HIV positive women and men. Virus Res 2002;89:201–11

39.

Araujo

ACL

, Melo

, Castro

LPF

, Association between viral load and CD4+ T lymphocyte count and cervical intraepithelial lesions in HIV-infected women. Revista Brasileira de Ginecologia e Obstetricia 2005;27:106–11

40.

Zimmermmann

, Melo

, Castro

LPF

, Association between CD4+ T-cell count and intraepithelial cervical neoplasia diagnosed by histopathology in HIV-infected women. Revista Brasileira de Ginecologia e Obstetricia 2006;28:345–51

41.

Lehtovirta

, Paavonen

, Heikinheimo

. Risk factors, diagnosis and prognosis of cervical intraepithelial neoplasia among HIV-infected women. Int J STD AIDS 2008;19:37–41

42.

Ahdieh-Grant

, Li

, Levine

, Highly active antiretroviral therapy and cervical squamous intraepithelial lesions in human immunodeficiency virus-positive women. J Natl Cancer Inst 2004;96:1070–76

43.

Paramsothy

, Jamieson

, Heilig

, The effect of highly active antiretroviral therapy on human papillomavirus clearance and cervical cytology. Obstet Gynecol 2009;113:26–31

44.

De Beaudrap

, Etard

, Diouf

, Modeling CD4+ cell count increase over a six-year period in hiv-1-infected patients on highly active antiretroviral therapy in Senegal. Am J Trop Med Hyg 2009;80:1047–53

45.

Sankaranarayanan

, Nene

, Shastri

, HPV screening for cervical cancer in rural India. N Engl J Med 2009;360:1385–94

46.

Ronco

, Segnan

. HPV testing for primary cervical cancer screening. Lancet 2007;370:1740–42