Human Papillomaviruses and Cervical Cancer in Bangkok. III. The Role of Husbands and Commercial Sex Workers
David B. Thomas1,
Roberta M. Ray1,
Jane Kuypers2,
Nancy Kiviat2,
Amorn Koetsawang3,
Rhoda L. Ashley4,
Qin Qin1 and
Suporn Koetsawang3
1 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA.
2 Department of Pathology, University of Washington, Seattle, WA.
3 Faculty of Medicine, Mahidol University, Department of Obstetrics and Gynecology, Siriraj Hospital, and Siriraj Family Planning Research Center, Bangkok, Thailand.
4 Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA.
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ABSTRACT
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Between September 1991 and September 1993, husbands of women with and without cervical neoplasia and commercial sex workers in one brothel and one massage parlor in Bangkok, Thailand, were interviewed; serologic tests for sexually transmitted infections were performed; and cervical and penile scrapings were tested for human papillomavirus (HPV) DNA. The risks of cervical carcinoma in monogamous women and of oncogenic HPV in their husbands were associated with the men's having unprotected intercourse with prostitutes. The prevalence of oncogenic HPV was higher in commercial sex workers than in women attending gynecologic and family planning clinics. Oncogenic HPV prevalence declined with age in human immunodeficiency virus (HIV)-negative, but not in healthy HIV-positive, commercial sex workers and was weakly associated with hepatitis B antigenemia, suggesting that persistence of HPV infection is due to subtle changes in immunity. Associations of HPV with recent pregnancy and oral contraceptive use suggest that hormonal factors may increase the risk of cervical neoplasia by enhancing persistence of HPV infection. The prevalence of high-grade squamous intraepithelial lesions was strongly related to oncogenic HPV types and weakly to HIV infection only in their presence. Commercial sex workers in Bangkok are reservoirs of oncogenic HPV, and cervical cancer in monogamous Thai women develops in part as a result of transmission of these viruses to them by their husbands from prostitutes.
cervix neoplasms; papillomavirus, human; prostitution; sexual partners
Abbreviations:
DMPA, depot-medroxyprogesterone acetate; HBsAg, hepatitis B surface antigen; HGSIL, high-grade squamous intraepithelial lesions; HIV, human immunodeficiency virus; HPV, human papillomavirus.
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INTRODUCTION
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It is now generally accepted that certain types of human papillomavirus (HPV) play an important role in the genesis of cervical carcinoma (1
). These viruses are sexually transmitted (1
, 2
) and, in cultures in which most women are virgins at marriage and monogamous afterward, the sexual behavior of men is more important than the sexual behavior of women in the transmission of oncogenic types of HPV and the genesis of cervical cancer in their wives (3











16
).
The prevalence of oncogenic types of HPV in men has been associated with contacts with prostitutes (17
, 18
), number of sexual partners (17
19
), and evidence of prior sexually transmitted disease (18
, 19
), providing further evidence of the importance of male sexual behavior in the transmission of these agents.
In a prior study of cervical cancer in Thailand (10
), based on interviews of the husbands of monogamous cases and controls, the risk of invasive squamous cell cervical carcinoma was shown to be associated with the husbands' having visited prostitutes without using a condom when the husbands were less than 30 years old. The prostitutes presumably serve as reservoirs of oncogenic types of HPV, and the husbands serve as vectors of transmission to their wives. This hypothesis is supported by observations that prostitutes are at increased risk of cervical cancer (20
) and have an elevated prevalence of cervical intraepithelial neoplasia (21
) and HPV infection (17
). This is a report of results from interviews of husbands of women with and without cervical cancer and from a survey of prostitutes in Bangkok that were conducted to further clarify the role of prostitutes as reservoirs of oncogenic HPV types and the determinants of HPV infections and their early neoplastic consequences in these heavily exposed women.
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MATERIALS AND METHODS
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Commercial sex workers in Bangkok work in a variety of establishments that cater to different types of men. Massage parlors tend to serve local men of middle and high socio-economic status and foreigners. Brothels provide sexual services largely to local men of low socioeconomic status. This study was conducted in one large massage parlor and one brothel in Bangkok, Thailand.
We included in this study 170 women who were working as masseuses and prostitutes in the massage parlor and 84 prostitutes who were working in the brothel at the time of the study workers' visits. Specially trained and experienced female study workers administered a standardized questionnaire to obtain information on date and place of birth, marital status, educational level, sexual history, history of sexually transmitted diseases, reproductive history, use of steroid and barrier contraceptives, and use of tobacco and alcohol. Information on history of sexually transmitted diseases was supplemented by reviewing medical records in clinics where the study subjects were treated.
In two case-control studies conducted in conjunction with this investigation (22
, 23
), women with histologically confirmed in situ or invasive cervical cancer, diagnosed between September 1991 and September 1993, who were born after 1929, who had resided in Thailand for at least the previous year, and who were treated in Siriraj Hospital, Bangkok, were recruited as cases. Two controls were selected for each woman with invasive disease from otolaryngology and general surgery wards of Siriraj Hospital, and two controls for each case of carcinoma in situ were selected from among women with normal cervical smears who attended the same clinics from which the corresponding cases came. An attempt was made to interview the current husbands of all women. The same questionnaire that was used in a prior study in Thailand (10
) was used to ascertain detailed information on the husbands' sexual history during each decade of adult life, including numbers of partners, visits to prostitutes, and use of condoms. Information was also ascertained on history of sexually transmitted diseases, genital hygiene, circumcision status, reproductive history, and use of tobacco and alcohol.
The prevalence of HPV DNA in the commercial sex workers was compared with the prevalence in women attending gynecologic clinics and in women attending family planning clinics at Siriraj Hospital. Controls for the case-control study of cervical intraepithelial neoplasia (23
) were selected from these clinics, and the two comparison groups included those controls, plus additional women selected in the same manner from each of the two clinics. Thai women who had resided in Thailand for at least the past year, who were born after 1929, who were returning to the clinics to learn the results of a recent cervical smear, and whose cervical smear revealed no suspicion of neoplastic change were randomly sampled and interviewed using the same questionnaire that was used in the case-control study.
A 15-ml blood specimen was obtained from the interviewed men and women. Four aliquots of serum were stored at -70°C, two of which were periodically shipped to Seattle on dry ice. As described previously (22
), serum samples were assayed for antibodies to human immunodeficiency virus (HIV), hepatitis B, Treponema pallidum, and herpes simples virus types 1 and 2, as well as for hepatitis B surface antigen (HBsAg).
Cervical smears were obtained from all women on the same day they were interviewed, as were scrapings for HPV DNA assays by scraping the cervix, including the cervical os, with a Teflon (E. I. du Pont de Nemours and Company, Wilmington, Delaware)-coated swab. An attempt was also made to obtain penile specimens for HPV assays from the interviewed husbands. The coronal sulcus was cleaned of visible smegma with dry gauze, and the area was then scraped with a Teflon-coated swab, as was the urethral opening. The Teflon-coated swabs were broken off into tubes of specimen transport medium (Digene Diagnostics, Inc., Beltsville, Maryland), and the specimens were stored at -70°C and periodically shipped to Seattle, Washington, on dry ice.
All cervical smears from the commercial sex workers were read by a single pathologist in Bangkok. Slides with suspicious lesions were reviewed by a pathologist in Seattle, and those designated high-grade squamous intraepithelial lesions (HGSIL) by the latter were considered as such for this report.
As detailed previously (22
), cervical and penile scrapings were tested for evidence of any HPV DNA and for type-specific DNA of types 6 and 11, type 16, type 18, types 31, 33, 35, and 39, and type 45 using polymerase chain reaction-based assays.
The cervical scrapings from four commercial sex workers who were HIV positive and who had HGSIL and from 30 HIV-positive sex workers with normal cervical cytology were tested for HIV type 1 DNA by nested polymerase chain reaction of the gag gene (24
).
The sexual behavior and HPV status of the husbands of the cases and controls were compared, as were the results of HPV assays in women and their husbands. When appropriate, odds ratios, as estimates of relative risks, were calculated using unconditional logistic regression methods (25
). Data from the commercial sex workers were analyzed to estimate the prevalence odds ratios and their 95 percent confidence intervals for specific types of HPV and for HGSIL using unconditional logistic regression (25), and 95 percent confidence intervals were estimated using exact logistic regression when analysis included cells with zero observations (26
).
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RESULTS
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Study of husbands
Interviews were conducted with 50 (28.6 percent) of the current husbands of 175 women with invasive squamous cell cervical carcinoma who gave a history of a single sexual partner and with 98 (36.0 percent) of the husbands of 272 allegedly monogamous hospital controls. Consistent with previous observations from a larger study in Thailand with higher response rates (10
), a trend of increasing risk of invasive squamous cell cervical carcinoma with increasing estimated number of lifetime visits to prostitutes by the women's husbands was observed (table 1), and risk was associated with the husband's number of visits to prostitutes per year when he was in his teens and twenties, but not at a later age, and with his using condoms less than 10 percent of the time at those ages (not shown). After controlling for lifetime visits to prostitutes, risk was not associated with husbands' history of sexually transmitted diseases, number of sexual partners other than prostitutes, herpes simples virus type 2 antibodies in the husband's serum, or his smoking history (not shown).
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TABLE 1. Odds ratios of invasive squamous cell cervical cancer in monogamous women in relation to their husband's experience with prostitutes, Bangkok, Thailand, 19911993
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Penile scrapings were obtained from 57 husbands of women with in situ or invasive disease (39 of whom were monogamous) and from 68 husbands of control women (56 being monogamous). Only eight men (6.4 percent) tested positive for any oncogenic HPV (including types 16, 18, 31, 33, 35, and 39), and the prevalence was not significantly higher in the husbands of the cases (7.0 percent) than in the husbands of the controls (5.9 percent). Moreover, the 44 husbands of cases with any oncogenic HPV did not have a higher prevalence of an oncogenic HPV type (6.8 percent) than did the 13 husbands of cases with no oncogenic type (7.7 percent). Compared with 79 interviewed husbands with no oncogenic HPV, a higher proportion of the seven interviewed husbands with such an infection reported a history of gonorrhea, multiple sexual partners, visits to prostitutes, and no use of condoms during such visits, although none of the differences reached statistical significance (not shown). The 45 husbands married to women with invasive disease had a lower prevalence of oncogenic HPV (4.4 percent) than did the 12 husbands of women with in situ disease (16.7 percent), although the difference could have occurred by chance (p > 0.05).
Study of commercial sex workers
Women who worked in the brothel were younger than the women who worked in the massage parlor (table 2), both the mean and median ages being 19 and 30 years, respectively. The prevalence of all types of HPV considered was significantly (p < 0.05) higher in the brothel workers than in the massage parlor workers. With the exception of HPV types 6/11, the prevalence of HPV DNA in cervical scrapings decreased with age in the brothel workers, but not appreciably so in the women in the massage parlor. Even the relatively low prevalence of HPV DNA in the massage parlor workers was higher than that in women of comparable age attending gynecologic and family planning clinics at Siriraj Hospital (table 3). Although women from those two clinics with smears suspicious of neoplasia are not represented, when the seven women from the massage parlor with HGSIL were omitted from the analyses, the results were similar to those presented.
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TABLE 2. Age-specific prevalence (%) of specific types of human papillomavirus DNA in cervical scrapings of commercial sex workers from a brothel and a massage parlor, Bangkok, Thailand, 19911993
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TABLE 3. Age-specific prevalence (%) of specific types of oncogenic human papillomavirus DNA in cervical scrapings from commercial sex workers in a massage parlor and from women attending gynecologic and family planning clinics, Bangkok, Thailand, 19911993
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Possible risk factors for HPV types 6/11, 16, and 31/33/35/39 are shown in tables 4, 5, and 7. Too few women were infected with other types for meaningful analysis. All prevalence odds ratios are adjusted for age and place of employment using the strata shown in table 2. The prevalence of none of the HPV types was significantly related to the number of customers per day, the days worked per month, the age at which the woman began working in the sex industry, or the frequency of condom use. The frequency of condom use was ascertained for each decade of sexual activity, and women whose average frequency of condom use was 50 percent or greater are in the "more frequently" category in the table; the remaining women are in the "less frequently" group. The prevalence of type 16 and of types 31/33/35/39 was higher in women with than without history of a sexually transmitted disease in the past year, although the 95 percent confidence limits of the prevalence odds ratios include unity. The risk of prevalent HPV types 6/11 and 31/33/35/39 was lower in women who had worked as prostitutes for 2 or more years than for newer employees, but those results could also readily be due to chance.
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TABLE 4. Prevalence odds ratios* of human papillomavirus types 6/11, 16, and 31/33/35/39 DNA in cervical scrapings from commercial sex workers in relation to sexual variables ascertained from interviews, Bangkok, Thailand, 19911993
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TABLE 5. Prevalence odds ratios* of human papillomavirus types 6/11, 16, and 31/33/35/39 DNA in cervical scrapings from commercial sex workers in relation to serologic factors, Bangkok, Thailand, 19911993
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TABLE 7. Prevalence odds ratios* of human papillomavirus types 6/11, 16, and 31/33/35/39 DNA in cervical scrapings from commercial sex workers in relation to hormonal factors, Bangkok, Thailand, 19911993
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As shown in table 5, the prevalence of all three groups of HPV types was only slightly higher in HIV-positive than HIV-negative women; somewhat more strongly associated with HBsAg; and slightly lower for women with than without a positive test for syphilis, antibodies to herpes simplex virus type 2, and antibodies to hepatitis B surface and core antigens. However, all of the prevalence odds ratio estimates have 95 percent confidence intervals that include one. Although the overall prevalence of the three HPV groups was not higher in the brothel workers with than without HIV infection (table 6), the prevalence of HPV types 16 and 31/33/35/39 declined with age in women without HIV infection but not in women who were HIV positive. A similar analysis could not be performed for the massage parlor workers because only three of them were HIV positive.
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TABLE 6. Age-specific prevalence (%) of specific types of human papillomavirus DNA in cervical scrapings of brothel workers with and without positive tests for human immunodeficiency virus, Bangkok, Thailand, 19911993
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As shown in table 7, the risk of prevalent HPV type16 is associated with having ever been pregnant, especially if within the past 6 years. No trend with the number of livebirths is evident. A similar pattern is seen for types 31/33/35/39 but not for types 6/11. A possible increase in risk of all types is seen in relation to the current use of oral contraceptives, but these observations could be due to chance. No relation of risk to use of the injectable progestational contraceptive, depot-medroxyprogesterone acetate (DMPA), is evident. There were no associations of risk with alcohol or tobacco use (not shown).
Commensurate with the higher prevalence of oncogenic HPV types in the brothel workers than in the massage parlor workers, HGSIL were found in six (8.3 percent) of 72 women in the brothel with an adequate cervical smear but in only seven (4.3 percent) of 161 successfully screened women in the massage parlor. Unlike the prevalence of oncogenic HPV, the prevalence of HGSIL was higher in the older than in the younger women represented in both groups of commercial sex workers (not shown). Eight (61.8 percent) of the 13 women with HGSIL tested positive for HPV type 16 compared with 13.7 percent of all 233 tested women (prevalence odds ratio = 19.2; 95 percent confidence interval: 5.3, 77). Four of these eight women also had other oncogenic HPV types. Three of the remaining women with HGSIL had only an untyped HPV (prevalence odds ratio = 1.8; 95 percent confidence interval: 0.4, 6.2), and two tested negative for any HPV type.
To provide larger numbers for analysis to evaluate the possible effect of HIV infection on the risk of HGSIL in the presence and absence of oncogenic HPV types, we combined the groups of women with HPV types 16 and 18. The risk of prevalent HGSIL was not associated with HIV infection in the absence of HPV type 16 or type 18 (table 8). In their presence, the risk of HGSIL is about doubled in women who also are infected with HIV, although this observation could have occurred by chance.
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TABLE 8. Prevalence (%) and prevalence odds ratios of high-grade squamous intraepithelial lesions of the cervix in commercial sex workers in relation to human papillomavirus type 16 or 18 DNA in cervical scrapings and human immuno-deficiency virus serologic test results, Bangkok, Thailand, 19911993
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The cervical scrapings from the four women with HGSIL who were serologically positive for HIV and the scrapings from 30 of the women without HGSIL who were similarly HIV positive were tested for the presence of HIV DNA. Scrapings from all four women with HGSIL, but from just nine (30 percent) of the 30 women without HGSIL, were positive for HIV DNA, giving an odds ratio of infinity with a lower 95 percent confidence interval of 1.2.
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DISCUSSION
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Although the response rate of the husbands in this study was low, the results based on interview data are consistent with those from a larger study in Thailand that utilized similar methodology (10
) and achieved a higher level of participation. Together, they provide strong evidence that the risk of cervical cancer in monogamous Thai women is enhanced if their husbands had unprotected sexual intercourse with prostitutes when the husbands were in their teens and twenties. The possible relation of HPV infection in the husbands to their having unprotected intercourse with prostitutes provides direct evidence for the role of husbands as vectors of HPV transmission from prostitutes, and observations by us and others (17
) of a higher prevalence of these viruses in commercial sex workers than in other sexually active women confirm that prostitutes serve as reservoirs of infection.
Since most women with cervical cancer in this study were monogamous and harbored an oncogenic type of HPV, the husbands likely transmitted the offending virus to their wives early in their marriage. The few cases with multiple partners could have contracted their HPV infection from another man and transmitted HPV to their husbands, so it is reasonable to conclude that virtually all of the husbands of cases had previously been infected by an oncogenic HPV. The low prevalence of oncogenic HPV DNA in the penile scrapings from the husbands of cases is consistent with the observation that men tend to clear acute HPV infections at higher rates than do women (27
). Positive tests for HPV DNA in men, even if based on highly sensitive polymerase chain reaction-based technology, are poor indicators of prior infections and, as also noted by others (16
), not reflective of the infection status of the man at the time relevant to his role in the genesis of cervical cancer in his wife.
A low level of concordance between HPV in women's cervical samples and their husbands' penile samples was observed in this study and by others (18
, 28
30
). In Thailand, women with cervical cancer are clearly not important sources of demonstrable HPV infection in their husbands, probably because symptoms of cervical carcinoma tend to preclude sexual intercourse. The lower prevalence of HPV in men married to women with invasive carcinoma than in men married to women with in situ disease is supportive of this explanation.
Consistent with other studies (27
, 31



36
), the prevalence of oncogenic HPV infection in brothel workers decreased with age, although the trend was less apparent in the women in the massage parlor. HPV infection was also associated with recent initial employment in the sex industry and a history of treatment for a sexually transmitted disease only within the past year, which are findings consistent with observations by others that risk in nonprostitutes is inversely related to years since initiating sexual activity (31
33
) and directly to the number of partners in the past year (31
, 32
, 37
) but not to the total number of partners. Women thus tend to develop an immune response to HPV infections with the passage of time since initial exposure.
The absence of a decline in the prevalence of oncogenic HPV types with age in women with an HIV infection and the higher prevalence of HPV infections in women with than without hepatitis B antigenemia, but not in women with than without a demonstrable antibody response to hepatitis B and several other sexually transmitted agents, suggest that women who have a compromised immunologic system are at increased risk of persistent oncogenic HPV. A weak association of HPV type16-associated invasive cervical carcinomas with HBsAg positivity (22
) is supportive of this hypothesis. Although the prevalence (38
, 39
) and persistence over time (40
, 41
) of HPV infection have been related to low levels of CD4 T lymphocytes, women in this study were generally healthy and actively working, suggesting that only subtle changes in immune status are necessary for persistence of oncogenic HPV types. Additional studies to characterize the nature of the immune status permissive to HPV persistence, especially in the absence of HIV infection, are warranted.
Our observations that the prevalence of oncogenic HPV types was weakly associated with a relatively recent pregnancy and current use of oral contraceptives are consistent with previous reports that the risk of cervical neoplasia is associated with use of oral contraceptives (22
, 23
, 42
), and in some studies with parity (43
, 44
), although not in others (45
, 46
), and suggest that the mechanism for these associations, if causal, is by enhancing the persistence of HPV infection. Prior studies that have not shown an association of HPV infection with parity (31
33
, 47
) or oral contraceptive use (27
, 33
, 47
) did not report risk in relation to recency of pregnancy and oral contraceptive exposure, and the influence of these hormonal factors on risk could be of short duration. Two studies in which cases of in situ and invasive cervical carcinoma were directly compared (23
, 34
) provide evidence that neither of these hormonal factors operates to enhance progression of intraepithelial lesions to invasion. The long recognized, but incompletely understood, interaction between steroidal sex hormones and both cell-mediated and hormonal immunity (48
) may provide the basis for a unifying explanation for these hormonal risk factors for HPV persistence and the relation of HPV infection to HIV and HbsAg, and it further suggests that studies of immunity in apparently healthy women may provide clues to the causes of HPV persistence and hence cervical carcinoma.
The absence of an association between DMPA use and HPV infection is consistent with studies showing no association of DMPA use with invasive cervical carcinoma (49) and is not supportive of an increase in risk of carcinoma in situ in DMPA users previously observed (23
, 50
).
The absence of an association of oncogenic HPV prevalence with smoking is consistent with most recent observations (27
, 31
32
33
, 47
), suggesting that if smoking enhances the risk of cervical carcinoma it does so by mechanisms other than immunosuppression and enhancement of HPV persistence.
The absence of evidence for a protective effect of condoms against HPV infections in prostitutes is also consistent with previous reports (4
, 32
, 37
, 47
). Inconsistent use is unlikely to provide protection against cervical cancer in women who are heavily exposed to oncogenic HPV. This observation is not inconsistent with our findings that men who seldom or never use condoms when visiting prostitutes are more likely to harbor oncogenic HPV DNA in exfoliated penile cells than men who do use condoms and with the observation that the risk of cervical cancer in monogamous Thai women is enhanced if their husbands have unprotected sexual intercourse with prostitutes (10
). Condoms regularly used by men may well provide them some protection against HPV infection.
As expected, the risk of prevalent HGSIL was strongly associated with oncogenic types of HPV, especially type 16. The prevalence of HGSIL did not decline with age in our study or in Costa Rica (35
), presumably because HGSIL develop in women who fail to clear their HPV infection. HPV-infected women were at greater risk of HGSIL if they were HIV positive than if they were HIV negative, but the risk of HGSIL was not associated with HIV status in women without oncogenic HPV DNA. These observations support conclusions from prospective studies (51
, 52
) that HIV enhances the risk of intraepithelial cervical neoplasia by suppressing the immune system and thus permitting oncogenic HPV infection to persist. A likely explanation for the association of cervical cancer with HIV in the absence of HPV in a recent meta-analysis (53
) is the presence of undetected HPV in cases classified as HPV negative.
An increase in the risk of HGSIL was observed in women with a positive serologic HIV test in relation to the presence of HIV DNA in exfoliated cervical cells. This is consistent with the observation that the risk of cervical intraepithelial neoplasia in HPV-infected women with HIV is associated with the degree of immunosuppression (41
, 54
), although more HIV-infected CD4 T cells could be shed from women with than without HGSIL because of greater bleeding or inflammation unrelated to immunosuppression.
In order to minimize the possibility of selection bias in this study, visits were made to the brothel and massage parlor on multiple days of the week. Although no sampling scheme was utilized, few women who were asked to participate refused. The investigators in Thailand have conducted many previous studies of the commercial sex workers in Bangkok and have established a level of rapport and trust to give us confidence in the validity of the answers to questions asked. Although we cannot ensure that the women employed in the two establishments in which this study was conducted are representative of all commercial sex workers in Bangkok, the consistency of our results with those of others and the biologic reasonableness of the findings give us confidence in the reliability and generalizability of the results.
Prostitutes in Bangkok are reservoirs of oncogenic HPV infection, both because of their high level of exposure to these sexually transmitted agents and because of their high level of HIV infection that facilitates persistence of HPV in the cervical mucosa. They consequently are at high risk of HGSIL.
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ACKNOWLEDGMENTS
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This study was supported by grant CA49044 from the US National Institutes of Health.
The assistance of Drs. Anna Marie Beckmann and Larry Corey is gratefully acknowledged.
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NOTES
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Dr. David B. Thomas, Program in Epidemiology, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109 (e-mail: dbthomas{at}fhcrc.org).
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Received for publication June 28, 2000.
Accepted for publication December 20, 2000.