Higher plasma myeloperoxidase levels are not associated with an increased risk for cardiovascular events in HIV-infected adults.

OBJECTIVES: Elevated myeloperoxidase (MPO) levels are predictive of high cardiovascular (CV) risk in the general population. The value of MPO as a CV marker in the HIV population has not been investigated. METHOD: Medical records were reviewed to identify HIV+ patients with a documented CV event (myocardial ischemia/infarction) and stored plasma samples within 12 months prior to the event. HIV+ adults with no CV history and with similarly available stored plasma samples were site-, age-, and gender-matched 1:1 to cases. RESULTS: We identified 124 participants (62 case-control pairs): 94% male, median age 46 years. Median (IQR) MPO levels (pmoles/L) were lower in cases vs. controls: 292 (235-376) vs. 320 (249-467); p= .004. Cases were more likely to have other CV risk factors, including smoking, hypertension, and higher cholesterol and triglycerides. The observed MPO directional difference persisted after controlling for CV risk factors. In the reduced model, observed differences in MPO remained independently and negatively associated with CV event (p= .03) after adjusting for two positively associated risk factors, differences in cholesterol levels (p= .01), and differences in smoking history (ever smoked vs. never smoked; p= .04). Differences in triglyceride levels and hypertension were not statistically significant independent risk factors in this sample (p> .05). Within cases, MPO was negatively correlated with CD4 count (rs= -0. 40, p= .0023) and age (rs= -0. 34, p= .01). In contrast, age at blood draw was positively correlated with MPO in controls (rs= 0.28, p= .031) and CD4 was uncorrelated (rs= -0. 01, p> .9). No other factors were significantly correlated with MPO within groups. CONCLUSION: In contrast to the general population, higher MPO levels were not predictive of CV events in this study, underscoring the fact that pathways operative in HIV arteriopathy may be distinct from traditional CV disease pathogenesis.

Predictive value of plasma HIV RNA level on rate of CD4 T-cell decline in untreated HIV infection.

CONTEXT: Plasma human immunodeficiency virus (HIV) RNA level predicts HIV disease progression, but the extent to which it explains the variability in rate of CD4 cell depletion is poorly characterized. OBJECTIVE: To estimate the proportion of variability in rate of CD4 cell loss predicted by presenting plasma HIV RNA levels in untreated HIV-infected persons. DESIGN: Repeated-measures analyses of 2 multicenter cohorts, comprising observations beginning on May 12, 1984, and ending on August 26, 2004. Analyses were conducted between August 2004 and March 2006. SETTING: Two cohorts of HIV-infected persons: patients followed up at 4 US teaching medical institutions or participating in either the Research in Access to Care for the Homeless Cohort (REACH) or the San Francisco Men's Health Study (SFMHS) cohorts and participants in the Multicenter AIDS Cohort Study (MACS) cohort. PARTICIPANTS: Antiretroviral treatment-naive, chronically HIV-infected persons (n = 1289 and n = 1512 for each of the 2 cohorts) untreated during the observation period (> or =6 months) and with at least 1 HIV RNA level and 2 CD4 cell counts available. Approximately 35% were nonwhite, and 35% had risk factors other than male-to-male sexual contact. MAIN OUTCOME MEASURES: The extent to which presenting plasma HIV RNA level could explain the rate of model-derived yearly CD4 cell loss, as estimated by the coefficient of determination (R2). RESULTS: In both cohorts, higher presenting HIV RNA levels were associated with greater subsequent CD4 cell decline. In the study cohort, median model-estimated CD4 cell decrease among participants with HIV RNA levels of 500 or less, 501 to 2000, 2001 to 10,000, 10,001 to 40,000, and more than 40,000 copies/mL were 20, 39, 48, 56, and 78 cells/microL, respectively. Despite this trend across broad categories of HIV RNA levels, only a small proportion of CD4 cell loss variability (4%-6%) could be explained by presenting plasma HIV RNA level. Analyses using multiple HIV RNA measurements or restricting to participants with high HIV RNA levels improved this correlation minimally (R2, 0.09), and measurement error was estimated to attenuate these associations only marginally (deattenuated R2 in the 2 cohorts, 0.05 and 0.08, respectively). CONCLUSIONS: Presenting HIV RNA level predicts the rate of CD4 cell decline only minimally in untreated persons. Other factors, as yet undefined, likely drive CD4 cell losses in HIV infection. These findings have implications for treatment decisions in HIV infection and for understanding the pathogenesis of progressive immune deficiency.

Renal dysfunction during high-dose cisplatin therapy and autologous hematopoietic stem cell transplantation: effect of aminoglycoside therapy.

PURPOSE: Renal dysfunction is a common cause of morbidity after cancer therapy and bone marrow transplantation. In this study, we evaluated the effects of aminoglycosides and other nephrotoxic antibiotics on the occurrence of renal dysfunction in patients who received high-dose cisplatin-containing chemotherapy regimens. PATIENTS AND METHODS: The subjects of this analysis were 102 consecutive patients, studied from September 1985 to February 1991, who received high-dose cisplatin, administered as 40 mg/m2 for 5 consecutive days in 3% saline with saline hydration and mannitol diuresis, followed by autologous stem cell transplantation. Renal dysfunction was defined as an increase in serum creatinine greater than or equal to 44.2 mumol/L above baseline. RESULTS: Characteristics of the 43 patients who were given aminoglycosides were similar to those in patients who did not receive aminoglycosides with respect to initial renal function, age, cancer type, and previous exposure to cisplatin. Patients who experienced serious treatment-related toxicities such as hemorrhage or septicemia were more likely to have received aminoglycoside antibiotics (p = 0.005). A multivariate analysis showed that increased duration of neutropenia, advanced patient age, and amphotericin B use were predictors of renal failure. Aminoglycoside therapy did not significantly increase the risk of renal dysfunction. CONCLUSIONS: Our data suggest that with appropriate supportive care measures, aminoglycosides can safely be administered to febrile, neutropenic patients who recently have received high-dose cisplatin therapy.

Induction of HIV type 1 expression correlates with T cell responsiveness to mycobacteria in patients coinfected with HIV type 1 and Mycobacterium tuberculosis.

An in vitro mononuclear cell system to model the microenvironment of coinfection with HIV-1 and Mycobacterium tuberculosis (MTB) was developed. This cellular system was used to assess the interaction of MTB-infected monocytes and T cells from dually infected HIV-1/TB patients with pulmonary tuberculosis (TB). Subjects with higher induction of HIV-1 gag/pol mRNA expression after MTB stimulation had increased MTB-specific T cell IFN-gamma and TNF-alpha production. Lack of HIV-1 mRNA induction did not correlate with increased induction of regulatory T cells (T-reg) as measured by MTB-induced Foxp3 mRNA. HIV-1 induction did not significantly correlate with clinical parameters including plasma HIV-1 viral load or CD4(+) T cell count. These data model MTB-induced HIV-1 replication at the microenvironment of MTB reactivation/infection. The data suggest that the magnitude of MTB-specific T cell responses drives local viral pathogenesis regardless of the stage of HIV-1 disease as reflected by plasma viral load or CD4(+) T cell count.

Differences in the growth of paired Ugandan isolates of Mycobacterium tuberculosis within human mononuclear phagocytes correlate with epidemiological evidence of strain virulence.

Previous studies have suggested that isolates of Mycobacterium tuberculosis responsible for tuberculosis outbreaks grow more rapidly within human mononuclear phagocytes than do other isolates. Clinical scenarios suggesting virulence of specific M. tuberculosis isolates are readily identified. Determination of appropriate "control" isolates for these studies is more problematic, but equally important for validating these assays and, ultimately, for identifying biologic differences between M. tuberculosis strains that contribute to virulence. We utilized the database from a study of Ugandan tuberculosis patients and their household (HH) contacts to identify M. tuberculosis isolates transmitted within HH and nontransmitted control isolates. Isolate pairs were evaluated from matched HH in each of three clinical scenarios: (i) coprevalent disease and no disease, (ii) incident disease and no disease, and (iii) M. tuberculosis infection (purified protein derivative [PPD] positive) and no infection (PPD negative). Intracellular growth of paired organisms was determined in a blinded fashion using two models of intracellular infection in which we have previously demonstrated correlation between intracellular growth and strain virulence, primary human monocytes (MN) and THP-1 human macrophage-like cells. In both models, transmitted isolates from coprevalent disease HH displayed more rapid growth than nontransmitted control isolates. In the THP-1 model, this was also true of transmitted isolates from HH with incident disease and their controls. Differences in production of tumor necrosis factor alpha and interleukin-10 by matched isolates showed correlation with growth patterns in the THP-1 cells but not in MN. Paired isolates characterized in this manner may be of particular interest for further investigations of the virulence of M. tuberculosis.