THE PREVALENCE OF HUMAN PAPILLOMAVIRUS (HPV), the primary cause of cervical cancer,1 has been shown to be higher among HIV-infected women than among HIV-uninfected women.2 The high-risk HPV prevalence among HIV-infected women was reported to be 83.2% in Brazil3 and 44.5% in the United States.4 Recently, a Thai study showed a lower prevalence of 23.4% high-risk HPV types among pregnant HIV-infected women.5 However, the risk for HPV infection in this antenatal population may not be representative of all HIV-infected women in Thailand.
The prevalence of squamous intraepithelial lesion (SIL) is higher among HIV-infected women compared with uninfected women.6 The U.S. Centers for Disease Control and Prevention (CDC) recommends that a Pap test be obtained twice in the first year after diagnosis of HIV infection and, if the results are normal, annually thereafter.7 However, cervical cancer screening is not included in the Thai national guidelines for HIV care,8 and few HIV-infected women currently receive screening for cervical cancer in Thailand.9 The low rate of 0.2% cervical cancer prevalence reported among women diagnosed with AIDS in Thailand,10 compared with 2.3% in Europe11 and 3.9% in the United States,12 likely reflects the low rate of cervical cancer screening.
As the Thai Ministry of Public Health (MOPH) expands access to antiretroviral treatment for eligible HIV-infected persons, HIV-infected women will live longer, likely resulting in an increase in cervical cancer incidence. Although some studies suggest that antiretroviral treatment may alter the course of HPV-induced cervical dysplasia among HIV-infected women by slowing progression and increasing regression of dysplasia,13 the incidence of invasive cervical cancer has not significantly decreased in the era of highly active antiretroviral treatment.14
We screened HIV-infected women at two clinics in Bangkok by Pap tests and referred them for diagnosis and treatment to prevent the development of cervical cancer. In addition, we determined the prevalence of high-risk HPV and cervical cancer to assess the need for strengthening cervical cancer screening programs for HIV-infected women in Thailand.
Women infected with HIV and seeking care at any of two clinics of the Thai MOPH, an infectious disease clinic at Bamrasnaradura Institute in Nonthaburi and a sexually transmitted infection (STI) clinic in central Bangkok at Bangrak Hospital, were screened for cervical cancer and HPV. Both clinics offer health care under the Royal Thai government’s universal healthcare program. The project started in July 2003 and data were collected through February 2004 to evaluate the program. A standardized data form was used to collect information on sexual behavior and the use of antiretroviral treatment.
Women consenting to screening underwent examination and samples were obtained for HPV DNA testing (Cervical Sampler; Digene Corp., Gaithersburg, MD) and Pap tests. The importance of annual Pap tests was emphasized, especially to women with tests positive for high-risk HPV. Cervical smears were assigned a diagnosis according to the Bethesda system into normal, atypical squamous cells of undetermined significance (ASCUS), atypical glandular cells (AGC), low-grade squamous intraepithelial lesion (LSIL), high-grade SIL (HSIL), or squamous cell carcinoma.15
Per routine, women with abnormal cervical cytology (ASCUS, AGC, SIL, or carcinoma) were referred for colposcopy at clinics covered by the universal healthcare program; these results were used to assess prevalence of abnormal cervical cytology. Pathology results were graded at referral clinics, which were requested by project staff for prevalence estimation. Women with abnormal cytology were contacted by mail and phone to ensure adequate follow-up.
This project also included screening and treatment of STIs along with risk reduction counseling and provision of condoms to reduce HIV transmission, as reported earlier.16 Screening included Chlamydia trachomatis and Neisseria gonorrhoeae by polymerase chain reaction Amplicor analysis (Roche Diagnostic System, Basel, Switzerland), Trichomonas vaginalis by light microscopy of a saline wet preparation, and syphilis by Venereal Disease Research Laboratory (VDRL) slide test as a screening test and Treponema pallidum hemagglutination assay (TPHA; Fuji-rebio Inc., Japan) as a confirmatory test.16
This project was approved by the Thai MOPH and the U.S. CDC as a programmatic activity not involving human subject research and did not require Institutional Review Board approval.
High-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) were detected by using the high-risk probe of the Digene Hybrid Capture 2 assay according to the manufacturer’s package insert (Digene Corporation, Gaithersburg, MD). HIV infection status was confirmed by Murex HIV1–2 enzyme-linked immunosorbent assay (Murex Biotech Ltd., Dartford, U.K.). CD4 cell count testing was performed using FACScan flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA).
Data were analyzed using Epi Info 2000 version 3.2 (February 4, 2004). P values were assessed by the chi-squared test and significant (P < 0.05) variables were adjusted for as potential confounders.
From July 2003 to February 2004, 272 consecutive HIV-infected women were offered cervical cancer screening through this project along with STI services.16 A total of 210 women (77.2%) consented to screening, 150 (70.8%) at the infectious disease clinic and 60 (100%) at the STI clinic. Time constraints or menstruation were common reasons to decline screening for women attending the infectious disease clinic. Although not statistically significant, women attending the infectious disease clinic tended to be younger than those attending the STI clinic (median 30.5 years vs. 33.0 years; P = 0.06) and tended to be diagnosed with HIV for a longer time (median 2.8 years vs. 2.3 years; P < 0.05). A smaller proportion of women at the infectious disease clinic reported a history of sex work (6.7% vs. 41.2%; P < 0.001) and more were using antiretroviral treatment (46.0% vs. 20.0%; P < 0.001) compared with women at the STI clinic.
Among the 210 women, 81 (38.6%) had high-risk HPV detected. Age did not differ significantly between women with or without high-risk HPV types (median 32.4 years vs. 32.3 years; P = 0.09). The detection of high-risk HPV was associated with sex work (P = 0.004) and having another STI (P = 0.03) in bivariate analysis (Table 1). The association with sex work remained significant after adjusting for STIs (P = 0.02); the association with having another STI did not remain significant after adjusting for sex work (P > 0.1).
Among the 210 women, 43 (20.5%) had abnormal cervical cytology. Abnormal cervical cytology was significantly more common at the STI clinic than at the infectious disease clinic and was strongly associated with detection of high-risk HPV (Table 2); both factors remained significant in stratified analysis adjusting for each other (P < 0.05 and P < 0.001, respectively). High-risk HPV was detected among 44 (26.3%) of 167 women with normal cervical cytology, 9 (75.0%) of 12 with ASCUS, 2 (100%) of 2 with AGC, 17 (85.0%) of 20 with LSIL, and all 9 (100%) with HSIL.
Duration of HIV diagnosis (median 2.7 years) was longer for HPV-positive women compared with HPV-negative women (median 3.5 years vs. 2.5 years) and for women with abnormal cervical cytology compared with those with normal cervical cytology (median 4.0 years vs. 2.5 years), but did not reach statistical significance (both P = 0.1).
A total of 43 women were referred for colposcopy at several clinics in Bangkok and pathology results were received by the project staff from 23 (53.5%) of them, including all women with Pap test results indicating HSIL for whom colposcopy had been especially emphasized. Among the 20 women from whom no pathology results were received, Pap test results indicated LSIL (n = 13) and ASCUS (n = 7).
Pathology results included invasive squamous cell carcinoma (n = 4), carcinoma in situ (n = 1), cervical intraepithelial neoplasia (CIN) 2 or 3 (n = 6), CIN 1 (n = 5), and the absence of dysplasia (n = 7). A diagnosis of invasive squamous cell carcinoma was made in four (1.9%; 95% confidence interval, 0.5–4.8%) of the total 210 HIV-infected women based on pathology reports from 23 (53.5%) of the 43 women. All these four women had high-risk HPV detected, four had Pap tests indicating HSIL, and one had ASCUS.
As previously reported, among the 210 women, 30 (14.3%) had one or more STIs, including chlamydial infection (n = 7), gonorrhea (n = 4), trichomoniasis (n = 1), syphilis (n = 9), and genital ulcer (n = 12), The STI prevalence was lower among women at the infectious disease clinic than at the STI clinic (8.0% vs. 30.0%; P < 0.01).16
We found a high-risk HPV prevalence of 38.6% among HIV-infected women attending either an infectious disease clinic or an STI clinic in Bangkok. The high-risk HPV prevalence among these women was higher than the 23.4% previously reported among pregnant HIV-infected women in Bangkok.5 History of sex work might not explain this difference, because the high-risk HPV prevalence in our population was also high among women without a history of sex work (34.3%). A longer time interval between HIV infection and detection of high-risk HPV types may result in a higher HPV prevalence because more incident and persistent HPV infections occur during HIV infection.2 Most of the pregnant women were newly identified as HIV-infected during screening to prevent mother-to-child HIV transmission,5 whereas our population reported several years since their HIV diagnosis and may have been infected with HIV for a longer time. It is likely that the longer life expectancy of HIV-infected women on antiretroviral treatment will lead to an increase in HPV prevalence and HPV-associated cervical cancer. Therefore, it will be important to offer all HIV-infected women access to screening programs and treatment of dysplastic lesions to prevent the development of cervical cancer.
We did not observe an association between HPV prevalence and age. Studies have shown higher HPV prevalence among younger compared with older women.2 However, such an decrease in HPV prevalence with increasing age has not been observed among HIV-infected women2,17 because they have more incident and persistent infections than HIV-uninfected women.2
Abnormal cervical cytology was common among HIV-infected women at both clinics in Bangkok, and this is the first report showing high cervical cancer prevalence among HIV-infected Thai women. The prevalence of cervical cancer is likely to have exceeded 1.9% if all pathology results had been received, although none of the women without pathology results had a Pap test indicating HSIL. However, our sample size was limited, leading to an estimated cervical cancer prevalence with a wide confidence interval. Nevertheless, cervical cancer prevalence among these women was higher than previously reported in Thailand10 and was similar to that reported among HIV-infected women in other parts of the world,11,12 emphasizing the importance of integrating cervical cancer screening into HIV care. Although the capacity for Pap tests, colposcopy, and pathology in Thailand is limited, leading to consideration of simplified screening approaches,18 standard methods for diagnosis and treatment of cervical dysplasia and cancer are now being strengthened as part of a recently launched national cervical cancer screening program.
We did not explore the role of HPV testing in selecting women with ASCUS for colposcopy referral. Colposcopy could be avoided for women not known to be HIV-infected with ASCUS and an HPV-negative test.19 Because inconclusive results from this strategy have been reported for HIV-infected women,20,21 colposcopy remains recommended for this population independent of HPV test results.19 Harris et al showed similar incidence of SIL among HIV-infected and uninfected women who had normal Pap tests and negative HPV tests at baseline.22 Although an HPV-negative test may be used to extend the yearly screening interval for HIV-infected women, this strategy was not included in previous published interim guidance on cervical cancer screening.23
Also, the cost of an HPV test surmounts the cost associated with a Pap test performed at public clinics in Thailand, questioning the value of additional HPV testing in the Thai cervical cancer screening program. In conclusion, the high cervical cancer prevalence within our population emphasizes the need to use the Thai national cancer screening program for the benefit of HIV-infected women and to integrate conventional Pap test screening into routine HIV care.
1. Walboomers J, Jacobs M, Manos M, et al. Human papillomavirus is a necessary cause of invasive cervical cancer world-wide. J Pathol 1999; 189:12–19.
2. Ahdieh L, Klein R, Burk R, et al. Prevalence, incidence and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women. J Infect Dis 2001; 184:690.
3. Levi JE, Kleter B, Quint WGV, et al. High prevalence of human papillomavirus (HPV) infections and high frequency of multiple HPV genotypes in human immunodeficiency virus-infected women in Brazil. J Clin Microbiol 2002; 40:3341–3345.
4. Palefsky JM, Minkoff H, Kalish LA, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high risk HIV-negative women. J Natl Cancer Inst 1999; 91:226–236.
5. Bollen LJM, Chuachoowong R, Kilmarx PH, et al. Human papillomavirus (HPV) detection among HIV-infected pregnant Thai women; implications for future HPV immunization. Sex Transm Dis 2006; 33:259–264.
6. Ellerbrock TV, Chiasson M, Bush T, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2001; 283:1031–1037.
7. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep 2002; 51:59.
8. Bureau of AIDS, TB and STIs, Thai Ministry of Public Health. National Guidelines for the Clinical Management of HIV Infection in Children and Adults, 8th ed, 2004. ISBN 974-297-298-2.
9. Srisongsom S, Lolekha R, Chunwimaleung S, et al. HIVQUAL-T: An innovative performance measurement tool for HIV care quality improvement in Thailand. International Conference on AIDS in Asia and the Pacific, 1–5 July, 2005; Abstract Sa B05–03. Kobe, Japan.
10. Chariyalertskak S, Sirisanthana T, Saengwonloey O, et al. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, 1994–1998: Regional variation and temporal trends. Clin Infect Dis 2001; 32:955–962.
11. Dal Maso L, Serraino D, Franceshchi S. Epidemiology of AIDS-related tumours in developed and developing countries. Eur J Cancer 2001; 37:1188–1201.
12. Maiman M, Frucher R, Guy L, et al. Cervical cancer as an AIDS-defining illness. Obstet Gynecol 1997; 89:76–80.
13. Minkoff H, Ahdieh L, Massad L, et al. The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women. AIDS 2001; 15:2157–2164.
14. Gates AE, Kaplan LD. AIDS malignancies in the era of highly active antiretroviral therapy. Oncology 2002; 16:657–665.
15. The 1991 Bethesda System for reporting cervical/vaginal cytologic diagnoses: Report of the 1991 Bethesda workshop. JAMA 1992; 267:1892.
16. Sirivongrangson P, Bollen LJM, Chaovavanich A, et al. Sexually transmitted infection services as a component of HIV care: Findings of a demonstration project among HIV-infected women in Thailand. J Acquir Immun Defic Syndr 2006; 41:671–674.
17. Thomas D, Ray NB, Kuypers J, et al. Human papillomaviruses and cervical cancer in Bangkok. III. The role of husbands and commercial sex workers. Am J Epidemiol 2001; 153:740–748.
18. Royal Thai College of Obstetricians and Gynaecologists (RTCOG)/JHPIEGO Corporation Cervical Cancer Prevention Group. Safety, acceptability, and feasibility of a single-visit approach to cervical-cancer prevention in rural Thailand: A demonstration project. Lancet 2003; 361:814–820.
19. Wright TC, Cox JT, Massad LS, et al. 2001 consensus guidelines for the management of women with cervical cancer abnormalities. JAMA 2002; 287:2120–2129.
20. Kirby TO, Allen ME, Alvarez RD, et al. High-risk human papillomavirus and cervical intraepithelial neoplasia at time of atypical squamous cells of undetermined significance cytologic results in a population with human immunodeficiency virus. J Low Genit Tract Dis 2004; 8:298–303.
21. Massad LS, Schneider MF, Watts DH, et al. HPV testing for triage of HIV-infected women with Papanicolaou smears read as atypical squamous cells of uncertain significance. J Womens Health 2004; 13:147–153.
22. Harris TG, Burk RD, Palefsky JM, et al. Incidence of cervical squamous intraepithelial lesions associated with HIV serostatus, CD4 cell counts, and human papillomavirus test results. JAMA 2005; 293:1471–1476.
23. Wright TC, Schiffman M, Solomon D, et al. Interim guidance for the use of human papillomavirus DNA testing as an adjunct to cervical cytology for screening. Obstet Gynecol 2004; 103:304–309.