Acceptability of self-collection of specimens for HPV DNA testing in an urban population.

PURPOSE: To assess the acceptability of self-collection of specimens for human papillomavirus (HPV) DNA testing and to explore whether use of self-collected specimens would increase intention to participate in regular screening among low-income, inner-city, minority women. METHODS: A written survey was administered to 172 women after they underwent gynecological examination and self-collection of a sample for HPV DNA testing. RESULTS: Participants agreed that ease of use (69%), less painful procedure (62%), "could do it myself" (56%), and privacy (52%) were desirable characteristics of the self-sampling procedure they performed. Most of the participants (57%) reported that there was nothing they did not like about self-sampling; however, the majority (68%) preferred the clinician-collected test. Those recruited through a sexually transmitted disease (STD) clinic were significantly more likely than those recruited at a cancer screening clinic (57% vs. 24%), those with some or more college education were significantly more likely than those with less education (43% vs. 26%), and those who were not Hispanic were significantly more likely than those who were Hispanic (49% vs. 28%) to prefer the self-collected test. Although most women (47%) reported that they would be most likely to attend regular screening if tested by a clinician during a pelvic examination, 21% asserted that self-collection at home would increase their likelihood of participation in screening. CONCLUSIONS: Although most of the predominantly Hispanic, low-income, uninsured, and recently screened women in the study preferred clinician-collected HPV tests to self-collected sampling, self-sampling is acceptable to the majority and may increase the likelihood of participation in cervical cancer screening programs.

Anal intraepithelial neoplasia in heterosexual and homosexual HIV-positive men with access to antiretroviral therapy.

BACKGROUND: Studies of human immunodeficiency virus (HIV)-positive men have demonstrated high rates of anal intraepithelial neoplasia (AIN), a precursor to anal carcinoma, mostly in white homosexual men and men not receiving effective antiretroviral therapy (ART). METHODS: Ninety-two participants--53% Latino, 36% African American, and 40% without a history of receptive anal intercourse (RAI)--were evaluated with a behavioral questionnaire, liquid-based anal cytological testing, Hybrid Capture 2 human papillomavirus (HPV) DNA assay and polymerase chain reaction, and anal colposcopy with biopsy of lesions. RESULTS: High-risk HPV DNA was identified in 61%, and this was associated with a history of RAI (78% vs. 33%; P<.001); 47% had abnormal cytological results, and 40% had AIN on biopsy. In multivariate analysis, both were associated with a history of RAI (odds ratio [OR], 10 [P<.001] and OR, 3.6 [P=.02], respectively) and lower nadir CD4(+) cell counts (P=.06 and P=.01). Current ART use was protective (OR, 0.09; P<.01 and OR, 0.18; P=.02). CONCLUSIONS: Although anal infections with high-risk HPV and AIN in HIV-positive men are associated with a history of RAI, both conditions are commonly identified in HIV-positive men without this history. Both lower nadir CD4(+) cell counts and lack of current ART were associated with AIN but not with the detection of anal HPV.

Incidence of cervical squamous intraepithelial lesions in HIV-infected women.

CONTEXT: Women infected with human immunodeficiency virus (HIV) are at increased risk for cervical squamous intraepithelial lesions (SILs), the precursors to invasive cervical cancer. However, little is known about the causes of this association. OBJECTIVES: To compare the incidence of SILs in HIV-infected vs uninfected women and to determine the role of risk factors in the pathogenesis of such lesions. DESIGN: Prospective cohort study conducted from October 1,1991, to June 30, 1996. SETTING: Urban clinics for sexually transmitted diseases, HIV infection, and methadone maintenance. PARTICIPANTS: A total of 328 HIV-infected and 325 uninfected women with no evidence of SILs by Papanicolaou test or colposcopy at study entry. MAIN OUTCOME MEASURE: Incident SILs confirmed by biopsy, compared by HIV status and risk factors. RESULTS: During about 30 months of follow-up, 67 (20%) HIV-infected and 16 (5%) uninfected women developed a SIL (incidence of 8.3 and 1.8 cases per 100 person-years in sociodemographically similar infected and uninfected women, respectively [P<.001]). Of incident SILs, 91% were low grade in HIV-infected women vs 75% in uninfected women. No invasive cervical cancers were identified. By multivariate analysis, significant risk factors for incident SILs were HIV infection (relative risk [RR], 3.2; 95% confidence interval [CI], 1.7-6.1), transient human papillomavirus (HPV) DNA detection (RR, 5.5; 95% CI, 1.4-21.9), persistent HPV DNA types other than 16 or 18 (RR, 7.6; 95% CI, 1.9-30.3), persistent HPV DNA types 16 and 18 (RR, 11.6; 95% CI, 2.7-50.7), and younger age (<37.5 years; RR, 2.1; 95% CI, 1.3-3.4). CONCLUSIONS: In our study, 1 in 5 HIV-infected women with no evidence of cervical disease developed biopsy-confirmed SILs within 3 years, highlighting the importance of cervical cancer screening programs in this population.

Risk of cancer among women with AIDS in New York City.

To evaluate the risk of cancer among women with AIDS in New York City (NYC), we compared the cancer experience of AIDS-infected women in NYC with that of the general population of women in NYC by matching the population-based New York State Cancer Registry with the New York City AIDS Registry. A probabilistic algorithm was used to match names, birth dates, and, where available, Social Security numbers between 15,146 women with AIDS and 232,902 women with cancer. Standardized incidence ratios (SIR) were calculated as the ratio of observed to expected cancer cases in the population of NYC women matched for age, race, and calendar period of cancer diagnosis. Period-specific relative risks (RR) of cancer prevalence prior to AIDS, and incidence at or after AIDS were calculated to determine which cancers increased in proximity to an AIDS diagnosis, a surrogate marker of increasing immunodeficiency. Analysis was limited to women between the ages of 15 to 69 who were diagnosed with AIDS between 1981 and 1994. Among 15,146 women diagnosed with AIDS, we found 1,194 matches with the Cancer Registry. For cancers included in the 1993 AIDS case definition, the SIR was 178.49 for Kaposi's sarcoma, 48.97 for non-Hodgkin's lymphoma, and 9.20 for invasive cervical cancer. The overall SIR for all non-AIDS-defining cancers was 2.20. Among non-AIDS-defining cancers, elevated SIRs were found for cancers of the lung (7.95), esophagus (7.69), multiple myeloma (7.37), oral cavity and pharynx (6.55), Hodgkin's disease (5.65), leukemias (4.52), and rectal/anal cancers (3.23). Statistically significant increases in period-specific risks were found for all non-AIDS-defining cancers combined, but not for individual cancers. Dual screening by two registries and unknown behavioral factors complicate the ascertainment of cancer risk. Our results show significantly elevated risks for several non-AIDS-defining cancers; these results are consistent with other studies of cancers among persons with AIDS. Extension of the time period of analysis is required to test for the effects of new anti-viral treatments and their association with cancer development among HIV-infected women.

Human papillomavirus infection in women infected with the human immunodeficiency virus.

BACKGROUND: Among women infected with the human immunodeficiency virus (HIV), there is a high prevalence of human papillomavirus (HPV) infections. However, little is known about the natural history of HPV infections in HIV-seropositive women, and persistent HPV infections may explain the increased risk of cervical squamous intraepithelial lesions and invasive cervical cancer in HIV-seropositive women. METHODS: A total of 220 HIV-seropositive and 231 HIV-seronegative women in the New York City area were evaluated at two or more semiannual gynecologic examinations that included a Pap test, a test for HPV DNA, and colposcopy. RESULTS: HPV DNA was detected at the initial examination in 56 percent of the HIV-seropositive and 31 percent of the HIV-seronegative women. After four examinations, the cumulative prevalence of HPV infection was 83 percent in the seropositive women and 62 percent in the seronegative women (P<0.001). Persistent HPV infections were found in 24 percent of the seropositive women but in only 4 percent of the seronegative women (P<0.001). Twenty percent of the seropositive women and 3 percent of the seronegative women had persistent infections with HPV-16-associated viral types (16, 31, 33, 35, or 58) or HPV-18-associated types (18 or 45) (P<0.001), which are most strongly associated with cervical cancer. The detection of HPV DNA in women with previously negative tests was not associated with sexual activity during the interval since the preceding examination. CONCLUSIONS: HIV-seropositive women have a high rate of persistent HPV infections with the types of HPV that are strongly associated with the development of high-grade squamous intraepithelial lesions and invasive cervical cancer. These persistent infections may explain the increased incidence of squamous intraepithelial lesions in HIV-seropositive women.

Increased prevalence of vulvovaginal condyloma and vulvar intraepithelial neoplasia in women infected with the human immunodeficiency virus.

OBJECTIVE: To compare the prevalence of human papillomavirus (HPV)-associated vulvovaginal lesions in human immunodeficiency virus (HIV)-positive and HIV-negative women. METHODS: For this cross-sectional study, all participants received a complete gynecologic examination including colposcopic evaluation and a structured interview about sociodemographic characteristics and risk factors for vulvovaginal disease. In addition, HPV DNA was assayed for in cervicovaginal lavages using polymerase chain reaction. RESULTS: Vulvar and/or vaginal condyloma acuminata were detected in 22 of 396 (5.6%) HIV-positive and in 3 of 375 (0.8%) HIV-negative women (odds ratio [OR] 7.3, P < .001). High-grade vulvar intraepithelial neoplasia (VIN) was present in two of the HIV-positive and none of the HIV-negative women. Human immunodeficiency virus-positive women with condyloma or VIN were significantly more likely to have cervical intraepithelial neoplasia (33%) than those without vulvovaginal lesions (17%) (OR 2.9, 95% confidence interval [CI] 1.1, 74). In multivariate logistic regression analysis, both HIV seropositivity (adjusted OR 5.3, 95% CI 1.3, 35.3) and HPV infection (adjusted OR 6.1, 95% CI 1.7, 39.4) were associated with vulvovaginal condyloma. CONCLUSION: The prevalence of vulvovaginal condyloma was increased in HIV-positive women even when controlling for HPV infection. Human papillomavirus-associated disease was more likely to be multicentric and involve the vulva, vagina, and cervix in HIV-positive than HIV-negative women. Detection of high-grade VIN in two of the HIV-positive women suggests that they may also be at risk for developing invasive vulvar carcinoma.

Prevalence of anal human papillomavirus infection and anal cytologic abnormalities in HIV-seropositive women.

OBJECTIVE: To determine the prevalence of anal human papillomavirus (HPV) infections and anal cytologic abnormalities in HIV-seropositive and HIV-seronegative women. DESIGN: This cross-sectional study of a cohort of women with known HIV serostatus involved a standardized interview and a gynecologic examination, including a cytologic evaluation of the cervix and anus. Anal swabs were tested for HPV DNA using the Hybrid Capture assay. SETTING: Two HIV/AIDS clinics, a sexually transmitted disease clinic, a methadone clinic and women enrolled in a study of HIV heterosexual transmission in the greater New York City metropolitan area. PATIENTS: One hundred and two HIV-seropositive and 96 HIV-seronegative women were selected from an ongoing study of the gynecologic manifestations of HIV infection. MAIN OUTCOME MEASURES: Detection of anal HPV DNA and anal cytologic abnormalities. RESULTS: Anal cytologic abnormalities were detected in 27 (26%) of the 102 HIV-seropositive women and in six (7%) of 96 HIV-seronegative women. Five (5%) of the anal smears from the HIV-seropositive women and one (1%) from the HIV-seronegative women had low-grade anal intra-epithelial neoplasia. The remainder of the anal cytologic abnormalities were classified as mild squamous cytologic atypia. HPV DNA was detected in 30 (29%) of 102 HIV-seropositive and two (2%) of 96 HIV-seronegative women. Of the 33 patients with anal cytologic abnormalities, 19 (58%) had anal HPV DNA detected as compared to 13 (8%) of 160 women without cytologic abnormalities (P < 0.001). In a multivariate logistic regression analysis, HIV-seropositivity was found to be an independent risk factor for both anal HPV infection and anal cytologic abnormalities and the strength of the association was greater in women with lower CD4+ T-lymphocyte counts. CONCLUSION: The prevalence of both anal cytologic abnormalities and anal HPV infection are significantly increased in HIV-seropositive women.

Significance of mild cytologic atypia in women infected with human immunodeficiency virus.

OBJECTIVE: To determine the prevalence of cervical intraepithelial neoplasia (CIN) in women who are infected with human immunodeficiency virus (HIV) and who have mild cytologic atypia. METHODS: As part of an ongoing, prospective study of cervical disease in HIV-infected women, Papanicolaou smears were analyzed cross-sectionally for the diagnosis of mild cytologic atypia. RESULTS: Mild cytologic atypia was diagnosed in 112 (25%) of the 453 HIV-infected women enrolled in this study, compared with 36 (9%) of the 401 HIV-uninfected women (odds ratio [OR] 3.3, 95% confidence interval [CI] 2.2-5.1; P < .001). Mild cytologic atypia was diagnosed more frequently in HIV-infected women with lower CD4+ T-lymphocyte counts (chi2 for trend, P = .015) and in those with a history of an abnormal Papanicolaou smear or treatment for cervical disease (OR 3.0, 95% CI 1.2-7.6; P = .008). Coexistent CIN was detected by colposcopically directed biopsy in 42 (38%) of the 112 HIV-infected women with mild cytologic atypia, compared with five (14%) of the 36 HIV-uninfected women (OR 3.7, 95% CI 1.3-11.9; P = .008). Severe inflammation with associated epithelial reparative atypia was diagnosed in 90 (20%) of the HIV-infected women and in 87 (22%) of the HIV-uninfected women. Coexistent CIN was detected in 12% of the HIV-infected women with severe inflammation and associated epithelial reparative atypia, compared with 2% of the HIV-uninfected women with this cytologic diagnosis (OR 5.9, 95% CI 1.2-23; P = .01). CONCLUSION: Mild cytologic atypia, a frequent diagnosis on Papanicolaou smears from HIV-infected women, is associated with CIN. We recommend that all HIV-infected women with mild cytologic atypia be referred for colposcopy.

Human papillomavirus infection in human immunodeficiency virus-seropositive women.

OBJECTIVE: To compare the prevalence of human papillomavirus (HPV) infections in women who are seropositive and seronegative for human immunodeficiency virus (HIV), and to determine if associations between HPV and cervical disease are altered in HIV-seropositive women. METHODS: In this cross-sectional study, 344 HIV-seropositive and 325 HIV-seronegative women underwent colposcopy and HPV DNA testing. RESULTS: Human immunodeficiency virus-seropositive women were more likely than HIV-seronegative women to have HPV DNA of any type detected (60 versus 36%, P < .001). Infections with HPV type 16 (27 versus 17%, P < .05), type 18 (24 versus 9%, P < .05), and more than one type of HPV (51 versus 26%, P < .05) were also more common in HIV-positive women. Although both latent HPV infection and HPV infections associated with cervical intraepithelial neoplasia (CIN) were more prevalent in the HIV-seropositive group, the ratio between these two types of infections was altered markedly in the HIV-seropositive women. Human immunodeficiency virus-seropositive women who were HPV-infected were significantly more likely to have CIN than were HPV-infected HIV-seronegative women, an increase observed at all levels of immunosuppression. Analysis of specific HPV types associated with latent HPV infection and CIN indicated that HIV seropositivity only minimally alters the known associations between specific types of HPV and cervical disease. CONCLUSION: Human papillomavirus infections are more common among HIV-seropositive women at all levels of immunosuppression. However, relationships between HIV and HPV are complex and cannot be explained completely by an increased susceptibility to new HPV infections in the immunosuppressed patient.

Cervical intraepithelial neoplasia in women infected with the human immunodeficiency virus: outcome after loop electrosurgical excision.

Our clinical experience with loop electrosurgical excision as therapy for cervical intraepithelial neoplasia (CIN) in women infected with human immunodeficiency virus is described. Information for this analysis was obtained from a retrospective chart review of all women with biopsy-confirmed CIN treated by loop electrosurgical excision who attended our colposcopy clinic during January 1991 to September 1992. Outcomes in women known to be HIV-seropositive were compared to those in women of unknown HIV serostatus. Patients included in the analysis were followed for at least 6 months or until the documentation of recurrent/persistent CIN, and all had at least one post-treatment colposcopic examination, including endocervical curettage and cervical biopsy of any acetowhite lesions. Recurrent/persistent CIN following loop excision was documented in 56% (19 of 34) HIV-infected women compared with 13% (10 of 80) women of unknown serostatus (OR 8.9, P < 0.001). HIV-infected women had a significantly higher rate of recurrent/persistent CIN than women of unknown serostatus, regardless of grade of CIN. In HIV-infected women, recurrent/persistent CIN following loop excision developed in 20% (1 of 5) with CD4+ T-lymphocyte counts > 500 cells/microliters compared to 61% (11 of 18) with CD4+ counts < or = 500 cells/microliters (P = 0.13). Loop electrosurgical excision has a high failure rate in HIV-infected women, and this failure rate may increase as the level of immunosuppression increases.

Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study.

OBJECTIVE: To define the prevalence of cervical intraepithelial neoplasia (CIN), the validity of Papanicolaou tests, and the associations between CIN and risk factors for cervical disease in human immunodeficiency virus (HIV)-infected women. METHODS: In this cross-sectional study, we enrolled 398 HIV-seropositive and 357 HIV-seronegative women from two HIV-AIDS clinics, two sexually transmitted disease clinics, a methadone clinic, and a clinic for participants in an HIV heterosexual transmission study. Each woman was interviewed and underwent a cytologic and colposcopic evaluation, and was tested for human papillomavirus (HPV) DNA. RESULTS: Eighty (20%) of the 398 HIV-seropositive women compared to 15 (4%) of the 357 seronegative women had colposcopically confirmed CIN (odds ratio 5.7; P < .001). No invasive cancers were found. The sensitivity and specificity of Papanicolaou tests in seropositive women were 81 and 87%, respectively. By multiple logistic regression analysis using a model that included behavioral and biologic risk factors for CIN, CIN was independently associated with HPV infection (odds ratio 9.8), HIV infection (odds ratio 3.5), CD4+ T-lymphocyte count less than 200 cells/microL (odds ratio 2.7), and age greater than 34 years (odds ratio 2.0). CONCLUSIONS: Cervical intraepithelial neoplasia is a common finding in HIV-infected women. However, the results of this study suggest that Papanicolaou tests should be effective for detecting cervical disease in this population.

Selective intracellular degradation of fibrinogen and its reversal in cultured hepatocytes.

Primary monolayer cultures of chick embryo hepatocytes were employed in pulse-chase experiments to examine plasma protein synthesis and secretion. The fates of [35S]methionine-labeled fibrinogen and transferrin were monitored in cell extracts and in spent culture media. It was found that hepatocytes, which were maintained in the absence of added hormones or serum, released into the medium virtually all of the label of transferrin but only 30% of the label in fibrinogen. The remainder of the labeled fibrinogen was retained by the cells, gradually disappearing in a manner suggestive of its intracellular degradation. To stimulate fibrinogen production on as many levels as possible, fetal bovine serum was added to the medium of the cultured cells. Serum elicited an increase in the level of fibrinogen mRNA which was accompanied by a 7-fold increase in the rate of fibrinogen synthesis as well as the complete release of fibrinogen label, resulting in an overall 20-fold enhancement in the hepatocellular output of this protein. Thus, both the amount of fibrinogen synthesized as well as the amount ultimately secreted are subject to modulation by the hepatocellular environment.

Murine tumor necrosis-inducing factor: purification and effects on myelomonocytic leukemia cells.

The tumor necrosis-inducing factor (TNF) found in sera of Corynebacterium parvum-treated, endotoxin-stressed BALB/C and outbred albino CD-1 mice has been purified to a single band of protein by polyacrylamide gel electrophoresis after identification and removal of contaminating albumin and transferrin. This purified TNF has a molecular weight of 140,000, is glycoprotein in nature, and migrates on free electrophoresis as an alpha 2-globulin. TNF activity was continuously monitored during purification by bioassay in vitro (tumor cell lysis) and was confirmed by demonstration of induction of tumor necrosis in vivo. A single target tumor cell line, murine myelomonocytic leukemia (WEHI/3), was used in both assays. In the in vivo assay, controls were heat-inactivated samples of TNF. As additional controls, a line of TNF-resistant WEHI/3 cells was used in the in vitro assay. Results from in vivo radiolabeling of TNF-sensitive and TNF-resistant cells indicated a difference between their cytoplasmic peptide profiles. Optimal TNF production was not altered in C. parvum-endotoxin-treated mice by treatment with silica, a substance that is specifically toxic for macrophages. Exposure of mice to 650 rad whole-body radiation, which is not markedly damaging to macrophage elements in the reticuloendothelial system, completely abrogated the ability of the mice to produce TNF after C. parvum-endotoxin treatment. These findings suggest that in the sera of C. parvum-endotoxin-treated mice the protein that induces necrosis in tumors may not be of macrophage origin.

A protein fraction (NHG) from serum of normal humans which is cytotoxic for HeLa cells in culture.

A fraction of the alpha-globulins (NHG) from normal human serum was cytotoxic for mouse L-cells in culture and Meth A tumors in mice. NHG inhibited the growth in vitro of human colon cancer (HT-29), melanoma (RPMI 7931) and a neuroblastoma cell line. Survival of HeLa S-3 cell colonies after 24 h exposure to 25, 50, 75 or 100 micrograms NHG/ml medium was 86%, 77%, 40% and 10%, respectively. Whole human serum or purified serum albumin had no anti-HeLa cell activity. These results confirm the presence of a protein in human serum with antitumor activity. An assay for NHG using HeLa S-3 tumor cells is described.

Evidence for the presence of an antitumor factor in serum of normal animals.

We have previously reported finding a factor with antitumor activity (TNF, tumor necrosis factor) in extracts of serum from normal mice. The possibility that TNF exists in the blood of normal animals of other species was explored. Horse, mouse, dog, human, sheep, calf, rat and shark serums were fractionated with (NH4)2SO4 and filtered through S-200 sephacryl gel. Proteins of molecular weight 90,000 to 180,000 were pooled, concentrated and dialyzed. TNF, determined by L-cell assay in vitro and Meth A assay in vivo found in fractions from mouse, dog and human serum. Agarose electrophoresis of the TNF from mouse and human serum indicated the principle components were alpha 1-alpha 2 globulins. Preparative PAGE indicated that mouse TNF migrated slowly and was made up of at least 4 components while human TNF was a faster moving, monomeric protein.