Background Among women infected with the human immunodeficiencyvirus (HIV), there is a high prevalence of human papillomavirus(HPV) infections. However, little is known about the naturalhistory of HPV infections in HIV-seropositive women, and persistentHPV infections may explain the increased risk of cervical squamousintraepithelial lesions and invasive cervical cancer in HIV-seropositivewomen.
Methods A total of 220 HIV-seropositive and 231 HIV-seronegativewomen in the New York City area were evaluated at two or moresemiannual gynecologic examinations that included a Pap test,a test for HPV DNA, and colposcopy.
Results HPV DNA was detected at the initial examination in 56percent of the HIV-seropositive and 31 percent of the HIV-seronegativewomen. After four examinations, the cumulative prevalence ofHPV infection was 83 percent in the seropositive women and 62percent in the seronegative women (P<0.001). Persistent HPVinfections were found in 24 percent of the seropositive womenbut in only 4 percent of the seronegative women (P<0.001).Twenty percent of the seropositive women and 3 percent of theseronegative women had persistent infections with HPV-16–associatedviral types (16, 31, 33, 35, or 58) or HPV-18–associatedtypes (18 or 45) (P<0.001), which are most strongly associatedwith cervical cancer. The detection of HPV DNA in women withpreviously negative tests was not associated with sexual activityduring the interval since the preceding examination.
Conclusions HIV-seropositive women have a high rate of persistentHPV infections with the types of HPV that are strongly associatedwith the development of high-grade squamous intraepitheliallesions and invasive cervical cancer. These persistent infectionsmay explain the increased incidence of squamous intraepitheliallesions in HIV-seropositive women.
Infection with the human immunodeficiency virus (HIV) is animportant risk factor for human papillomavirus (HPV) infectionand the development of HPV-associated lesions in the femalegenital tract. HPV DNA is 2 to 3 times as frequent in cervicovaginal-lavagespecimens and almost 15 times as common in anal-swab specimensfrom HIV-seropositive women as in those from HIV-seronegativewomen.1,2,3,4,5,6 In addition, HIV-seropositive women are aboutfive times as likely as HIV-seronegative women to have squamousintraepithelial lesions, vulvovaginal condyloma acuminata, oranal intraepithelial neoplasia.2,3,4,5,6,7,8 These findingssuggest that HIV infection, HIV-associated immunosuppression,or both increase a woman's susceptibility to HPV infection oralter the natural history of preexisting HPV infection.
In HIV-seronegative women, the majority of anogenital HPV infectionsappear to be transient and self-limited.9 Persistent infectionwith certain types of HPV, such as types 16, 18, 31, 33, 35,and 45, is thought to be necessary for the development of high-gradesquamous intraepithelial lesions and cervical cancer.10 SinceHIV-seropositive women have an increased prevalence of squamousintraepithelial lesions, we suspect that these women are atincreased risk for persistent HPV infection. However, most studiesof anogenital HPV infections in HIV-seropositive women havebeen cross-sectional in design, and information about persistenceand other aspects of the natural history of HPV infections inHIV-seropositive women is limited.
We conducted a prospective cohort study to determine the gynecologiccharacteristics associated with HIV infection. Women enrolledin this study underwent periodic HPV DNA testing, which enabledus to examine the effects of HIV infection and HIV-associatedimmunosuppression on the natural history of HPV infection.
Methods
Study Design
A total of 424 HIV-seropositive and 381 HIV-seronegative womenwere recruited from the New York City area during the periodfrom 1991 through 1993. The cohort is described in detail elsewhere.1,7In brief, women were recruited from clinics for sexually transmitteddiseases, methadone maintenance, and HIV infection and froma study of HIV transmission in couples. Women were enrolledwithout regard to their risk of HPV infection or the clinicalstatus of those infected with HIV. Informed consent was obtainedfrom all the women enrolled, and the study was approved by theinstitutional review boards of all the participating institutions.
At enrollment and at approximately six-month intervals thereafter,participants were interviewed and underwent a gynecologic examinationthat included a Pap test, a cervicovaginal lavage of 10 ml ofphosphate-buffered saline (pH 7.4), and colposcopy with biopsy,if indicated. The current analysis is restricted to women withoutsquamous intraepithelial lesions on the initial examinationwho had HPV tests at two or more examinations within a 12-monthperiod. CD4+ T-lymphocyte counts within six months of each examinationwere obtained from clinic records or were obtained specificallyfor the study.
Detection of HPV DNA
Polymerase-chain-reaction (PCR) tests for HPV DNA were performedin a blinded fashion. Genomic DNA was isolated from cervicovaginal-lavagespecimens1 and amplified with the use of both the HPV L1 consensusprimers of Manos et al., which amplify 25 types of anogenitalHPV,11 and type-specific E6 primers for HPV 16 and 18.12 Sampleswere defined as positive for HPV DNA if they contained an ethidiumbromide–stained band of the correct molecular weight afteramplification and polyacrylamide-gel electrophoresis. The HPVtype was determined by analysis of restriction-fragment–lengthpolymorphism of the L1 PCR product.13 In some cases, L1 PCRproducts could not be typed in this manner because too manytypes of HPV were present (in 3 percent of the samples) or therewas too little amplification product (in 12 percent). Type-specificPCR for HPV types 16 and 18 detected considerably more infectionswith HPV types 16 and 18 than did the L1 PCR; 46 of 101 HPV-16infections (46 percent) and 66 of 92 HPV-18 infections (72 percent)were detected only with the type-specific E6 primers. In contrast,only 24 of 101 HPV-16 infections (24 percent) and 7 of 92 HPV-18infections (8 percent) were detected only with the L1 method.
Samples that were negative for HPV DNA were amplified with primersfor the cKi-ras gene to ensure the integrity of the samples.12Samples in which neither HPV DNA nor the cKi-ras gene was amplifiedwere considered inadequate for analysis and were excluded.
Statistical Analysis
The cumulative prevalence of HPV infection, defined as the cumulativeprobability of a positive test for HPV DNA at each sequentialexamination, was estimated with the use of the Kaplan–Meiermethod and the log-rank test.14 Cumulative-prevalence curveswere calculated according to the time to the first positiveHPV test. In all Kaplan–Meier estimates, missing examinationswere ignored.
Among women with detectable HPV DNA of any type at the initialexamination, the probability of positive HPV tests at subsequentvisits was estimated with the use of the Kaplan–Meiermethod and the log-rank test. These curves were calculated accordingto the time to the first negative HPV test. However, this approachdoes not differentiate among the specific types of HPV thatare shed, and different types could be shed at different times.Therefore, we also examined persistent HPV infections, definedas the detection of the same type of HPV at two or more examinationsduring a period of 3 to 12 months. To compare the percentagesof HIV-seropositive and HIV-seronegative women with persistentHPV infections, odds ratios and confidence intervals were calculatedfrom logistic-regression models,15 which were adjusted for thenumber of examinations by using indicator variables for two,three, four, five, or six or more examinations.
New HPV infections were analyzed among the women with no HPVdetected on two or more consecutive examinations. The rate ofnew infections was defined as the number of newly detected HPVinfections after two or more negative tests, divided by thenumber of examinations until an infection was detected or, ifno infection was detected, the end of follow-up. For women withnew HPV infections, information about sexual behavior duringthe interval between the examination at which HPV was firstdetected and the preceding examination was analyzed, and forwomen with no new infections, information about sexual practicesduring the interval between the last two examinations was analyzed.
Results
Sociodemographic Characteristics of the Cohort
The cohort was composed of 424 HIV-seropositive and 381 HIV-seronegativewomen, of whom 220 HIV-seropositive and 231 HIV-seronegativewomen were included in the analysis. The two reasons for exclusionfrom the analysis were that cervical disease was detected atthe initial examination (in 104 HIV-seropositive and 24 HIV-seronegativewomen) and that results were unavailable for two HPV tests withina 12-month interval during the study period (in 100 HIV-seropositiveand 126 HIV-seronegative women). The women who were excludedfrom the analysis because they had fewer than two HPV testsdid not differ significantly from those included in the analysisin age, race or ethnic group, education, marital status, ordetection of HPV DNA at the initial examination (P>0.05 forall comparisons). However, women with two or more HPV testswere less likely to report a history of injection-drug use thanthose with fewer than two HPV tests (35 percent vs. 45 percent,P = 0.01). Data from a total of 787 examinations in HIV-seropositivewomen and 721 in HIV-seronegative women were included in theanalysis.
Among the women included in the analysis, those who were HIV-seropositivewere similar to those who were HIV-seronegative in terms ofage, race or ethnic group, education, and income. The mean agein both groups was 35 years. Forty percent of the seropositivewomen and 46 percent of the seronegative women were black (P= 0.13), 45 percent of the seropositive women and 37 percentof the seronegative women had not completed high school (P =0.07), and 63 percent of each group had an annual income ofless than $10,000. The seropositive and seronegative women weresimilar in terms of the reported number of lifetime sexual partners,condom use, and age at first sexual intercourse. However, therewere some differences in other characteristics. For example,27 percent of the seropositive women and 39 percent of the seronegativewomen were married (P = 0.03), 24 percent of the seropositivewomen and 16 percent of the seronegative women reported a historyof prostitution (P = 0.05), and 40 percent of the seropositivewomen and 31 percent of the seronegative women reported sexualabstinence during the month before the initial examination (P= 0.04).
Cumulative Prevalence of HPV DNA
HPV DNA was detected at the initial examination in 56 percentof the HIV-seropositive women and 31 percent of the HIV-seronegativewomen. The cumulative prevalence of HPV DNA was higher in theHIV-seropositive women than in the HIV-seronegative women (P<0.001by the log-rank test) and was inversely related to the CD4+T-lymphocyte count. For example, the cumulative HPV prevalenceafter four examinations was 62 percent in the seronegative women,74 percent in the seropositive women with CD4+ counts of 500or higher per cubic millimeter, and 95 percent in the seropositivewomen with CD4+ counts that were below 500 per cubic millimeter.
The cumulative prevalence of specific phylogenetic groupingsof HPV types was also analyzed.16Figure 1 shows the cumulativeprevalence of the high-risk HPV-16–associated types (16,31, 33, 35, and 58), the high-risk HPV-18–associated types(18 and 45), the intermediate-risk types (51 and 53), and thelow-risk types (6, 11, 43, and 44). The cumulative prevalenceof each group of HPV types was higher in the HIV-seropositivewomen (P<0.001 for both groups of high-risk types, P = 0.002for the intermediate-risk types, and P = 0.02 for the low-risktypes, by the log-rank test).
Figure 1. Kaplan–Meier Estimates of the Cumulative Prevalence of Types of HPV DNA in 220 HIV-Seropositive Women and 231 HIV-Seronegative Women.
The high-risk HPV-16–associated types were 16, 31, 33, 35, and 58, the high-risk HPV-18–associated types were 18 and 45; the intermediate-risk types were 51 and 53; and the low-risk types were 6, 11, 43, and 44.
HPV-16–associated types and HPV-18–associated typesare of particular interest because they are strongly associatedwith high-grade squamous intraepithelial lesions and invasivecancer in women in the general population. At the initial examination,the prevalence of HPV-16–associated types was 6 percent(95 percent confidence interval, 3 to 10 percent) in the seronegativewomen and 15 percent (95 percent confidence interval, 10 to19 percent) in the seropositive women, and the prevalence ofHPV-18–associated types was 1 percent (95 percent confidenceinterval, 0 to 3 percent) in the seronegative women and 7 percent(95 percent confidence interval, 3 to 10 percent) in the seropositivewomen. After four examinations, the cumulative prevalences inthe seronegative and seropositive women were 18 percent (95percent confidence interval, 13 to 24 percent) and 42 percent(95 percent confidence interval, 35 to 50 percent) for HPV-16–associatedtypes and 6 percent (95 percent confidence interval, 3 to 9percent) and 22 percent (95 percent confidence interval, 16to 28 percent) for HPV-18–associated types, respectively.
Women who were positive for HPV at the initial examination frequentlybecame negative for HPV during follow-up. Figure 2 shows theprobability of detecting HPV DNA at subsequent examinationsin women with detectable HPV at the initial examination. HIV-seropositivewomen were more likely than HIV-seronegative women to have positiveHPV tests during subsequent examinations (P<0.001), and HIV-seropositivewomen with CD4+ T-lymphocyte counts of less than 500 per cubicmillimeter were more likely than those with CD4+ counts of 500or more per cubic millimeter to have positive HPV tests duringsubsequent examinations (P<0.001).
Figure 2. Kaplan–Meier Estimates of the Probability of Persistent HPV Infection at Subsequent Examinations among Women with Detectable HPV at the Initial Examination, According to HIV Status and According to the CD4+ Count among HIV-Seropositive Women.
Persistence of HPV Infection
Persistent infection with a high-risk type of HPV may be necessaryfor the development of high-grade squamous intraepithelial lesionsand invasive cervical cancer. We defined persistent infectionas the detection of the same type of HPV at two or more examinationsduring a period of 3 to 12 months. HIV-seropositive women weremore likely to have persistent HPV infections than HIV-seronegativewomen (24 percent vs. 4 percent, P<0.001) (Table 1). Amongthe seropositive women, 19 percent with CD4+ counts of 500 ormore per cubic millimeter, 24 percent with counts of 200 to499 per cubic millimeter, and 33 percent with counts of lessthan 200 per cubic millimeter had persistent HPV infections(P = 0.23) (Table 2).
Table 1. Persistent HPV Infections among Women without Squamous Intraepithelial Lesions at the Initial Examination, According to HPV Type and HIV Serologic Status.
Table 2. Persistent HPV Infections among Women without Squamous Intraepithelial Lesions at the Initial Examination, According to Sociodemographic Characteristics and Potential Risk Factors for HPV Infection.
Fourteen percent of the HIV-seropositive women and 3 percentof the HIV-seronegative women had persistent infections withHPV-16–associated viral types (P = 0.004) (Table 1). Persistentinfections with HPV-18–associated viral types were foundin 8 percent of the HIV-seropositive women but in none of theHIV-seronegative women. Overall, infections with high-risk HPVtypes (those associated with HPV-16 or HPV-18) were persistentin 20 percent of the seropositive women and 3 percent of theseronegative women (P<0.001). The proportions of women whohad persistent infections with other HPV types were also higherin the seropositive group than in the seronegative group. However,the distribution of HPV types was similar in the two groups,and HPV-16–associated types were the most common in both.Figure 3 shows the pattern of HPV shedding in the women withpersistent HPV-16 infections. Although HPV detection variesfrom examination to examination, most women with persistentHPV-16 infections shed some type of HPV DNA at almost everyexamination.
Figure 3. Patterns of HPV Detection in Women with Persistent HPV-16 Infections.
Four HIV-seronegative and 19 HIV-seropositive women had persistent infections with HPV-16. Each woman is represented by a horizontal line, and each examination by a colored circle or oval. Green circles represent the detection of HPV-16; blue circles the detection of an HPV type other than HPV-16 that was identified at least twice in the same patient; yellow circles the detection of HPV that could not be typed or was a type detected only once in the patient; and gray circles undetectable HPV.
Risk Factors for Persistent HPV Infection
In the univariate analysis, in which we controlled for the numberof examinations, factors significantly associated with persistentHPV infection were HIV seropositivity, a CD4+ count of lessthan 200 cells per cubic millimeter, less than 12 years of education,and a history of injection-drug use (Table 2). Unmarried womenwere more likely to have persistent HPV infections than marriedwomen. In the multivariate analysis, after adjustment for age,race or ethnic group, education, marital status, history ofprostitution, history of injection-drug use, condom use, smoking,and history of cervical disease, HIV-seropositive women withCD4+ counts of less than 500 per cubic millimeter and thosewith counts of 500 or more per cubic millimeter were more likelyto have persistent HPV infections than HIV-seronegative women.Being unmarried and having a history of injection-drug use remainedsignificantly associated with persistent infection in the multivariatemodel with all the above-listed risk factors.
New HPV Infections
Forty-eight of 151 women (32 percent) who had negative HPV testsat the first and second examinations had detectable HPV at asubsequent examination. The rate of new infections among thewomen with initially negative HPV tests was 11 per 100 examinationsin the HIV-seropositive group and 9 per 100 examinations inthe HIV-seronegative group. The detection of new HPV infectionsin women with previously negative HPV tests was not associatedwith serologic status or with sexual activity since the precedingexamination. The detection rate was 9 per 100 examinations amongthe women who reported no sexual activity since the prior examination,9 per 100 examinations among those who reported intercoursewith consistent use of condoms, and 12 per 100 examinationsamong those who reported intercourse with intermittent or nouse of condoms (P = 0.72). Among the women who became positivefor HPV after two consecutive negative tests, 9 of 21 who wereHIV-seropositive (43 percent) and 5 of 27 who were HIV-seronegative(19 percent) reported no sexual activity since the precedingexamination.
Discussion
HIV seropositivity and HIV-induced immunosuppression are knownto be associated with an increased prevalence of anogenitalHPV infections in men and women.1,2,3,4,5,6,7 This associationinvolves HPV infections of all types, as well as infectionswith multiple types of HPV, including those associated withneoplasia, such as HPV-16 and HPV-18. The increased prevalenceof these infections suggests that HIV-seropositive women areat increased risk for squamous intraepithelial lesions and invasivecancer of the cervix, vagina, vulva, anus, and perianal region.HIV-associated alterations in the natural history of HPV infectionmay also influence the risk of HPV-associated disease in HIV-seropositivewomen. In women in the general population, the shedding of HPVfrom the lower genital tract is highly variable, and severalstudies have shown that persistent shedding of high-risk typesof HPV is an important factor in the development of squamousintraepithelial lesions of the cervix.9 If HIV infection causespersistent HPV shedding, this effect may promote the developmentof anogenital squamous intraepithelial lesions and cancers inHIV-seropositive women.
In our study, we found that HPV shedding was highly variablein both HIV-seropositive and HIV-seronegative women. Of thewomen examined three or more times, only 49 percent in the HIV-seropositivegroup and 42 percent in the HIV-seronegative group were consistentlypositive or negative for HPV at all examinations. In many women,several different HPV types were detected at different examinations.Therefore, studies that have tested HIV-seropositive women forHPV infections on a single occasion may have considerably underestimatedthe prevalence of such infections. In our study, the cumulativeprevalence of infection with any type of HPV after four examinations(during approximately two years of follow-up) was 95 percentin the HIV-seropositive women with CD4+ counts of less than500 per cubic millimeter and 74 percent in those with CD4+ countsof 500 or more per cubic millimeter. After four examinations,the cumulative prevalences of infection with HPV-16 and HPV-18,high-risk "oncogenic" types of HPV, were 21 percent and 22 percent,respectively, in HIV-seropositive women. These cumulative prevalences,which are considerably higher than the point prevalences inour previous study,7 indicate that most HIV-seropositive womenhave cervicovaginal HPV infections and that a large proportionof these women are infected with high-risk types of HPV.
Few studies have determined the cumulative prevalence of anogenitalHPV infections in women in the general population. In a studyof predominantly white middle-class women with normal cervicalcytologic findings, 26 percent had HPV in cervicovaginal-lavagespecimens, detected with a PCR assay, at the first visit.17After two visits, the cumulative prevalence was 36 percent.17Similarly, in a population-based study of 276 young women inSweden, HPV DNA was detected in 21 percent of the women at theinitial visit, and the cumulative prevalence was 25 percentafter two examinations, with the use of a nested-PCR methodto amplify HPV DNA from cervical scrapings.18
Persistent infection with high-risk types of HPV appears tohave a central role in the development of squamous intraepitheliallesions and invasive cervical cancer. In a cohort of women withabnormal cervical cytologic findings, Ho et al. found that persistentinfection with specific types of HPV resulted in chronic cervicaldysplasia.19 However, little is known about the persistenceof HPV infection, or about the relation between persistent infectionand the development of squamous intraepithelial lesions, inHIV-seropositive women. In our study, both HIV seropositivityand higher levels of immunosuppression were important determinantsof persistent HPV infection. HIV-seropositive women were aboutseven times as likely to have persistent infection as HIV-seronegativewomen, and women with CD4+ counts of less than 200 per cubicmillimeter were more than twice as likely to have persistentinfection as those with counts of 500 or more per cubic millimeter.The higher frequency of persistent HPV infection in HIV-seropositivewomen than in HIV-seronegative women may explain why squamousintraepithelial lesions occur so frequently in HIV-seropositivewomen.
Supported in part by a collaborative agreement (U64/CCU206822)with the Centers for Disease Control and Prevention.
Source Information
From the Department of Pathology, College of Physicians and Surgeons (X.-W.S., T.C.W.), and the Gertrude H. Sergievsky Center and Division of Epidemiology (L.K.), Columbia University, New York; the Division of HIV/AIDS Prevention, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta (T.V.E., T.J.B.); and the Bureau of Disease Intervention Research, New York City Department of Health, New York (M.A.C.).
Address reprint requests to Dr. Wright at the Department of Pathology, Room 16-402, College of Physicians and Surgeons, Columbia University, 630 W. 168th St., New York, NY 10032.
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