Roksana Karim

T Cell Activation and Senescence Predict Subclinical Carotid Artery Disease in HIV-Infected Women

Background. Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults. Methods. T cell phenotyping and carotid ultrasound were assessed among 115 HIV-infected women and 43 age- and race/ethnicity-matched HIV-uninfected controls participating in the Womens Interagency HIV Study. Multivariate analyses were used to assess the association of T cell activation (CD38+HLA-DR+) and senescence (CD28−CD57+) with subclinical carotid artery disease. Results. Compared with HIV-uninfected women, frequencies of CD4+CD38+HLA-DR+, CD8+CD38+HLA-DR+, and CD8+CD28−CD57+ T cells were higher among HIV-infected women, including those who achieved viral suppression while receiving antiretroviral treatment. Among HIV-infected women, adjusted for age, antiretroviral medications, and viral load, higher frequencies of activated CD4+ and CD8+ T cells and immunosenescent CD8+ T cells were associated with increased prevalence of carotid artery lesions (prevalence ratiolesions associated with activated CD4+ T cells, 1.6 per SD [95% confidence interval {CI}, 1.1–2.2]; P = .02; prevalence ratiolesions associated with activated CD8+ T cells, 2.0 per SD [95% CI, 1.2–3.3]; P < .01; prevalence ratiolesions associated with senescent CD8+ T cells, 1.9 per SD [95% CI, 1.1–3.1]; P = .01). Conclusions. HIV-associated T cell changes are associated with subclinical carotid artery abnormalities, which may be observed even among those patients achieving viral suppression with effective antiretroviral therapy.

AIDS-Related Burkitt's Lymphoma Versus Diffuse Large-Cell Lymphoma in the Pre–Highly Active Antiretroviral Therapy (HAART) and HAART Eras: Significant Differences in Survival With Standard Chemotherapy

PURPOSE To compare outcomes of patients with HIV-Burkitts lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre-highly active antiretroviral therapy (HAART) versus HAART eras. PATIENTS AND METHODS Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART. RESULTS There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm(3) independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era. CONCLUSION Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.

Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology

Reproductive factors are associated with reduced risk of breast cancer, but less is known about whether there is differential protection against subtypes of breast cancer. Assuming reproductive factors act through hormonal mechanisms they should protect predominantly against cancers expressing oestrogen (ER) and progesterone (PR) receptors. We examined the effect of reproductive factors on subgroups of tumours defined by hormone receptor status as well as histology using data from the NIHCD Womens Contraceptive and Reproductive Experiences (CARE) Study, a multicenter case–control study of breast cancer. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) as measures of relative risk using multivariate unconditional logistic regression methods. Multiparity and early age at first birth were associated with reduced relative risk of ER + PR + tumours (P for trend=0.0001 and 0.01, respectively), but not of ER − PR − tumours (P for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk of both receptor-positive (P for trend=0.0002) and receptor-negative tumours (P=0.0004). Our results were consistent across subgroups of women based on age and ethnicity. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumours. Our results indicate that parity and age at first birth are associated with reduced risk of receptor-positive tumours only, while lactation is associated with reduced risk of both receptor-positive and -negative tumours. This suggests that parity and lactation act through different mechanisms. This study also suggests that reproductive factors have similar protective effects on breast tumours of lobular and ductal origin.

Impact of Highly Active Antiretroviral Therapy on Anemia and Relationship Between Anemia and Survival in a Large Cohort of Hiv-infected Women: Women’s Interagency Hiv Study

BackgroundAnemia is common in HIV-infected individuals and may be associated with decreased survival. ObjectiveTo ascertain the impact of highly active antiretroviral therapy (HAART) on anemia and the relationship between anemia and overall survival in HIV-infected women. MethodsA prospective multicenter study of HIV-1 infection in women. Visits occurred every 6 months, including a standardized history, physical examination, and comprehensive laboratory evaluation. The setting was a university-affiliated clinic at 6 sites in the United States. Participants were 2056 HIV-infected women from the Women’s Interagency HIV Study (WIHS). The outcome measure was anemia, defined as hemoglobin (Hb) <12 g/dL. Survival analysis was based on overall mortality during the follow-up period. ResultsAmong HIV-infected women who were not anemic at baseline, 47% became anemic by 3.5 years of follow-up. On multivariate analysis, the use of HAART was associated with resolution of anemia even when used for only 6 months (odds ratio [OR] = 1.45; P < 0.05). In the multivariate model, a CD4 cell count <200 cells/μL (OR = 0.56; P < 0.001); HIV-1 RNA level ≥50,000 copies/mL (OR = 0.65; P < 0.001), and mean corpuscular volume (MCV) value <80 fL (OR = 0.40; P < 0.001) were also associated with an inability to correct anemia. Similarly, use of HAART for 12 months or more was associated with a protective effect against development of anemia (OR = 0.71; P < 0.001). Among HIV-infected women, anemia was independently associated with decreased survival (hazard ratio [HR] = 2.58; P < 0.001). Other factors associated with decreased survival included a CD4 cell count <200 cells/μL (HR = 5.83; P < 0.001), HIV-1 RNA level ≥50,000 copies/mL (HR = 2.12; P < 0.001), and clinical diagnosis of AIDS (HR = 2.83; P < 0.001). ConclusionsAnemia is an independent risk factor for decreased survival among HIV-infected women. HAART therapy for as little as 6 months is associated with resolution of anemia.

Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy.

PURPOSE To compare the prognostic factors for survival and the validity of the International Prognostic Index (IPI) in patients with HIV-related diffuse large-cell lymphoma (HIV-DLCL) treated with curative intent in the pre-highly active antiretroviral therapy (HAART) era versus the HAART era. PATIENTS AND METHODS We retrospectively reviewed 192 patients with HIV-DLCL diagnosed from 1982 to 2003. Pre-HAART era included 120 patients who did not receive HAART, whereas the HAART era included 72 patients diagnosed after January 1997 who received HAART. RESULTS There were no statistically significant differences in terms of either lymphoma or HIV-related characteristics in the two time periods. The complete response rate improved from 32% in the pre-HAART to 57% in the HAART era (P = .0006), and median survival time improved from 8.3 to 43.2 months (P = .0005). In groups with low-, low-intermediate-, and high-intermediate-risk IPI disease, 3-year overall survival rates were 20%, 22%, and 5% in the pre-HAART era and 64%, 64%, and 50% in the HAART era, respectively. On multivariate analysis, factors independently associated with decreased survival in both periods were increasing IPI scores and failure to attain complete remission, whereas CD4 less than 100 cells/microL predicted shorter survival in only the pre-HAART era. CONCLUSION Prognostic factors and overall survival of patients with HIV-DLCC have changed. Clinical outcomes in patients with HIV-DLCL are now approaching the outcomes of patients with de novo lymphoma.

Variations in Serum Mullerian Inhibiting Substance Between White, Black and Hispanic Women

OBJECTIVE To compare serum müllerian inhibiting substance (MIS) levels between white, black, and Hispanic women to determine whether ovarian aging occurs at a different time course for women of different racial groups. DESIGN Longitudinal study of serum MIS levels in women of different race and ethnicity over two different time points. SETTING Womens Interagency HIV Study, a multicenter prospective cohort study. PATIENT(S) Serum samples obtained from 809 participants (122 white, 462 black, and 225 Hispanic women). INTERVENTION(S) Comparison of serum MIS between women of different race and ethnicity at two time points (median age 37.5 years and 43.3 years). MAIN OUTCOME MEASURE(S) Variation in MIS by race and ethnicity over time, controlling for age, body mass index, HIV status, and smoking. RESULT(S) Compared with white women, average MIS values were lower among black (25.2% lower) and Hispanic (24.6% lower) women, adjusting for age, body mass index, smoking, and HIV status. CONCLUSION(S) There is an independent effect of race and ethnicity on the age-related decline in MIS over time.

Hip fracture in postmenopausal women after cessation of hormone therapy: Results from a prospective study in a large health management organization

Objective:Millions of women in the United States and across the globe abruptly discontinued postmenopausal hormone therapy (HT) after the initial Womens Health Initiative trial publication. Few data describing the effects of HT cessation on hip fracture incidence in the general population are available. We evaluated the impact of HT cessation on hip fracture incidence in a large cohort from the Southern California Kaiser Permanente health management organization. Methods:In this longitudinal observational study, 80,955 postmenopausal women using HT as of July 2002 were followed up through December 2008. Data on HT use after July 2002, antiosteoporotic medication use, and occurrence of hip fracture were collected from the electronic medical record system. Bone mineral density (BMD) was assessed in 54,209 women once during the study period using the dual-energy x-ray absorptiometry scan. Results:After 6.5 years of follow-up, age- and race-adjusted Cox proportional hazard models showed that women who discontinued HT were at 55% greater risk of hip fracture compared with those who continued using HT (hazard ratio, 1.55; 95% CI, 1.36-1.77). Hip fracture risk increased as early as 2 years after cessation of HT (hazard ratio, 1.52; 95% CI, 1.26-1.84), and the risk incrementally increased with longer duration of cessation (P for trend < 0.0001). Longer duration of HT cessation was linearly correlated with lower BMD (&bgr; estimate [SE]) = −0.13 [0.003] T-score SD unit per year of HT cessation; P < 0.0001). Conclusions:Women who discontinued postmenopausal HT had significantly increased risk of hip fracture and lower BMD compared with women who continued taking HT. The protective association of HT with hip fracture disappeared within 2 years of cessation of HT. These results have public health implications with regard to morbidity and mortality from hip fracture.

Activation of CD8 T Cells Predicts Progression of HIV Infection in Women Coinfected with Hepatitis C Virus

BACKGROUND Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression. METHODS Kaplan-Meier and multivariate Cox regression models were used to study the risk of incident clinical AIDS and AIDS-related deaths among 813 HCV-negative women with HIV infection, 87 HCV-positive nonviremic women with HIV coinfection, and 407 HCV-positive viremic women with HIV coinfection (median follow-up time, 5.2 years). For 592 women, the percentages of activated CD4 and CD8 T cells expressing HLA-DR (DR) and/or CD38 were evaluated. RESULTS HCV-positive viremic women had a statistically significantly higher percentage of activated CD8 T cells (P < .001) and a statistically significantly higher incidence of AIDS compared with HCV-negative women (P < .001 [log-rank test]). The AIDS risk was greater among HCV-positive viremic women in the highest tertile compared with the lowest tertile (>43% vs <26%) of CD8(+)CD38(+)DR(+) T cells (hazard ratio, 2.94 [95% confidence interval, 1.50-5.77]; P = .001). This difference was not observed in the HCV-negative women (hazard ratio, 1.87 [95% confidence interval, 0.80-4.35]; P = .16). In contrast, CD4 activation predicted AIDS in both groups similarly. Increased percentages of CD8(+)CD38(-)DR(+), CD4(+)CD38(-)DR(-), and CD8(+)CD38(-)DR(-) T cells were associated with a >60% decreased risk of AIDS for HCV-positive viremic women and HCV-negative women. CONCLUSION HCV-positive viremic women with HIV coinfection who have high levels of T cell activation may have increased risk of AIDS. Earlier treatment of HIV and HCV infection may be beneficial.

Relation of Framingham Risk Score to Subclinical Atherosclerosis Evaluated Across Three Arterial Sites

The Framingham risk score (FRS) is widely used in clinical practice to identify subjects at high risk for developing coronary heart disease. However, FRS may not accurately identify subjects at risk. We measured subclinical atherosclerosis in the coronary arteries and aorta with the presence of calcium and in the common carotid artery by intima-media thickness in 498 healthy subjects. The distribution of these subclinical atherosclerosis measures was evaluated across 3 strata of the FRS. Coronary arteries with the presence of calcium, aorta with the presence of calcium, and carotid artery by intima-media thickness were significantly independently associated with FRS. The FRS increased with the number of arterial sites with atherosclerosis; 69% of the subjects categorized in the low risk group (FRS <10%), 95% of the intermediate risk group (FRS 10% to 20%), and 100% of the high risk group (FRS >20%) had > or = 1 vascular imaging studies demonstrating subclinical atherosclerosis. In the low risk group, subjects with atherosclerosis had a longer history of lifetime smoking compared with those without atherosclerosis. In conclusion, subclinical atherosclerosis is prominent across the spectrum of FRS. Evaluation of subclinical atherosclerosis in different arterial sites in addition to FRS may be useful in targeting subjects for lifestyle and other interventions.

Microalbuminuria is associated with all-cause and AIDS mortality in women with HIV infection.

Objectives:Prevalence of microalbuminuria is increased in patients with HIV. Microalbuminuria is associated with increased mortality in other populations, including diabetics, for whom microalbuminuria testing is standard of care. We investigated whether microalbuminuria is associated with mortality in HIV-infected women not receiving antiretroviral therapy. Methods:Urinalysis for proteinuria and semiquantitative testing for microalbuminuria were performed in specimens from 2 consecutive visits in 1547 HIV-infected women enrolled in the Womens Interagency HIV Study in 1994-1995. Time to death was modeled using proportional hazards analysis. Results:Compared with women without albuminuria, the hazard ratio (HR) for all-cause mortality was increased in women with 1 (HR: 3.4; 95% CI: 2.2 to 5.2) or 2 specimens positive for either proteinuria or microalbuminuria (HR: 3.9; 95% CI: 2.1 to 7.0). The highest risk was observed in women with both specimens positive for proteinuria (HR: 5.8; 95% CI: 3.4 to 9.8). The association between albuminuria and all-cause mortality risk remained significant after adjustment for demographics, HIV disease severity, and related comorbidities. Similar results were obtained for AIDS death. Conclusions:We identified a graded relationship between albuminuria and the risk of all-cause and AIDS mortality.