Affiliations of authors: J. M. Palefsky, University of California, San Francisco; H. Minkoff, State University of New York, NY; L. A. Kalish, New England Research Institutes, Watertown, MA; A. Levine, University of Southern California, Los Angeles; H. S. Sacks, Mount Sinai Medical Center, New York, NY; P. Garcia, Northwestern University, Chicago, IL; M. Young, Georgetown University, Washington, DC; S. Melnick, National Cancer Institute, Bethesda, MD; P. Miotti, National Institute of Allergy and Infectious Diseases, Bethesda; R. Burk, Albert Einstein College of Medicine, New York, NY.
Correspondence to: Joel M. Palefsky, M.D., Department of Laboratory Medicine, University of California, San Francisco, Rm. C634, Box 0100, San Francisco, CA 94143 (e-mail: joelp{at}labmed.ucsf.edu).
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ABSTRACT |
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INTRODUCTION |
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Several earlier studies have characterized HPV infection in HIV-positive women. However, these studies included only small numbers of women and were usually performed at one study site with a relatively homogeneous study group with respect to ethnicity and HIV risk factors (20-25). In addition, previous studies (16,20,21,23,24) characterized only a limited number of HPV types. Consequently, relatively little is known about the prevalence of HPV infection in HIV-positive women of different racial/ethnic backgrounds and HIV risk categories, the range of HPV types present, or the risk factors for HPV infection in these women. Although several previous studies have shown an association between HPV infection and reduced number of CD4 positive T cells, no studies have yet reported the association between HPV infection and HIV viral RNA load.
The Women's Interagency HIV Study (WIHS) is a prospective cohort study of 2056 HIV-positive and 569 HIV-negative women at six sites around the United States. The study began enrollment in October 1994. The aim of the WIHS is to characterize the natural history and pathogenesis of HIV infection and its complications in a large, geographically and ethnically diverse population of HIV-positive women when compared with a group of age-matched and risk-matched HIV-negative control subjects. The WIHS study population has been shown to accurately reflect demographic, social, and biologic characteristics of women infected with HIV in the United States (26). The aim of the present study was to characterize cervicovaginal HPV infection in the WIHS participants using cervicovaginal lavage specimens collected at enrollment. The prevalence of 29 different individual HPV types was determined along with the risk factors for HPV infection, including medical and sexual history, substance use, HIV status, blood levels of CD4 -positive T cells, and plasma HIV viral RNA load.
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METHODS |
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HPV testing was performed using polymerase chain reaction (PCR) with L1 consensus primers as described previously (28). Amplification of ß-globin DNA was performed as a positive control for the presence of amplifiable DNA in the specimen. Testing was performed in two different laboratories (Chicago, Los Angeles, and San Francisco sites by J. Palefsky and Bronx/Manhattan, Brooklyn, and Washington, DC, sites by R. Burk). Duplicate testing of 129 randomly chosen samples was performed to measure interlaboratory variability. There was agreement in 110 (85%) of the samples overall with respect to the presence or absence of HPV, and when samples (n = 25) classified as equivocally positive by either of the laboratories were excluded, there was 94% agreement. Among the 41 samples tested by both laboratories in which both reported specific HPV types, there was agreement for at least one HPV type in 39 (95%) samples. Among cases in which both laboratories reported one or two HPV types, Palefsky detected 78% of the specific types detected by Burk, and Burk detected 80% of the types detected by Palefsky. Among samples reported by both laboratories to have three or more specific HPV types, Palefsky detected 59% of the specific types detected by Burk, and Burk detected 56% of the types detected by JP.
Briefly, 1 mL of cervicovaginal lavage material was removed for PCR analysis after vortexing the aspirated cervicovaginal lavage material. Cellular sediment (40-80 µL) was added to 100 µL of digestion solution containing 400 µg/mL of proteinase K (Boehringer Mannheim GmbH, Mannheim, Germany) in 100-mM Tris-HCl, 2 mM EDTA, and 2% Laureth 12. After two hours at 55 °C, the proteinase K was inactivated by heating tubes to 95 °C for 10 minutes. The tubes were then stored at -20 °C until PCR analysis was performed. To perform PCR, 2-10 µL of the digest was removed and added to tubes containing 10 mM Tris-HCl; 50 mM KCl; 4 mM MgCl2; 200 µM of each deoxyribonucleotide triphosphate; 2.5 U Taq DNA polymerase; 0.5 µM of HPV primers MY09 and MY11 and the HPV 51 HMB01 primer; as well as ß-globin primers GH20 and PC04 as described (29).
The presence or absence of HPV and ß-globin DNA was determined using DNA hybridization. Negative controls for each blot consisted of amplification of DNA of HuH7 or BJAB cells and tubes containing all reaction components except target DNA. Positive controls consisted of amplification of DNA from 100 SiHa cells as well as amplified DNA from the individual HPV types being sought. Five percent of the samples were amplified in duplicate. PCR amplification mixtures (2-6 µL) were applied to dot blots and the DNA was fixed on the membrane. To detect HPV DNA, the membranes were pretreated in 0.1x sodium chloride-sodium phosphate-EDTA (SSPE) and 0.5% sodium dodecyl sulfate for 30 minutes at 65 °C. Probes consisting of amplified biotinylated DNA from HPV16, HPV18, HPV11, and HPV51 were denatured and added in the presence of 2 mg/mL sheared salmon sperm DNA to the hybridization buffer and hybridized at 55 °C for at least 1.5 hours. After washing, streptavidin-horseradish peroxidase (Vector Laboratories, Inc., Burlingame, CA) was added to the blots at a concentration of 30 ng/mL in 250 mL of wash solution and binding allowed to occur with gentle agitation for 15 minutes at room temperature. After vigorous washing, detection of HPV types was performed using Enhanced ChemiLuminescent detection (Amersham Life Science Inc., Arlington Heights, IL) according to the manufacturer's instructions. Type-specific probing was performed using biotinylated oligonucleotide probes at a final concentration of 0.5 pmol/mL for the following HPV types individually: 6, 11, 16, 18, 26, 31, 32, 33, 35, 39, 40, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 66, 68, 69, 70, 73, Pap 155, Pap 291, and AE2. A sample was considered HPV positive when it was positive with the consensus probes. Specimens positive with the consensus probes but negative with the individual type probes were considered to have one or more "other" types. Specimens negative for ß-globin gene amplification were excluded from analysis.
For some analyses, selected HPV types were classified according to oncogenic risk. High-risk types included types 16, 18, 31, or 45. Medium- to high-risk HPV types included high-risk types as well as HPV types 33, 35, 39, 51, 52, 56, 58, 59, 68, and 73. Low HPV risk types included 6, 11, 53, 54, 55, 66, Pap 155, and Pap 291. If a woman had HPV types from more than one group, the result was assigned to the highest risk category.
Blood was obtained for HIV testing, to determine HIV viral RNA load, and to determine CD4 level at the same time at which cervicovaginal lavages were collected. HIV testing was performed using enzyme-linked immunosorbent assay and all positive results were confirmed by western blot analysis. CD4 levels were measured using standardized two- or three-color fluoresence methods and HIV viral load was measured using a nucleic acid sequence-based amplification assay (NASBA) (Organon Teknika, Oklahoma City, OK) (26).
Statistical Analysis
Prevalences of HPV or of specific HPV types were expressed as percentages within subgroups and were compared in univariate analysis using Pearson's chi-squared test, Fisher's exact test or the Mantel extension trend test for ordered categorical covariates (30,31). CD4 count and HIV plasma viral load cut points were chosen a priori using conventional clinical categories for CD4 and approximate quartiles for HIV viral load. However, since the first quartile was below the limit of detection for the NASBA assay (4000 copies/mL), 4000 copies/mL were used for the first cut point. Subgroups formed by the cross-classification of HIV status, plasma HIV viral load, and CD4 count that had similar HPV prevalences were combined a posteriori, leaving four strata with a gradation of HPV risks. This stratification provided the basis for adjusting the univariate comparisons simultaneously for HIV, viral load, and CD4 level using stratified Mantel-Haenzel procedures (30,32). Covariates with P values <.15 in this adjusted analysis were considered further in multivariate analyses of the HIV-infected cohort using logistic regression models (33). The resulting model was then fit in the HIV-negative cohort and both are presented. Formal comparisons of race/ethnic groups were restricted to the three dominant groups: Hispanic, Caucasian, and African-American. All P values were two-sided and were not adjusted for multiple comparisons.
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RESULTS |
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Demographics of the Study Population
The demographic characteristics of the HIV-positive and HIV-negative
women with assessable HPV results are shown in Table
1. The demographic characteristics of these women
were similar to those of the entire WIHS cohort (26). The
demographic characteristics of the HIV-positive women were similar to
the HIV-negative women with the following exceptions: the HIV-positive
women were older, a higher proportion had a history of an abnormal
cervical cytology, and a lower proportion were current smokers.
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Overall, of 1127 (63%) of 1778 HIV-positive women and 149 (30%) of 500 HIV-negative women were positive for HPV DNA. Among the HIV-positive women, HPV infection was found in 226 (73%) of 310 Bronx women, in 184 (72%) of 257 Brooklyn women, in 175 (68%) of 256 Washington, DC, women, in 197 (63%) of 311 San Francisco women, in 132 (55%) of 240 Chicago women, and in 213 (53%) of 404 Los Angeles women. Among the HIV-negative women, HPV infection was found in 30 (30%) of 100 Bronx women, in 19 (29%) of 65 Brooklyn women, in 32 (36%) of 89 Washington, DC, women, in 29 (35%) of 84 San Francisco women, in six (12%) of 51 Chicago women, and in 33 (30%) of 111 Los Angeles women.
Relationship Between Detection of HPV and HIV status, CD4 Level, and Plasma HIV Viral Load
The relationship between plasma HIV viral load, CD4 level, and
detection of HPV DNA among HIV-positive women is shown in Table
2. Detection of HPV DNA was associated with both
lower CD4 level (P<.0001) and higher HIV viral load
(P<.0001). Overall, the women with the highest prevalence
of HPV DNA were those with a CD4 level of less than 200/mm3,
regardless of HIV viral load. At CD4 levels above 200/mm3, a
higher prevalence of HPV DNA was found among women with an HIV viral
load of greater than 20 000 copies/mL compared with those with
an HIV viral load of less than 20 000 copies/mL. The lowest
prevalence of HPV DNA was found among those women with a CD4 level
above 500/mm3 and an HIV viral load of less than 4000 copies/mL.
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The distribution of HPV types in the overall study population is
shown in Table 3. The spectrum of HPV types was
similar between the HIV-positive and HIV-negative women and the range
of HPV types was very broad. No individual HPV type was found in more
than 9% of either the HIV-positive or HIV-negative women. HPV16 was
detected in 5% and 2% of HIV-positive and HIV-negative women,
respectively, and HPV18 was detected in 4% and 1%,
respectively. As shown in Table 4,
when the
individual HPV types were grouped into high oncogenic risk,
intermediate risk, and low risk, positivity with one or more HPV types
in each of these categories was significantly more common among
HIV-positive women than among HIV-negative women. In contrast to the
results with the 29 individual HPV types tested, the proportion of
HIV-positive and HIV-negative women with HPV types other than the 29
individual types was equivalent (18%) (Table 3
).
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Table 5 shows that among all women who were HPV
positive, the number of individual HPV types detected was higher among
HIV-positive women than among HIV-negative women (P<.0001).
Thirty-six percent of HIV-positive women with HPV infection were
infected with two or more types compared with 12% of HIV-negative
women with HPV infection (P<.0001). Among HIV-positive
women with HPV infection, infection with multiple HPV types was most
common among those with lower CD4 levels (P<.0001), and
28% of women with CD4 counts less than 200/mm3 were
infected with three or more HPV types.
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Risk factors for HPV infection were examined in univariate analysis
and are shown in Table 6, unadjusted
and adjusted for HIV status, CD4 level, and HIV viral RNA load. The
P values in this section refer to adjusted analyses. Among the
demographic factors, younger age (P<.0001), single marital
status (P = .004), and lower household income (P =
.0004) were associated with HPV infection. History of intravenous
drug use was not associated with increased risk of HPV infection
(P = .28). Among the gynecologic factors, higher number of
previous pregnancies was associated with HPV infection (P =
.02) but not current pregnancy (P = .35) or menopausal
status (P = .60). Among the self-reported sexually transmitted
agents or diseases, history of genital warts (P= .004) and an
abnormal Pap smear (P = .003) were both associated with
detection of HPV, as were history of syphilis (P = .02) and
pelvic inflammatory disease (P = .02). In contrast,
self-reported history of chlamydia (P = .63), trichomonas
vaginalis (P = .29), candida (P = .21), or bacterial
vaginosis (P = .57) were not associated with HPV detection.
Lifestyle habits, including smoking, alcohol use, and drug use, were
assessed for association with HPV detection. Of these, current smoking
(P = .0002) and ever smoking (P = .04) were each
associated with increased risk of HPV detection, as were ever use of
amphetamines and use of crack in the previous 6 months. However,
pack-years among smokers (P = .69, data not shown), use of
amphetamines (P = .34), or crack cocaine (P = .94) in
the past 6 months and ever use of crack cocaine, cocaine, or heroin
(P = .26) were not associated with HPV infection.
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Since the women in the WIHS cohort were recruited between October 1994 and November 1995, very few HIV-positive women were on highly active antiretroviral therapy, including protease inhibitors, at the time the sample was obtained. However, a high proportion of HIV-positive women had a history of ever taking at least one antiretroviral agent (64%) or of taking at least one antiretroviral agent in the previous 6 months (36%). While both were strongly correlated with having a higher prevalence of HPV infection (P = .0001 and .0003, respectively), this association disappeared after adjustment for CD4 levels (P = .98 and .17, respectively). These data are indicative of confounding by indication for treatment.
A logistic regression model of risk factors for HPV infection among the
HIV-positive women was constructed using factors shown to be
significant in adjusted univariate analysis. These are shown in Table
7. To determine if the same factors were significant
among HIV-negative women, a separate analysis of these women was
performed using the same model. Among HIV-positive women, significant
factors associated with HPV detection in the logistic regression model
included the following: more advanced HIV disease as determined by CD4
count/HIV viral RNA load classification; WIHS site; race/ethnicity,
with African-American women having the highest risk followed by
Hispanic women; self-reported history of genital warts; history of an
abnormal Pap smear; and current smoking. Protective factors included
older age at enrollment; household income above $12 000 per
year; and a higher number of prior pregnancies. When the same factors
(without inclusion of CD4 count/HIV viral RNA load stratum) were
analyzed among HIV-negative women, similar trends for most of the
factors were noted with the exception of WIHS site and household
income. However, many of these factors in HIV-negative women did not
reach statistical significance.
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DISCUSSION |
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Our data confirm earlier observations (15,34-37) that HPV infection is significantly more common among HIV-positive women when compared with high-risk HIV-negative women. HIV infection and more advanced HIV disease as determined by lower CD4 level and higher HIV viral load were the strongest independent risk factors for HPV infection in logistic regression analysis, and these data are consistent with an important role for the immune response in controlling HPV infection. Combined with the absence of a significant role for sexual activity in the previous 6-month period, these data suggest that detection of HPV in HIV-positive women more likely reflects either reactivation or persistence of pre-existing HPV types rather than recent HPV acquisition. Consistent with this, history of an abnormal Pap smear and genital warts were also independent risk factors for HPV infection among HIV-positive women, likely reflecting past exposure to HPV.
Previous studies of the role of HIV infection in detection of HPV were
limited to measures of CD4 count as an indicator of the stage of HIV
disease. However, CD4 levels and HIV viral load have been shown to be
independent predictors of the course of HIV disease (38). In
this study we examined different risk strata for HPV using a
combination of these two measures of HIV disease severity. Our data
show that a combination of CD4 levels and HIV viral load, as shown in
Tables 2 and 8
, may be optimal in predicting the
risk of HPV infection
in HIV-positive women. The risk of HPV was highest at CD4 counts less
than 200 cells/mm3, regardless of HIV viral load, but was
also uniformly high at a HIV viral load of greater than 20 000
copies/mL. Our data suggest that at their extremes, both factors may be
important in activation of HPV replication and facilitation of
subsequent HPV detection. Overall, HIV-positive women were at the
lowest, intermediate, and highest risk of HPV infection, respectively,
when they had a CD4 level greater than 200/mm3 with an HIV
viral load of less than 20 000 copies/mL, a CD4 level greater
than 200/mm3 with an HIV viral load of greater than
20 000 copies/mL, and a CD4 level less than 200/mm3.
Ten of the 11 most prevalent HPV types among the HIV-positive and HIV-negative women were common to both cohorts. The spectrum of HPV types detected was thus similar among HIV positive and HIV-negative women, and no single HPV type was detected in more than 9% of the women in either group. HPV types representing the entire spectrum of oncogenic risk were found and there was no particular predilection for detection of the high-risk oncogenic HPV types, such as HPV 16 or 18, consistent with an earlier study (37). However, among the HIV-positive women, certain HPV types were significantly more common among those with lower CD4 levels, and these also spanned the range of oncogenic risk. These included HPV 6, 11, 18, 40, 45, 51, 53, 54, 56, 59, 68, and Pap 155. Of interest, in a study of anal HPV infection in HIV-positive and HIV-negative men, the four HPV types shown to increase in prevalence with lower CD4 counts were HPV types 18, 45, 53, and 59, a subset of this group of HPV types detected more commonly among the more immunosuppressed women (39). Of these types, HPV 18, 45, and 59 are closely related phylogenetically (40) and it is possible that these types share one or more epitopes that render them particularly sensitive to the loss of immune control as reflected by declining CD4 levels.
Most HIV-negative women reported to be HPV positive had only one HPV type detected at the time of sample collection. In our study, 12% of HIV-negative and HPV-positive women were infected with multiple types, while 36% of HIV-positive and HPV-positive women were infected with multiple types. These data likely represent an underestimate of the true number of HPV types, since our probes do not detect all HPV types. A clear trend was also seen between lower CD4 levels and detection of a higher number of HPV types. Like the overall prevalence of HPV positivity, the higher number of HPV types detected in women with lower CD4 levels reflects either persistence or activation of pre-existing HPV infections in the setting of declining immunity rather than recent acquisition. It is currently unknown if the presence of multiple HPV types potentiates the pathogenesis of SIL. However, in studies of anal HPV infection in HIV-positive and HIV-negative men, detection of multiple HPV types was common (39) and was associated both with concurrent anal lesions and progression of anal lesions to a higher grade over a 2-year follow-up period in both HIV-positive and HIV-negative men when compared with detection of a single type or no HPV infection (41). Furthermore, multiple cervical HPV types were risk factors for persistent cervical HPV infection among young women, and persistent HPV infection was a risk factor for development of cervical lesions (42,43).
In most earlier studies of HIV-positive women in which multivariate analyses were performed, HIV status and lower CD4 levels were dominant risk factors for HPV infection (15,34-37). In part, this may have reflected inadequate power to detect more modest relative risks. Because of the relatively large number of study subjects, our study permitted us to explore risk factors that also play a role in detection of HPV as well as to compare risk factors between HIV-positive and HIV-negative women.
Among the covariates in logistic regression analysis that could be compared between HIV-positive and HIV-negative women, some were found to be significant only among the HIV-positive women, including current smoking. Smoking may be a risk factor for the development of cervical intraepithelial neoplasia (3). However, consistent with the lack of association among HIV-negative women in our study, most studies (3,44-46) of women have shown that smoking is not an independent risk factor for HPV detection. Since smoking may suppress immune response in HIV-positive individuals (47), including local immune response through an effect on Langerhans cells (48,49), it is possible that HIV-positive women may be uniquely susceptible to the effects of smoking.
Other risk factors studied in HIV-positive and HIV-negative women were found to be significant in both groups, including younger age. Epidemiologic studies (44,50) of younger women have shown that cervical HPV infection is acquired early after initiation of sexual activity. A large proportion of sexually active young women are HPV positive as detected by PCR, but the prevalence peaks in the late teens and early twenties and then declines (51,52). Risk factors for HPV infection in young women have primarily been shown to reflect sexual activity including younger age, younger age at first intercourse, number of recent male sex partners, the male partner's sexual behavior, and race (29,43,46,53-55). Although the mechanism of the age-related decline of HPV prevalence is not well understood, it may reflect acquisition of cell-mediated immunity. Since younger age was independent of HIV status and stage of HIV disease as a risk factor in this study, our data suggest that in this study population, the protection afforded by older age may be due to mechanisms other than acquisition of immunity. However, even though the older women in our study had a lower prevalence of HPV infection than the younger women, they also had a remarkably high prevalence of HPV infection when compared with women in the general population of a similar age. Thus, the scenario of an infection that is acquired at an early age and then cleared or suppressed to the level at which it can no longer be detected among women in the general population is dramatically different among HIV-positive women, and to a lesser extent among high-risk HIV-negative women.
Higher number of prior pregnancies was another factor that was significant among both HIV-positive and HIV-negative women and showed a protective effect for HPV infection. These data are consistent with an earlier study of women at low risk of HPV infection that showed a higher risk of HPV infection with nulliparity (46,55) but differed from another in which pregnancy was positively associated with HPV infection (45).
Several risk factors were significant among the HIV-positive women and showed a similar but not statistically significant trend among the HIV-negative women, possibly due to the smaller number of HIV-negative subjects. These include race or ethnicity, history of genital warts, and an abnormal Pap smear. Among the racial and ethnic groups studied, African-American women had the highest risk of HPV infection, consistent with earlier studies of HIV-negative women (29,44). Certain major histocompatibility complex (MHC) class II haplotypes, such as DRB1*1501-DQB1*0602, have been associated with increased risk of cervical cancer among Hispanic women (56). Among African-American women, the DQB1*0303 and DQB1*0604 haplotypes were associated with an increased risk of cervical cancer (57). It is possible that African-American women may have a higher prevalence of MHC class II haplotypes that predispose to HPV infection, perhaps through impaired immune response.
The prevalence of HPV infection among HIV-positive women was higher in East Coast U.S. cities than in Chicago or West Coast cities. Although we cannot exclude confounding due to HPV testing being performed in two different laboratories, this is unlikely given the high interlaboratory agreement rate, which was comparable to that of another interlaboratory study (Burk R: personal communication). In addition, similar rates of HPV detection were noted in East and West Coast cities among the HIV-negative women. The lowest rate of HPV detection was found in HIV-negative women in Chicago, and this group was also found to have very low rates of cytologic abnormalities (58). Since the HIV-negative women would be more likely to have lower HPV DNA copy numbers than the HIV-positive women, any artifacts introduced by differences in sensitivity of detection between the two laboratories should have been more apparent among the HIV-negative women. The geographic distribution of HPV prevalence did not reflect race or ethnicity of the women, since race/ethnicity were independently associated with HPV. HIV risk category was also unlikely to play a role, since there was no significant difference between women with a history of intravenous drug use and those who probably acquired HIV heterosexually.
The data in this study should be interpreted with caution, since they represent a cross-sectional analysis. Earlier studies of HIV-negative (59,60) and HIV-positive (37) women have shown that detection of specific HPV types may vary over time, even at short testing intervals. The significance of a "one-time detection"; of different HPV types will become clearer with longitudinal studies using serial collection of cervicovaginal lavages from the same women, with establishment of the pattern of infection/reinfection with different HPV types. In addition, we were unable to assess the impact of antiretroviral treatment on HPV detection. Since enrollment in the WIHS ended in November 1995, before widespread use of protease inhibitors, there was very little use of highly active antiretroviral therapy in the WIHS cohort prior to baseline. Furthermore, because of confounding by indication for treatment, it was not possible to assess the impact of single- or double-agent antiretroviral therapy in the cohort. Finally, there were a large number of statistical tests in this analysis that increased the probability of type I error. Coupled with the large sample size, this means that some of the weaker observed associations should be interpreted with caution.
In summary, HIV-positive women had a higher prevalence of HPV infection than high-risk HIV-negative women. Since HPV infection is strongly associated with SIL, a high proportion of HIV-positive women are at risk for this disease. Compared with HIV-negative women, HIV-positive women had a higher number of HPV types per person but did not appear to be at increased risk of oncogenic HPV types relative to types with lower oncogenic risk. Many of the same risk factors for HPV infection were significant or showed similar trends between HIV-positive and high risk HIV-negative women, including younger age, fewer prior pregnancies, history of genital warts, and race/ethnicity. Risk factors unique to the HIV-positive women included lower household income, smoking, and measures of more advanced HIV disease. Our data point to a dominant, but not exclusive, role for HIV-related immunosuppression in explaining the difference in prevalence of HPV infection between HIV-positive and HIV-negative women. They also support the hypothesis that the higher prevalence of HPV infection among HIV-positive women reflects persistence or reactivation of previously acquired HPV types rather than recent acquisition of new HPV types.
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NOTES |
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We thank Maria Da Costa, Yevan deSouza, Yvette Cruz, Weimin Qu, and Quam-Quilin for their expert technical assistance.
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Manuscript received April 20, 1998; revised November 20, 1998; accepted December 1, 1998.
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