This is the first long-term retrospective cohort study of cervical squamous cell abnormalities in HIV-infected Thai women. It is well recognized that women with HIV infections have a higher prevalence, incidence, persistence, and progression of squamous intraepithelial lesions as compared with those without the infection. The prevalence of cervical squamous cell abnormalities and SILs in the present study was similar to that in our previous study. Compared with several previous studies[5–8], the result of Pap smear screenings from the present study showed a slightly lower prevalence (15.4% vs.20%-40%). In addition to the different backgrounds, this may be due to the fact that the majority of participants in this study were either ante-partum, or immediate postpartum.
Interestingly, the cumulative incidence of ASCUS+ in the present study gradually increased to 37% in the first 3.5 years of follow-up appointments (first 7 times) and tended to plateau in the last 2 years. In addition, one woman with cytological diagnosis of HSIL and with a histologic diagnosis of CINIII was diagnosed from the Pap smear at her seventh follow-up appointment. Comparable with this study, a previous study found that among HIV- infected women whose initial Pap smear was negative for intraepithelial lesion (NIL), about 20%-35% of them would develop cytologic abnormalities over 3.0-5.5 years. This supports the fact that there is a high rate of false negative Pap smear results among HIV-infected patients, as mentioned in a previous study. The findings prompted us to reconsider the appropriate interval of Pap smear screenings for HIV-infected women as recommended by The US Public Health Service and The Infectious Disease Society of America in our setting. Our population might require more than two normal semi-annual Pap smear before shifting to annual cytologic screening. As the present study had high drop-out rate in the first 2 years, we believe that the real incidence of ASCUS+ might be higher. Previous studies have base analysis on less frequent Pap smears than ours; some of them did not pay sufficient attention to the lag period which is supposed to play an important part in cervical carcinogenesis.
Many studies demonstrated that women with a CD4 count < 200 cells/μL were at particular risk of cervical cell abnormalities[4, 16–19]. This means that immunological status also plays a crucial part in cervical carcinogenesis. We found that the women with ASCUS+ had significantly higher proportions of receiving HAART than those with NIL. This is the most likely reflection that these women had an underlying poor immune status by their own merit without any correlation of HAART. The CD4 count cut-off point that we used to predict cumulative incidence of ASCUS+ was 350 cells/μL, which is compatible with a study from Brazil. Recently, the Thai Ministry of Public Health initiates HAART for all HIV-infected patients who have CD4 counts at this level or lower. The CD4 counts < 200 cells/μL seem to be far too low to detect new ASCUS+ cases and may be too low for basing a decision to initiate HAART regimen. However, we did not look at the change of CD4 count and its impact on cumulative incidence of ASCUS+.
A well-designed study demonstrated that the incidence of SILs increased with time, especially the ones with lower CD4 count and oncogenic HPV infection. In addition, a study from Italy with 132 HIV-infected women who had invasive cervical cancer (ICC) showed that the interval between the first HIV-positive test and invasive cancer diagnosis was longer than 10 years in almost half of the women. We also found that the assumed duration of HIV infection and the CD4 count nadir level were associated with a high prevalence of ASCUS+ from the initial Pap smear. However, they were not associated with the cumulative incidence of ASCUS+.
In the present study only 0.1% (1/821) of HIV-infected women had invasive squamous cell carcinoma. This woman had a baseline CD4 count of 148 cells/μL and had a 14-year duration assumed HIV infection. She had a cytologic HSIL at the third Pap smear and colposcopic diagnosis of HSIL. With a lower incidence of invasive squamous cell carcinoma, our study may not represent the whole picture of HIV-infected women in Thailand - since the incidence in this study was lower than the figure reported from a previous study conducted in Thailand. A high number of women were already on HAART at commencement of the study. HAART might have beneficially protective on preventing cervical carcinogenesis[22, 23]. More important reasons were the early detection by a regular semi-annual check-up, the development of health education, and the growth of trust between health care providers and patients. Smoking was not included in the baseline characteristics because almost all Thai women were not current or ex-smokers.
Several studies are currently investigating the benefits of adding HPV DNA tests to improve screening for cervical lesions and cancer - as screening for oncogenic HPV types is a more sensitive predictor of high grade squamous intra-epithelial lesions. Overall, the HPV test had a higher sensitivity among HIV-infected women as compared with HIV-uninfected women. One study in Thailand reported that the prevalence of high risk HPV infection in Thai HIV-seropositive women was 38.6%, which was lower than that found in American (83.2%) and Brazilian women (44.5%)[24, 25]. However, HPV DNA testing is not a routine screening test in this clinic due to its high cost. In addition, the specificity for cervical lesions of the test was low in HIV-infected women, resulting largely from a very high prevalence of HPV infection in women without cervical lesions. Thus, a HPV test may not provide benefits for cervical surveillance in the setting of HIV, because of its low specificity and poor predictive value[26, 27].
In 1999, Holcomp, et al. demonstrated the significance of ASCUS in HIV-infected women by comparing cytological and histological results. They found that 32% of ASCUS had histological cervical intraepithelial neoplasia (CIN). As a result, they suggested that early colposcopy should be considered in HIV infected women with ASCUS. There were a total of 16 women with ASCUS in our study, 14 were able to undergo colposcopy and 10 had colposcopic diagnosis of SILs (9 women with HPV/CIN I and 1 woman with CIN II-III) (Table 4). Although our study demonstrated that there was a high incidence of colposcopic diagnosis of SILs in women with ASCUS, only one woman in this group had colposcopic diagnosis of CIN II-III which had to be confirmed by tissue diagnosis. Since most of them had colposcopic diagnosis of HPV/CIN I and had a low socio-economic background, it was unlikely that biopsies with pathological reports in these cases could be met.
There were a number of limitations in the present study that warranted mentioning. (1) The primary outcome was mainly the surrogate outcome of cervical cancer. Even though the incidence of abnormal lesions was high, these were mainly low grade lesions which could be regression, especially in younger women. (2) False negative Pap smear was not included in the scope of the present study and this might have impact the findings as a previous study found a high false negative Pap smear rate in HIV-infected women with CD4 count < 500 cells/μL. (3) The lack of viral load, colposcopy with tissue biopsy could not be performed in all cases; instead, a 'see and treat' technique was applied in order to decrease costs. (4) Due to the government universal coverage program and limited seats at Siriraj Hospital, many participants, especially a number in our study who were either ante-partum, or immediate post partum, were required to follow-up at their registered hospitals causing 250 women to be lost to follow up by the 6 month visit (36%) and a further 133 (20%) lost at 12 months. This is a loss of over 50% of study participants in the first year of follow-up. In addition, an effort to try to establish some relationship between health care providers and HIV- infected women was very difficult because of stigmatization of HIV. As a consequence, the rate of follow-up was quite low leading to the potential biases, such as survivorship bias/retention in care. In addition, other AIDS-indicated conditions and established risk factors of cervical cancer were not accounted for and there was one patient who died from an opportunistic infection during the follow-up period.