Showing papers by "Kathryn Anastos published in 2003"

Effect of Highly Active Antiretroviral Therapy on Time to Acquired Immunodeficiency Syndrome or Death using Marginal Structural Models

Abstract: To estimate the net (i.e., overall) effect of highly active antiretroviral therapy (HAART) on time to acquired immunodeficiency syndrome (AIDS) or death, the authors used inverse probability-of-treatment weighted estimation of a marginal structural model, which can appropriately adjust for time-varying confounders affected by prior treatment or exposure. Human immunodeficiency virus (HIV)-positive men and women (n = 1,498) were followed in two ongoing cohort studies between 1995 and 2002. Sixty-one percent (n = 918) of the participants initiated HAART during 6,763 person-years of follow-up, and 382 developed AIDS or died. Strong confounding by indication for HAART was apparent; the unadjusted hazard ratio for AIDS or death was 0.98. The hazard ratio from a standard time-dependent Cox model that included time-varying CD4 cell count, HIV RNA level, and other time-varying and fixed covariates as regressors was 0.81 (95% confidence interval: 0.61, 1.07). In contrast, the hazard ratio from a marginal structural survival model was 0.54 (robust 95% confidence interval: 0.38, 0.78), suggesting a clinically meaningful net benefit of HAART. Standard Cox analysis failed to detect a clear net benefit, because it does not appropriately adjust for time-dependent covariates, such as HIV RNA level and CD4 cell count, that are simultaneously confounders and intermediate variables.

Human Papillomavirus Type 16 and Immune Status in Human Immunodeficiency Virus-Seropositive Women

Abstract: Background Human papillomavirus (HPV) type 16 is etiologically associated with approximately half of all cervical cancers. It is important, therefore, to determine the characteristics that distinguish HPV16 from other HPV types. A preliminary result based on cross-sectional baseline data in the Women's Interagency Human Immunodeficiency Virus (HIV) Study (WIHS) suggested that the prevalence of HPV16 might have a weaker association with immune status in HIV-seropositive women than that of other HPV types. To address this issue, we examined HPV test results from repeated study visits in the WIHS and from an independent study, the HIV Epidemiology Research Study (HERS). Methods HIV-seropositive women in the WIHS (n = 2058) and in the HERS (n = 871) were assessed semiannually. HPV DNA was detected in cervicovaginal lavage specimens by using polymerase chain reaction assays. Prevalence ratios were used to compare the prevalence of each HPV type in women with the lowest CD4+ T-cell counts ( or =500 T cells/mm3). A summary prevalence ratio for each HPV type (i.e., across visits and studies) was estimated using generalized estimating equations. The association of CD4+ T-cell stratum with type-specific HPV incidence was measured using multivariable Cox regression models. All statistical tests were two-sided. Results The prevalence ratio for HPV16 was low compared with that of other HPV types at every study visit in both cohorts. The generalized estimating equation summary prevalence ratio for HPV16 (1.25, 95% confidence interval [CI] = 0.97 to 1.62) was the smallest measured, and it was statistically significantly lower than that of all other HPV types combined (P =.01). The association of CD4+ T-cell stratum with HPV16 incidence was also among the smallest measured (hazard ratio = 1.69, 95% CI = 1.01 to 2.81). Conclusions The prevalent and incident detection of HPV16 is more weakly associated with immune status in HIV-seropositive women than that of other HPV types, suggesting that HPV16 may be better at avoiding the effects of immune surveillance, which could contribute to HPV16's strong association with cervical cancer.

Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women

Abstract: Objective To assess the association between protease inhibitor (PI) use and the incidence of diabetes mellitus (DM) among participants in the Women's Interagency HIV Study. Design Prospective multicenter cohort study. The diagnosis of DM was based on self-report at semiannual interviews conducted from 1994 to 1998. Setting Six inner-city clinical sites in the United States (Brooklyn, NY; Bronx, NY; Washington, DC; Chicago, IL; San Francisco, CA; and Los Angeles, CA). Participants A total of 1785 nonpregnant women who had no history of prior DM. The women made up four groups: 1) PI users (n = 609, person-years [PY] at risk = 707); 2) reverse transcriptase inhibitor (RTI)-only users (n = 932, PY = 1486); 3) HIV-infected women reporting no antiretroviral therapy (ART) ever (n = 816, PY = 1480); and 4) HIV-uninfected women (n = 350, PY = 905). Main outcomes Incidence of DM and median body mass index (BMI) from 1995 to 1998 were compared among the four groups. Results Sixty-nine incident cases of DM occurred among 1785 women (1.5 cases per 100 PY; 95% CI: 1.2-1.9). The incidence of DM among PI users was 2.8 cases per 100 PY (2.8%) versus 1.2% among both RTI users and women on no ART (95% CI: 1.6-4.1 [PI]; 0.7-1.8 [RTI and no ART]; P = 0.01 for comparison of the PI group with the RTI group) and 1.4% among HIV-uninfected women (95% CI: 0.7-2.2, P = 0.06 for comparison with PI group). Weight gain was not associated with either PI or RTI use. Multivariate models identified PI use (hazard ratio [HR] = 2.90 [95% CI: 1.50-5.60]; P = 0.002), age (HR = 1.75 per 10 years [95% CI: 1.31-2.34]; P = 0.0002) and BMI as independent risk factors for DM. Conclusions PI use was associated with a threefold increase in the risk of reporting incident DM. Routine screening for diabetes, particularly among older and heavier patients using PI therapy, is advisable.

HIV-1 in genital tract and plasma of women: Compartmentalization of viral sequences, coreceptor usage, and glycosylation

Abstract: Worldwide, 90% of HIV-1 infections are transmitted heterosexually. Because the genital mucosa are the sites of initial contact with HIV-1 for most exposed individuals, study of the virus from the genital tract is critical for the development of vaccines and therapeutics. Previous analyses of HIV-1 in various tissues have documented compartmentalization of viral genomes. Whether compartmentalization was associated with viral phenotypic differences or immune status, however, was not well understood. We compared HIV-1 gp120 env sequences from the genital tract and plasma of 12 women. Eight women displayed compartmentalized HIV-1 RNA genomes, with viral sequences from each site that were clearly discrete, yet phylogenetically related. The remaining four exhibited env sequences that were intermingled between the two sites. Women with compartmentalized HIV-1 genomes had higher CD4+ cell counts than those displaying intermingled strains (P = 0.02). Intrapatient HIV-1 recombinants comprising sequences that were characteristic of both sites were identified. We next compared viral phenotypes in each compartment. HIV-1 coreceptor usage was often compartmentalized (P ≤ 0.01). The number of N-linked glycosylation sites, associated with neutralization resistance, also differed between compartments (P < 0.01). Furthermore, disparities between the density of gp120 glycosylations in each compartment correlated with higher CD4+ counts (P = 0.03). These data demonstrate that the genital tract and plasma can harbor populations of replicating HIV-1 with different phenotypes. The association of higher CD4+ cell counts with compartmentalization of viral genomes and density of gp120 glycosylations suggests that the immune response influences the development of viral genotypes in each compartment. These findings are relevant to the prevention and control of HIV-1 infection.

Serum immunoglobulin G response to human papillomavirus type 16 virus-like particles in human immunodeficiency virus (HIV)-positive and risk-matched HIV-negative women.

Abstract: Serum samples from 2008 human immunodeficiency virus (HIV)-positive and 551 HIV-negative women were tested for immunoglobulin A (IgA) to human papillomavirus (HPV) type 16 capsids. IgA seropositivity was lower than previously reported IgG seropositivity (7% vs. 51%), but, like IgG antibodies, HPV 16 IgA was associated with sexual behavior, cervicovaginal HPV 16 DNA, and cytological abnormalities. IgA seropositivity was higher in HIV-positive women than in HIV-negative women (7.7% vs. 4.9%; P=.02), but the association was lost after adjustment for HPV 16 cervicovaginal infection. IgA, but not IgG, seropositivity was associated with progression to high-grade cytological abnormalities (relative hazard [RH], 2.2 [95% confidence interval, 1.2-4.2]), raising the possibility that an IgA response to HPV 16, as described for other DNA viruses, may be a marker of persistent viral replication. The risk of incident infection with non-16-related HPV types was increased in IgA seropositive women (RH, 1.8 [95% confidence interval, 1.3-2.6]), compared with seronegative women (RH, 2.2 [95% confidence interval, 0.9-5.4]), but there was no difference in the risk of incident HPV 16 or HPV 16-related infections. This may be evidence of partial type-specific or clade-specific immunity conferred by seropositivity to HPV 16 capsids.

Serum albumin is a powerful predictor of survival among HIV-1-infected women.

Abstract: BACKGROUND We previously reported that single measurements of albumin strongly predict survival in HIV-1-infected women independent of disease-specific markers. We now extend this to the use of serial measurements and single albumin values prior to initiation of highly active antiretroviral therapy. DESIGN Prospective cohort study of 1941 women enrolled at six sites in the Women's Interagency HIV Study. RESULTS Albumin fell 0.44 g/L/y in 1627 women who survived and at a faster rate in 397 who died (1.54 g/L/y; p 42 g/L. The RH of serum albumin or =200 cells/micro L was 8.2 [95% CI: 4.2-15.8]) versus only 3.8 [95% CI: 2.4-6.1] in those with counts 42 g/L) than were other factors. CONCLUSION Serum albumin is a strong independent predictor of mortality in HIV-1-infected women after adjustment for known disease markers and may be useful for clinical monitoring.

Effect of hormonal contraceptive use on plasma HIV-1-RNA levels among HIV-infected women.

Abstract: We compared the HIV-1-RNA and CD4 lymphocyte counts from users and non-users of hormonal contraception cross-sectionally upon entry into the Women's Interagency HIV Study, and again longitudinally. There did not appear to be an association between hormonal contraception use and HIV-1-RNA levels in our study. There was a small increase in CD4 cell counts among hormonal users of doubtful clinical significance.

CC Chemokine Receptor 5 Genotype and Susceptibility to Transmission of Human Immunodeficiency Virus Type 1 in Women

Abstract: Human immunodeficiency virus type 1 (HIV-1) currently infects ∼40 million people worldwide [1]. More than 95% of all new cases occur in developing countries, with heterosexual transmission being the predominant route of infection [1]. Rates of HIV-1 infection continue to increase, particularly among nonwhites and women [1]. In sub-Saharan Africa, a region that accounts for 70% of infected individuals globally, women with HIV-1 now outnumber men with HIV-1 [1]. Host differences may contribute to the rapid spread of HIV-1 in some areas of the world; specific genetic traits have been found to influence susceptibility to HIV-1 transmission and disease progression. In addition to CD4, the primary HIV-1 receptor, a functional secondary receptor is required to initiate infection. Human β-chemokine receptors serve this function, with CCR5 serving as coreceptor for macrophage-tropic strains of HIV-1 [2]. A 32-bp deletion (Δ32) in the CCR5 gene renders this receptor nonfunctional, and cells that are homozygous for this mutation are highly resistant to infection by macrophage-tropic strains of HIV-1 [3]. The mutation is most common in white populations, where the frequency of the Δ32 allele ranges from 4% to 16%; ∼20% of whites are heterozygous, and 1% are homozygous for Δ32 [4]. However, this allele is less common among US blacks and Latinas and was absent in Africans and Asian populations studied in anthropological surveys and investigations of non–HIV-related conditions [4]. Investigation of large cohorts of individuals exposed sexually or parenterally to HIV-1 found that the homozygous Δ32 mutation confers a high level of resistance to infection [5–8]. These studies, primarily composed of white men, also found that Δ32 heterozygotes exhibit delayed HIV-1 disease progression but were not protected against transmission [6–8]. However, a more recent study of high-risk HIV-1–seronegative men did demonstrate partial protection against HIV-1 infection in those with the Δ32 heterozygous genotype [9]. Because Δ32 heterozygotes of either sex express a reduced number of CCR5 receptors, compared with individuals with the wild-type genotype, the partial protection and delayed disease progression in heterozygotes may be related to the decreased number of CCR5 receptors and the resulting decreased virus load. Transmission studies involving women showed variable results; 2 studies suggested that the heterozygous state confers partial protection against HIV-1 infection [5, 10], whereas 3 other studies did not [9, 11, 12]. However, all the previous analyses had a suboptimal statistical power for assessing this question, with no more than 630 women in each study. Recently, investigators constructed a mathematical model of the dynamics of HIV-1 transmission in populations with or without the Δ32 mutation. This model predicted that the Δ32 allele would slow the heterosexual spread of the epidemic in populations where the mutation was common [13]. This prediction, coupled with the results from previous cohort studies, points out the importance of studying the role of the Δ32 deletion in HIV-1 transmission in a larger cohort of women. Studies have documented sex-specific differences in HIV-1 transmission, infection, and disease progression [10, 14–18]. Because the routes and mechanisms of HIV-1 infection may differ in significant ways between men and women, we investigated the relationship of CCR5 genotype to the likelihood of HIV-1 infection among women enrolled in the Women's Interagency HIV Study (WIHS), a large study of HIV-1 infection in women conducted in 5 US cities.