High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection Sten H. Vermund, MD, PhD,.·b Karen F. Kelley, MPH: Robert S. Klein, MD,.·c Anat R. Feingold, MD, MPH: Klaus Schreiber, MD/ Gary Munk, PhD: and Robert D. Burk, MDb. f. g Bronx, New York We investigated the relationship of human papillomavirus (by cervicovaginal lavage and Southern blot), human immunodeficiency virus, and squamous intraepithelial lesions in 96 high-risk women in the Bronx, New York. Antibodies for human immunodeficiency virus were detected in 51 (53%) women. Of the 33 women with symptomatic human immunodeficiency virus infection, 23 (70%) had human papillomavirus infection compared with 4 of 18 (22%) asymptomatic women who were human immunodeficiency virus seropositive and 10 of 45 (22%) uninfected women (p < 0.0001). The rate of squamous intraepithelial lesions was 52% (14 of 27) for women with both viruses detected, 18% (6 of 34) for women with either virus detected, and 9% (3 of 35) for un infected women. Among symptomatic human immunodeficiency virus-infected women, a strong association between human papillomavirus infection and squamous intraepithelial lesions was demonstrated (odds ratio, 12; 95% confidence interval, 1.3 to 108). Risk was highest for younger women from ethnic or racial minority groups. Advanced human immunodeficiency virus-related disease, with its associated immunosuppression, seems to exacerbate human papillomavirus-mediated cervical cytologic abnormalities. Public health measures are needed to provide Papanicolaou smear screening and appropriate clinical follow-up and treatment for women at high risk for human immunodeficiency virus infection. (AM J OaSTET GYNECOL 1991 ;165:392-400.)
Key words: Human immunodeficiency virus, human papillomavirus, cervix, sexually transmitted diseases, squamous intraepithelial lesions
Immunosuppression, whether from chemotherapy, malignancy, or infection, has been shown to be associated with higher than expected rates and advanced pathologic consequences of human papilloma virus (HPV) infection. 1. 4 Immunosuppressed women from a wide range of age, racial, and socioeconomic groups have been reported to manifest greater HPV frequency and pathogenicity.3. 4 Therefore the cervix is likely to be a target organ for HPV-related pathologic conditions among women who have been immunosuppressed by a variety of causes. Studies in pregnant From the Departments of Epidemiology and Social Medicine: Pediatrics,' Medicine,' and Pathology (Divisions of Cytopathologyd and Virology'), Montefiore Medical Center, and the Departments of Epidemiology and Social Medicine," Pediatrics,' Medicine,' Pathology, d. , Obstetrics and Gynecology,! and Microbiology and Immunology/ Albert Einstein College of Medicine. Supported by CenteTS for Disease Control Cooperative Agreement No. U62-CCU200714-06. Presented in part at the Fifth International Conference on AIDS, Montreal, Quebec, Canada, June 8, 1989. Received for publication August 8, 1990; revised January 15, 1991 ; accepted January 31, 1991. Reprint requests: Dr. Sten Vermund, EBIDAlDSINIAlDIN1H, 6003 Executive Blvd., Room 240P, Bethesda, MD 20892. 6/1/28538
392
women, renal allograft reCIpients, Hodgkin's disease patients, and other women on a regimen of immunosuppressive drugs have suggested a dose-response relationship between severity of HPV -induced lesions and increased immunosuppression. 5 • 6 In addition, immunosuppressed women often respond poorly to conventional treatment for HPV-induced cytologic lesions, and residual infection often leads to the progression of a cytologic lesion even after treatment. 1.2 Women with human immunodeficiency virus (HIV) infection have been reported to show a high prevalence of cervical intraepithelial neoplasia or squamous intraepithelial lesions, although most published or presented studies to date have not included a comparable uninfected control group.6 A few controlled studies have suggested an association of HIV with cervical cytologic abnormality.7.l3 Cytologic evidence from these studies suggests that HIV infection may promote the pathologic consequences of HPV, which is analogous to the course of HPV infection among other immunosuppressed patients. 7. 8 HIV may affect local cervical immunity by diminishing quantity or function of Langerhans' cells, a plausible mechanism for pathophysiologic changes. 6. 14, 15 Preliminary reports using
Volume 165 Number 2
molecular diagnosis of HPV in some studies suggest that advanced HIV-related clinical disease or immunosuppression seems to predispose to higher rates of cervical intraepithelial neoplasia,6, 13 , 16~18 including a preliminary report of a subset of the women reported here. 19 However, other preliminary studies found no such association. 20, 21 The strong relationship that exists between HPV, HIV, and anal dysplasia among homosexual men who engage in unprotected receptive anal intercourse 22, 23 suggests a common HIV immunosuppression -mediated mechanism of HPV -related neoplastic changes in selected genital epithelial tissues in both women and men. This study was designed to investigate the hypothesis that HIV-infected women who are also infected with HPV, detected by molecular hybridization, are more likely to have cervical cytologic abnormalities than are women with only one or neither virus. Important potential confounding factors are considered. Additionally, we have sought to determine whether stage of HIV infection, i.e., asymptomatic or symptomatic, may be associated with frequency and severity of cervical cytologic abnormalities. Methods
Subjects. The subjects included 97 women with known HIV serologic status, 96 of whom had cervicovaginal lavage samples that were sufficient for HPV determination and were thus included in this analysis. The protocol was approved by the hospital institutional review board for the protection of human subjects. Seventy-three were women with a history of heroin use attending a Bronx, New York, methadone maintenance program affiliated with a major medical center and enrolled in a longitudinal study of the natural history of HIV infection. 19 Twenty-two participants were recruited from women who were enrolled in a study of HIV transmission among heterosexual partners of intravenous drug users at the same medical center. 7 One woman was a transfusion recipient of HIV -seropositive blood, who was included because she was from the same geographic and socioeconomic background as the other subjects. HIV antibody status was determined by enzyme immunoassay (ELISA, DuPont) and confirmed by Western blot; positive results by both methods were noted in 51 (53%) of the 96 subjects. Consecutive subjects were enrolled on the basis of availability of study personnel and provision of informed consent at the time of their visits. Women in the methadone program who were coming for annual physical examination and women who were enrolled in a heterosexual transmission study were recruited at the time of a research visit. A few high-risk women were recruited from the infectious disease clinic or medical ward of the hospital at a time when a Papanicolaou
HIV and HPV exacerbate squamous intraepitheliallesions
393
smear was medically indicated. All sexually active women with known or obtainable HIV serologic results from these recruitment environments were deemed eligible for the study. After written informed consent was obtained, a brief questionnaire was administered to obtain demographic characteristics and smoking and gynecologic history. A pelvic examination was performed and a Papanicolaou smear was obtained with a cotton swab and a wooden Ayres spatula. Endocervical samples were then collected for Chlamydia trachomatis, Neisseria gonorrhoeae, and herpes simplex virus cultures with a calcium alginate swab on an aluminum shaft for chlamydia and a cotton swab for gonorrhea and herpes simplex virus. Exfoliated cervicovaginal cells were obtained for HPV determination by cervicovaginal lavage as previously described. 19, 24~26 Patient health status (e.g., rashes, chancres) and syphilis serologic results by Venereal Disease Research Laboratory test or reagin precipitin reaction were assessed at or near the time of the pelvic examination. If a positive test was noted, a fluorescent treponemal antibody test was performed. Syphilis was diagnosed if primary or secondary lesions were present with positive results for all tests or if the Venereal Disease Research Laboratory test or reagin precipitin reaction titer had not fallen after prior treatment for clinically confirmed syphilis. Cytology. Papanicolaou smears were interpreted and classified, by personnel who were blinded to patient HIV and HPV status, on the basis of the Bethesda Terminology and Classification system for cervical and vaginal cytology.27 All abnormal and most normal smears were confirmed by one of the authors (K.S.). For analyses, we compared subjects with smears considered benign (negative or showing only reactive or reparative changes) with those having "positive" smears (smears providing evidence of squamous intraepithelial lesions or cancer). To provide a more striking clinical comparison, most analyses were repeated to exclude subjects from the analysis whose Papanicolaou smears showed only reactive or reparative changes; these repeat analyses contrasted characteristics of women with completely negative smears with those of women with squamous intraepitheliallesions. Women were referred for colposcopic examination where clinically indicated; however, follow-up is incomplete and results of additional gynecologic evaluations are therefore not presented. Molecular biology. Deoxyribonucleic acid (DNA) extracted from cervicovaginal cells was tested for human papillomavirus DNA by Pst I restriction analysis and Southern blot hybridization, with a mixed probe of HPV DNA types 11, 16, and 18. Hybridizations were performed under conditions of low stringency (i,e.,
394 Vermund et al.
August 1991 Am J Obstet Gynecol
Table I. Sociodemographic and behavioral characteristics and presence of concurrent sexually transmitted diseases, by HIV and HPV infection status, N = 96
HIV positive HPV
Mean age (yr. mean ± SD and range) Race (No. and column %) White Black Hispanic Education (yr. mean ± SD and range) Patient source (No. and column %) Methadone clinic Other Smoking history (pack yr*) Median Geometric mean Women pregnant at time of examination (No. and %) Mean age at first coitus (yr. mean ± SD and range) Median No. of sexual partners Lifetime Last year Concurrent sexually transmitted diseases (No. and %)t Chlamydia Gonorrhea Syphilis Herpes simplex virus Oral contraceptive use (yr. mean ± SD and range) Pregnancies (No .• mean ± SD and range)
HIV negative HPV
HPV
HPV
positive (n = 27)
negative (n = 24)
positive (n = 10)
negative (n = 35)
33.9 ± 4.8 (24-42)
34.1 ± 5.8 (24-48)
34.7 ± 3.9 (29-40)
35.5 ± 7.2 (23-58)
2 (7.4) 8 (30) 17 (63) 11.3 ± 2.5 (7-17)
4 (17) 5 (21) 15 (63) 10.8 ± 2.6 (5-16)
6 (60) 2 (20) 2 (20) 11.6 ± 1.8 (10-16)
13 (37) 4 (II) 18 (51) 11.5 ± 2.6 (5-17)
17 (63) 10 (37)
14 (58) 10 (42)
10 (100) 0(0)
27 (77) 8 (23)
18.1 18.5 3 (II)
9.3 10.9 1 (4.2)
15.0 14.1 2 (20)
18.9 15.4 5 (14)
15.8 ± 2.3 (10-22)
15.6 ± 2.7 (11-25)
16.4 ± 1.4 (14-19)
16.2 ± 3.2 (9-27)
7.0 1.0
5.0 1.0
5.0 1.0
6.0 1.0
1127 (3.7) 1123 (4.3) 5/22 (23) 0/27 (0) 1.4 ± 3.8 (0-17) 3.9 ± 2.2 (1-8)
1124 (4.2) 1123 (4.3) 4/23 (17) 0/24 (0) 2.6 ± 3.9 (0-14) 5.3 ± 1.8 (2-9)
0110 (0) 0110 (0) 2/10 (20) 0/10 (0) 3.0 ± 3.6 (0-10) 4.1 ± 2.2 (0-7)
2/35 (5.7) 1135 (2.9) 1135 (2.9) 0/35 (0) 1.7 ± 3.1 (0-16) 4.2 ± 2.4 (0-8)
*Estimated number of packs of cigarettes per day times number of years smoked. tSome data missing because of inadequate or lost specimens.
tm = - 40° C), followed by a low-stringent wash, after which filters were exposed for 1 to 3 days. Then a subsequent wash at high stringency was followed by exposure for 1 to 2 weeks!4 All HPV DNA determinations were made without the knowledge of any laboratory or clinical findings. Clinical assessment. Chart review of all medical records of the 51 HIV-infected women was performed to assess signs and symptoms of HIV disease, and classification was made according to the Centers for Disease Control scheme. 28 On the basis of data from the clinical and research records, women were classified into one of four groups: group I. acute infection; group 2, asymptomatic infection; group 3, persistent generalized lymphadenopathy; and group 4, other diseases associated with HIV infection. No patient had evidence of acute infection, and patients in groups 3 and 4 were combined into one category for purposes of analysis, comparing HIV -infected persons without signs or symptoms (termed asymptomatic) with HIV-infected persons with signs or symptoms (termed symptomatic).
Seven subjects (all symptomatic HIV infected) were being treated with zidovudine and three others were taking acyclovir as prophylaxis for recurrent HSV infection. Eight subjects were participating in a doubleblind, placebo-controlled trial of zidovudine efficacy in asymptomatic, HIV-seropositive persons. These 18 HIV-infected women had behavioral and sociodemographic characteristics similar to those of the other 33 HIV-positive patients and were analyzed with their appropriate clinical symptom group. Biostatistics. Standard statistical methods were used for data analysis including X2 tests (with Yates' correction for 2 X 2 tables) or two-tailed Fisher's exact tests when sample size did not permit use of the X2. Odds ratios and Mantel-Haenszel odds ratios with 95% confidence intervals were used to measure strength of stratum-specific and overall associations in multivariate analyses. One-way analysis of variance was used to compare average age of subgroups. Evidence of squamous intraepithelial lesions at cervical cytologic testing was the outcome studied. Women
HIV and HPV exacerbate squamous intraepithelial lesions
Volume 165 Number 2
395
Table II. Association of symptomatic and asymptomatic HIV and HPV among 96 high-risk women HIV Seropositive, asymptomatic
Seropositive, symptomatic No.
HPV Positive Negative TOTAL
23 10 33
I
Column
70 30 100
%
No .
I
Column
4 14 18
22 78 100
Seronegative
%
No.
I
Column
Total
%
No .
1
Column
10 35
22 78
37
59
39 61
45
100
96
100
%
P < 0.0001, by X 2 • were grouped into six categories on the basis of the two major independent variables: (1) symptomatic HIVinfected and HPV-infected, (2) symptomatic HIVinfected and HPV -uninfected, (3) asymptomatic HIV-infected and HPV-infected, (4) asymptomatic HIV-infected and HPV-uninfected, (5) HIVuninfected and HPV-infected , and (6) HIV-uninfected and HPV -uninfected. For some analyses, categories 1 and 3 (HIV-infected and HPV-infected), 2 and 4 (HIV-infected and HPV-uninfected), and 5 and 6 (HIV-uninfected) were collapsed. One summary analysis combined categories 3 through 6 into one group (asymptomatic HIV -infected or HIV -uninfected). Given the heterogeneous rates for HIV, HPV, and squamous intra epithelial lesions in various racial and ethnic categories (see Results), the key analyses that associate HIV and HPV and that associate HIV, HPV, and Papanicolaou smear results were stratified by race. Age was controlled with stratum-specific analyses comparing women
Key words: Human immunodeficiency virus, human papillomavirus, cervix, sexually transmitted diseases, squamous intraepithelial lesions
Immunosuppression, whether from chemotherapy, malignancy, or infection, has been shown to be associated with higher than expected rates and advanced pathologic consequences of human papilloma virus (HPV) infection. 1. 4 Immunosuppressed women from a wide range of age, racial, and socioeconomic groups have been reported to manifest greater HPV frequency and pathogenicity.3. 4 Therefore the cervix is likely to be a target organ for HPV-related pathologic conditions among women who have been immunosuppressed by a variety of causes. Studies in pregnant From the Departments of Epidemiology and Social Medicine: Pediatrics,' Medicine,' and Pathology (Divisions of Cytopathologyd and Virology'), Montefiore Medical Center, and the Departments of Epidemiology and Social Medicine," Pediatrics,' Medicine,' Pathology, d. , Obstetrics and Gynecology,! and Microbiology and Immunology/ Albert Einstein College of Medicine. Supported by CenteTS for Disease Control Cooperative Agreement No. U62-CCU200714-06. Presented in part at the Fifth International Conference on AIDS, Montreal, Quebec, Canada, June 8, 1989. Received for publication August 8, 1990; revised January 15, 1991 ; accepted January 31, 1991. Reprint requests: Dr. Sten Vermund, EBIDAlDSINIAlDIN1H, 6003 Executive Blvd., Room 240P, Bethesda, MD 20892. 6/1/28538
392
women, renal allograft reCIpients, Hodgkin's disease patients, and other women on a regimen of immunosuppressive drugs have suggested a dose-response relationship between severity of HPV -induced lesions and increased immunosuppression. 5 • 6 In addition, immunosuppressed women often respond poorly to conventional treatment for HPV-induced cytologic lesions, and residual infection often leads to the progression of a cytologic lesion even after treatment. 1.2 Women with human immunodeficiency virus (HIV) infection have been reported to show a high prevalence of cervical intraepithelial neoplasia or squamous intraepithelial lesions, although most published or presented studies to date have not included a comparable uninfected control group.6 A few controlled studies have suggested an association of HIV with cervical cytologic abnormality.7.l3 Cytologic evidence from these studies suggests that HIV infection may promote the pathologic consequences of HPV, which is analogous to the course of HPV infection among other immunosuppressed patients. 7. 8 HIV may affect local cervical immunity by diminishing quantity or function of Langerhans' cells, a plausible mechanism for pathophysiologic changes. 6. 14, 15 Preliminary reports using
Volume 165 Number 2
molecular diagnosis of HPV in some studies suggest that advanced HIV-related clinical disease or immunosuppression seems to predispose to higher rates of cervical intraepithelial neoplasia,6, 13 , 16~18 including a preliminary report of a subset of the women reported here. 19 However, other preliminary studies found no such association. 20, 21 The strong relationship that exists between HPV, HIV, and anal dysplasia among homosexual men who engage in unprotected receptive anal intercourse 22, 23 suggests a common HIV immunosuppression -mediated mechanism of HPV -related neoplastic changes in selected genital epithelial tissues in both women and men. This study was designed to investigate the hypothesis that HIV-infected women who are also infected with HPV, detected by molecular hybridization, are more likely to have cervical cytologic abnormalities than are women with only one or neither virus. Important potential confounding factors are considered. Additionally, we have sought to determine whether stage of HIV infection, i.e., asymptomatic or symptomatic, may be associated with frequency and severity of cervical cytologic abnormalities. Methods
Subjects. The subjects included 97 women with known HIV serologic status, 96 of whom had cervicovaginal lavage samples that were sufficient for HPV determination and were thus included in this analysis. The protocol was approved by the hospital institutional review board for the protection of human subjects. Seventy-three were women with a history of heroin use attending a Bronx, New York, methadone maintenance program affiliated with a major medical center and enrolled in a longitudinal study of the natural history of HIV infection. 19 Twenty-two participants were recruited from women who were enrolled in a study of HIV transmission among heterosexual partners of intravenous drug users at the same medical center. 7 One woman was a transfusion recipient of HIV -seropositive blood, who was included because she was from the same geographic and socioeconomic background as the other subjects. HIV antibody status was determined by enzyme immunoassay (ELISA, DuPont) and confirmed by Western blot; positive results by both methods were noted in 51 (53%) of the 96 subjects. Consecutive subjects were enrolled on the basis of availability of study personnel and provision of informed consent at the time of their visits. Women in the methadone program who were coming for annual physical examination and women who were enrolled in a heterosexual transmission study were recruited at the time of a research visit. A few high-risk women were recruited from the infectious disease clinic or medical ward of the hospital at a time when a Papanicolaou
HIV and HPV exacerbate squamous intraepitheliallesions
393
smear was medically indicated. All sexually active women with known or obtainable HIV serologic results from these recruitment environments were deemed eligible for the study. After written informed consent was obtained, a brief questionnaire was administered to obtain demographic characteristics and smoking and gynecologic history. A pelvic examination was performed and a Papanicolaou smear was obtained with a cotton swab and a wooden Ayres spatula. Endocervical samples were then collected for Chlamydia trachomatis, Neisseria gonorrhoeae, and herpes simplex virus cultures with a calcium alginate swab on an aluminum shaft for chlamydia and a cotton swab for gonorrhea and herpes simplex virus. Exfoliated cervicovaginal cells were obtained for HPV determination by cervicovaginal lavage as previously described. 19, 24~26 Patient health status (e.g., rashes, chancres) and syphilis serologic results by Venereal Disease Research Laboratory test or reagin precipitin reaction were assessed at or near the time of the pelvic examination. If a positive test was noted, a fluorescent treponemal antibody test was performed. Syphilis was diagnosed if primary or secondary lesions were present with positive results for all tests or if the Venereal Disease Research Laboratory test or reagin precipitin reaction titer had not fallen after prior treatment for clinically confirmed syphilis. Cytology. Papanicolaou smears were interpreted and classified, by personnel who were blinded to patient HIV and HPV status, on the basis of the Bethesda Terminology and Classification system for cervical and vaginal cytology.27 All abnormal and most normal smears were confirmed by one of the authors (K.S.). For analyses, we compared subjects with smears considered benign (negative or showing only reactive or reparative changes) with those having "positive" smears (smears providing evidence of squamous intraepithelial lesions or cancer). To provide a more striking clinical comparison, most analyses were repeated to exclude subjects from the analysis whose Papanicolaou smears showed only reactive or reparative changes; these repeat analyses contrasted characteristics of women with completely negative smears with those of women with squamous intraepitheliallesions. Women were referred for colposcopic examination where clinically indicated; however, follow-up is incomplete and results of additional gynecologic evaluations are therefore not presented. Molecular biology. Deoxyribonucleic acid (DNA) extracted from cervicovaginal cells was tested for human papillomavirus DNA by Pst I restriction analysis and Southern blot hybridization, with a mixed probe of HPV DNA types 11, 16, and 18. Hybridizations were performed under conditions of low stringency (i,e.,
394 Vermund et al.
August 1991 Am J Obstet Gynecol
Table I. Sociodemographic and behavioral characteristics and presence of concurrent sexually transmitted diseases, by HIV and HPV infection status, N = 96
HIV positive HPV
Mean age (yr. mean ± SD and range) Race (No. and column %) White Black Hispanic Education (yr. mean ± SD and range) Patient source (No. and column %) Methadone clinic Other Smoking history (pack yr*) Median Geometric mean Women pregnant at time of examination (No. and %) Mean age at first coitus (yr. mean ± SD and range) Median No. of sexual partners Lifetime Last year Concurrent sexually transmitted diseases (No. and %)t Chlamydia Gonorrhea Syphilis Herpes simplex virus Oral contraceptive use (yr. mean ± SD and range) Pregnancies (No .• mean ± SD and range)
HIV negative HPV
HPV
HPV
positive (n = 27)
negative (n = 24)
positive (n = 10)
negative (n = 35)
33.9 ± 4.8 (24-42)
34.1 ± 5.8 (24-48)
34.7 ± 3.9 (29-40)
35.5 ± 7.2 (23-58)
2 (7.4) 8 (30) 17 (63) 11.3 ± 2.5 (7-17)
4 (17) 5 (21) 15 (63) 10.8 ± 2.6 (5-16)
6 (60) 2 (20) 2 (20) 11.6 ± 1.8 (10-16)
13 (37) 4 (II) 18 (51) 11.5 ± 2.6 (5-17)
17 (63) 10 (37)
14 (58) 10 (42)
10 (100) 0(0)
27 (77) 8 (23)
18.1 18.5 3 (II)
9.3 10.9 1 (4.2)
15.0 14.1 2 (20)
18.9 15.4 5 (14)
15.8 ± 2.3 (10-22)
15.6 ± 2.7 (11-25)
16.4 ± 1.4 (14-19)
16.2 ± 3.2 (9-27)
7.0 1.0
5.0 1.0
5.0 1.0
6.0 1.0
1127 (3.7) 1123 (4.3) 5/22 (23) 0/27 (0) 1.4 ± 3.8 (0-17) 3.9 ± 2.2 (1-8)
1124 (4.2) 1123 (4.3) 4/23 (17) 0/24 (0) 2.6 ± 3.9 (0-14) 5.3 ± 1.8 (2-9)
0110 (0) 0110 (0) 2/10 (20) 0/10 (0) 3.0 ± 3.6 (0-10) 4.1 ± 2.2 (0-7)
2/35 (5.7) 1135 (2.9) 1135 (2.9) 0/35 (0) 1.7 ± 3.1 (0-16) 4.2 ± 2.4 (0-8)
*Estimated number of packs of cigarettes per day times number of years smoked. tSome data missing because of inadequate or lost specimens.
tm = - 40° C), followed by a low-stringent wash, after which filters were exposed for 1 to 3 days. Then a subsequent wash at high stringency was followed by exposure for 1 to 2 weeks!4 All HPV DNA determinations were made without the knowledge of any laboratory or clinical findings. Clinical assessment. Chart review of all medical records of the 51 HIV-infected women was performed to assess signs and symptoms of HIV disease, and classification was made according to the Centers for Disease Control scheme. 28 On the basis of data from the clinical and research records, women were classified into one of four groups: group I. acute infection; group 2, asymptomatic infection; group 3, persistent generalized lymphadenopathy; and group 4, other diseases associated with HIV infection. No patient had evidence of acute infection, and patients in groups 3 and 4 were combined into one category for purposes of analysis, comparing HIV -infected persons without signs or symptoms (termed asymptomatic) with HIV-infected persons with signs or symptoms (termed symptomatic).
Seven subjects (all symptomatic HIV infected) were being treated with zidovudine and three others were taking acyclovir as prophylaxis for recurrent HSV infection. Eight subjects were participating in a doubleblind, placebo-controlled trial of zidovudine efficacy in asymptomatic, HIV-seropositive persons. These 18 HIV-infected women had behavioral and sociodemographic characteristics similar to those of the other 33 HIV-positive patients and were analyzed with their appropriate clinical symptom group. Biostatistics. Standard statistical methods were used for data analysis including X2 tests (with Yates' correction for 2 X 2 tables) or two-tailed Fisher's exact tests when sample size did not permit use of the X2. Odds ratios and Mantel-Haenszel odds ratios with 95% confidence intervals were used to measure strength of stratum-specific and overall associations in multivariate analyses. One-way analysis of variance was used to compare average age of subgroups. Evidence of squamous intraepithelial lesions at cervical cytologic testing was the outcome studied. Women
HIV and HPV exacerbate squamous intraepithelial lesions
Volume 165 Number 2
395
Table II. Association of symptomatic and asymptomatic HIV and HPV among 96 high-risk women HIV Seropositive, asymptomatic
Seropositive, symptomatic No.
HPV Positive Negative TOTAL
23 10 33
I
Column
70 30 100
%
No .
I
Column
4 14 18
22 78 100
Seronegative
%
No.
I
Column
Total
%
No .
1
Column
10 35
22 78
37
59
39 61
45
100
96
100
%
P < 0.0001, by X 2 • were grouped into six categories on the basis of the two major independent variables: (1) symptomatic HIVinfected and HPV-infected, (2) symptomatic HIVinfected and HPV -uninfected, (3) asymptomatic HIV-infected and HPV-infected, (4) asymptomatic HIV-infected and HPV-uninfected, (5) HIVuninfected and HPV-infected , and (6) HIV-uninfected and HPV -uninfected. For some analyses, categories 1 and 3 (HIV-infected and HPV-infected), 2 and 4 (HIV-infected and HPV-uninfected), and 5 and 6 (HIV-uninfected) were collapsed. One summary analysis combined categories 3 through 6 into one group (asymptomatic HIV -infected or HIV -uninfected). Given the heterogeneous rates for HIV, HPV, and squamous intra epithelial lesions in various racial and ethnic categories (see Results), the key analyses that associate HIV and HPV and that associate HIV, HPV, and Papanicolaou smear results were stratified by race. Age was controlled with stratum-specific analyses comparing women
