The effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic HPV among HIV-infected women.

OBJECTIVE: Cervical intraepithelial neoplasia (CIN), a common condition among HIV-infected women, has been linked to HIV load and immune status. Highly active antiretroviral therapy (HAART) improves immunologic and virologic status. This study was undertaken to determine the relationship between HAART use and CIN. DESIGN: Cohort study. The Women's Interagency HIV Study (WIHS) in five cities in the USA (Bronx/Manhattan, New York; Brooklyn, New York; Chicago, Illinois; Los Angeles, California; San Francisco Bay area, California; Washington, District of Columbia). METHODS: HIV-infected women were followed every 6 months with Papanicolaou smears and cervicovaginal lavage for human papillomavirus (HPV) DNA testing. To characterize exposures that changed over time and to capture the dynamic nature of cytologic changes, Papanicolaou smear findings from each participant's consecutive visits were defined as a pair. We determined the proportion of all pairs that exhibited either regression or progression, according to HAART exposure, HPV results and Papanicolaou smear status. As participants could contribute multiple pairs, inferences were based on robust methods to adjust for correlated observations. RESULTS: Women with persistent HPV infection were more likely to have progression of their lesions. After adjustment for CD4 cell count and Papanicolaou smear status, women on HAART were 40% (95% confidence interval, 4-81%) more likely to demonstrate regression and less likely (odds ratio, 0.68; 95% confidence interval, 0.52-0.88) to demonstrate progression CONCLUSIONS: HAART altered the course of HPV disease in HIV-infected women, reducing progression and increasing regression. As HPV disease is a common sex-specific manifestation of HIV disease this effect of HAART would be a major additional benefit from this modality of therapy.

Evolution of cervical abnormalities among women with HIV-1: evidence from surveillance cytology in the women's interagency HIV study.

OBJECTIVE: To determine incidence, progression, and regression rates for abnormal cervical cytology and their correlates among women with HIV. METHODS: In a multicenter prospective cohort study conducted October 1, 1994, through September 30, 1999 at university, public, and private medical centers and clinics, 1639 HIV-seropositive and 452 seronegative women were evaluated every 6 months for up to 5 years using history, cervical cytology, T-cell subsets, and quantitative plasma HIV RNA. Human papillomavirus (HPV) typing at baseline was determined by polymerase chain reaction. Cytology was read using the Bethesda system, with any smear showing at least atypia considered abnormal. Poisson regression identified factors associated with incident cytologic abnormalities whereas logistic regression identified those associated with progression and regression after an abnormality. RESULTS: At least one abnormal smear was found during all of follow-up among 73.0% of HIV-seropositive patients and 42.3% of seronegatives (p <.001). Only 5.9% of seropositives ever developed high-grade lesions, and the proportion with high-grade findings did not rise over time. Incidence of atypical squamous cells of uncertain significance (ASCUS) or more severe lesions among HIV-seropositive patients and seronegative patients was 26.4 and 11.0/100 woman-years (rate ratio [RR], 2.4; 95% confidence interval [CI], 1.9-3.0), whereas that of at least low-grade squamous intraepithelial lesions (SIL) was 8.9 and 2.2/100 (RR, 4.0; CI, 2.6-6.1). HIV status, detection of the presence of human papillomavirus (HPV), CD4 lymphocyte count, and HIV RNA level predicted incidence of abnormal cytology (p <.05); HPV detection and HIV RNA level predicted progression (p <.01); and HPV detection, CD4 lymphocyte count, and HIV RNA level predicted regression (p <.001). Rates of incidence, progression, and regression of abnormal cytology did not differ between HIV seronegative women and seropositive women with CD4 lymphocyte counts >200/mm(3) and HIV RNA levels <4000/ml of similar HPV status. CONCLUSIONS: Although HIV infected women were at high risk for abnormal cytology, high-grade changes were uncommon. HIV status, HPV detection, CD4 lymphocyte count, and HIV RNA level predicted the incidence of cervical cytologic abnormalities. Progression was significantly increased only among the most immunosuppressed women, while regression was significantly reduced in all HIV seropositive women except those with the best controlled HIV disease.

Prevalence, incidence, and type-specific persistence of human papillomavirus in human immunodeficiency virus (HIV)-positive and HIV-negative women.

Human immunodeficiency virus (HIV) infection and related immunosuppression are associated with excess risk for cervical neoplasia and human papillomavirus (HPV) persistence. Type-specific HPV infection was assessed at 6-month intervals for HIV-positive and HIV-negative women (median follow-up, 2.5 and 2.9 years, respectively). The type-specific incidence of HPV infection was determined, and risk factors for HPV persistence were investigated by statistical methods that accounted for repeated measurements. HIV-positive women were 1.8, 2.1, and 2.7 times more likely to have high-, intermediate-, and low-risk HPV infections, respectively, compared with HIV-negative women. In multivariate analysis, high viral signal, but not viral risk category, was independently associated with persistence among HIV-positive subjects (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-2.9). Furthermore, persistence was 1.9 (95% CI, 1.5-2.3) times greater if the subject had a CD4 cell count <200 cells/microL (vs. >500 cells/microL). Thus, HIV infection and immunosuppression play an important role in modulating the natural history of HPV infection.

Pregnancy and infection with human immunodeficiency virus.

During the past decade, there has been a dramatic increase in the number of women infected with HIV and the number of women with clinical AIDS. One of the most prominent features of HIV infection is that it is usually diagnosed during the peak reproductive years, and in 1998, HIV/AIDS was the fourth leading cause of death among women between the ages of 25 and 44 years. For this reason, there has been long-standing concern regarding the obstetric implications of HIV infection: both the impact of pregnancy on possibly accelerating the course of HIV disease and the impact of HIV infection on the course of pregnancy. There appears to be some immunologic changes associated with pregnancy, but they are not dramatic, and immune markers generally resume their prepregnancy values after delivery. With regard to long-term effects of pregnancy on HIV disease progression, no study to date has shown significant increases in mortality or in AIDS incidence associated with pregnancy. Studies have generally been small, however, and none have accounted for antiretroviral therapy usage. Many studies have shown that certain adverse outcomes are more common in HIV-positive pregnant women as compared with HIV-negative pregnant women, and concerns have been raised that spontaneous abortions may be more common among HIV-infected women and that this may impact fertility rates. Although important understanding has been acquired regarding the associations between pregnancy and the course of HIV infection, much remains to be understood. Additional, well-designed studies are clearly needed to rigorously address the many remaining questions that exist. We can anticipate that the resolution of these questions will continue to be of broad public health interest as the epidemic impacts increasing numbers of women, a large fraction of whom will be adolescents.

The relationship of pregnancy to the use of highly active antiretroviral therapy.

OBJECTIVE: Public health agencies have recommended that the criteria for the use of highly active antiretroviral therapy should not be modified because of pregnancy. However, little information has been published with regard to the degree to which these recommendations are being followed. We report here the frequency of highly active antiretroviral therapy use among pregnant women in the Women's Interagency HIV Study and compare the frequencies of its use by pregnant women meeting published criteria for implementing highly active antiretroviral therapy and its use by nonpregnant women meeting the same criteria. STUDY DESIGN: From October 1994 through November 1995, a total of 2059 human immunodeficiency virus type 1-seropositive women were enrolled in a cohort study. Participants were evaluated at baseline and at 6-month intervals with standardized interview instruments. In addition to a general physical examination at each visit, patients had a urine pregnancy test performed and were asked about current pregnancies, pregnancies since the last visit, and which antiretroviral medications they had used since the last visit. Highly active antiretroviral therapy was defined according to 1997 National Institutes of Health guidelines. RESULT: At each calendar interval after October 1996, a greater proportion of nonpregnant women than pregnant women reported the use of highly active antiretroviral therapy. The use of monotherapy declined for both groups during the course of multiple calendar periods (P <.01), although the use of monotherapy remained higher among the pregnant women. In any given calendar period, pregnant women meeting published criteria for highly active antiretroviral therapy use were slightly less likely than similar nonpregnant women to receive highly active antiretroviral therapy (odds ratio, 0.28-0.98). Because of the sample size these differences reached significance in only one calendar period (P =.02). With time pregnant women did demonstrate an increase in the percentage receiving highly active antiretroviral therapy. In nearly all calendar periods a larger percentage of pregnant than nonpregnant women were receiving a regimen that included zidovudine. CONCLUSIONS: Highly active antiretroviral therapy is being received by an increasing percentage of women who meet published criteria for its use, and pregnancy is a relatively small impediment to its use. Further efforts are needed to bolster the use of highly active antiretroviral therapy by all appropriate candidates and to ensure equal access to this therapy for pregnant women. Because of the increasingly frequent use of highly active antiretroviral therapy during pregnancy, ongoing efforts are needed to monitor any long-term effects of in utero exposure to multiple antiretroviral agents.

Intra-laboratory reproducibility of human papillomavirus identification in cervical specimens by a polymerase chain reaction-based assay.

BACKGROUND: polymerase chain reaction (PCR)-based assays for human papillomavirus (HPV) sequences are in wide use in clinical and epidemiological studies. The reproducibility of these assays is not extensively studied. OBJECTIVES: to estimate the intra-laboratory reproducibility of generic and type-specific HPV diagnoses by the MY09/MY11/HMB01 consensus L1 primer-based PCR assay. STUDY DESIGN: systematically collected specimens (n=207) were masked and retested. RESULTS: when specimens negative in both initial and repeat assays were excluded from analysis, the diagnostic reproducibility was 98. 6% for beta-globin, 90.7% for generic HPV (any HPV type), and 76.9% for type-specific HPVs. The reproducibility of type-specific diagnosis increased with increase in signal strength in the hybridization reaction of the initial assay. When a specimen contained five or more HPV types in the initial assay, it was rare to identify all of the HPV types in the repeat assay. CONCLUSIONS: the degree of reproducibility of the PCR diagnosis should be taken into account in the interpretation of HPV data in clinical and epidemiological studies.

Selection by indication of potent antiretroviral therapy use in a large cohort of women infected with human immunodeficiency virus.

To characterize selection factors related to therapy initiation, the authors investigated the extent to which key markers of human immunodeficiency virus (HIV) disease severity were associated with initiation of potent antiretroviral therapy (ART). Logistic regression was used to determine the effects of CD4+ cell count and HIV RNA level on potent ART initiation during 6-month periods among 2,059 HIV-infected US women enrolled in the Women's Interagency HIV Study. Low CD4+ counts and high HIV RNA levels were significantly (p < 0.05) associated with initiation of potent ART. During all periods between April 1996 and March 1998, CD4+ counts were more strongly associated with potent ART initiation than HIV RNA levels were; however, during the last period, both were associated (odds ratio per 100 CD4+-count decrease = 1.17, p < 0.01; odds ratio per 1 log10 increase in HIV RNA level = 1.48, p < 0.05). For a CD4+ count of 500 cells/ml and an HIV RNA level of 5,000 copies/ml, the probability of potent ART initiation increased from 0.5% to 16.8% between October 1995-March 1996 and October 1997-March 1998, suggesting earlier initiation of potent ART. Given the documented occurrence of confounding by indication, prospectively collected, time-dependent data on markers of disease progression and therapy use should be considered when making population-level comparisons before and after introduction of potent ART.

Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women.

Increased risk for cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected women may be explained by repeated positivity of human papillomavirus (HPV) infection facilitated by HIV infection and related immunosuppression. As part of a longitudinal study with semiannual examinations, 268 women in Baltimore, Maryland (of whom 184 were HIV+), provided 1,426 cervicovaginal lavage specimens tested for HPV DNA by a polymerase chain reaction-based assay between 1992 and 1998. HPV positivity and time to HPV clearance according to HIV serostatus and CD4+ cell count were compared using models for correlated binary data and survival analysis. Of the 187 participants who had at least one positive measurement, the probability of subsequent HPV positivity among HIV- women and HIV+ women with CD4+ > or =200 and <200 cells/microl was 47.5%, 78.7%, and 92.9% (p < 0.001). Within-women HPV results were correlated (i.e., clustered) in each group (p < 0.01). Compared with HIV-participants, the relative incidence of HPV clearance was 0.29 and 0.10 among HIV+ women with CD4+ > or =200 and <200 cells/microl (p < 0.001). At the end of follow-up, 11 women had biopsy-confirmed CIN. The association of HIV and CIN (p = 0.014) was fully explained by repeated HPV positivity induced by HIV infection (p = 0.648). Reversal of immunosuppression following potent antiretroviral therapy must be expected to have a dramatic impact on HIV-related CIN.

Causal pathways for CCR5 genotype and HIV progression.

A homozygous 32-bp deletion in the gene encoding CCR5, a major coreceptor for HIV-1, leads to resistance to infection with HIV-1, and heterozygosity for the deletion is associated with delayed disease progression in persons infected with HIV-1. We investigated the effect of CCR5 heterozygosity on disease progression as measured by both CD4+ T-cell count decline and the occurrence of clinical AIDS symptoms. Using a unified statistical model for CD4 count progression and AIDS development, we examined whether the effect of CCR5 heterozygosity on clinical AIDS is direct or indirect through its effect on CD4 counts. Based on data from the Multicenter AIDS Cohort Study, we noted a protective effect of CCR5 heterozygosity on both CD4 cell count progression and on AIDS occurrence. Furthermore, we found that this protective effect on the occurrence of AIDS was completely mediated through an effect on the CD4 marker. Additional adjustment for the effect of an initial viral load measurement indicate that CCR5 heterozygosity did not have predictive value for either CD4 progression or the development of AIDS beyond its association with early viral load.

Use of the terms 'race', 'ethnicity', and 'national origins': a review of articles in the American Journal of Public Health, 1980-1989.

OBJECTIVES: To assess the use of the categories of race, ethnicity, and national origin in recent public health research. METHODS: We reviewed all research articles on human populations published in the American Journal of Public Health from January 1980 through December 1989. Articles were classified by (1) mention of the categories, (2) use of the categories, (3) presence of explicit definitions, and (4) definitional criteria. RESULTS: Specific categories (e.g. 'black', 'Chinese', 'Hispanic') or generic categories (e.g. 'race', 'ethnicity', 'national origin') were mentioned in 461 (50.4%) of 914 articles on human populations. In most studies (65.1%), single categories (e.g. race or ethnicity) were considered; in 1.3% of studies, two terms (e.g. both race and ethnicity) were examined independently; in 1.3%, categories were used interchangeably; in 5.6% of the studies, combined categories (e.g. race-ethnicity) were used; and in 27.5% of the studies, specific population groups were named without reference to a generic category. Explicit definitions of categories were present in only 8.4% of the articles in which the categories were considered. Absence of explicit definitions and use of combined and interchangeable categories suggest a lack of clarity and conceptual consistency in research on race, ethnicity, and national origin-related topics. CONCLUSION: To improve our assessment of differences in health status among racial, ethnic, and national origin groups, research involving these categories should assess their validity and should define concepts clearly, explicitly, and consistently. Such research would minimize misclassification, improve the interpretation of findings, facilitate comparison among studies, and enhance the understanding of causes underlying differences in health status among populations of different racial, ethnic, and national origins.