Influence of Sex/Gender and Race on Responses to Raltegravir Combined With Tenofovir-Emtricitabine in Treatment-Naive Human Immunodeficiency Virus-1 Infected Patients: Pooled Analyses of the STARTMRK and QDMRK Studies.

BACKGROUND: Antiretroviral therapy in human immunodeficiency virus (HIV)-infected women and blacks merits particular scrutiny because these groups have been underrepresented in clinical trials. METHODS: To document the effects of raltegravir across sex and racial lines, we conducted a pooled subgroup analysis of the efficacy and safety of raltegravir 400 mg BID plus tenofovir-emtricitabine by sex (women vs men) and self-identified race (black vs non-black) using phase 3 studies in treatment-naive patients. RESULTS: Study participants included 42 black women, 102 non-black women, 48 black men, and 477 non-black men. Clade B infections were less common in women (43.8%) than men (84.6%) and in blacks (45.6%) than non-blacks (80.5%). Baseline CD4 counts were ≤200 cells/µL in 52.2% of blacks and 31.6% of non-blacks. Black men had the largest proportion of patients with baseline CD4 counts/µL and the highest nontreatment-related discontinuation rate among the 4 sex-by-race subgroups. Human immunodeficiency virus-ribonucleic acid levels/mL were achieved at week 48 in 92.7% (95% confidence interval [CI], 80.1-98.5) of black women, 93.6% (95% CI, 86.6-97.6) of non-black women, 82.9% (95% CI, 67.9-92.8) of black men, and 91.4% (95% CI, 88.4-93.8) of non-black men. Serious clinical adverse events were reported in 9.0% of women versus 8.8% of men and in 11.1% of blacks versus 8.5% of non-blacks. CONCLUSIONS: In this post hoc analysis of patients with previously untreated HIV-1 infection receiving raltegravir plus tenofovir-emtricitabine, generally comparable results were achieved across sex and racial subgroups. However, black men had a lower response rate than either black women or non-black men, partially attributable to lower baseline CD4 counts and higher discontinuation rates

Inflammatory biomarker changes and their correlation with Framingham cardiovascular risk and lipid changes in antiretroviral-naive HIV-infected patients treated for 144 weeks with abacavir/lamivudine/atazanavir with or without ritonavir in ARIES.

Propensity for developing coronary heart disease (CHD) is linked with Framingham-defined cardiovascular risk factors and elevated inflammatory biomarkers. Cardiovascular risk and inflammatory biomarkers were evaluated in ARIES, a Phase IIIb/IV clinical trial in which 515 antiretroviral-naive HIV-infected subjects initially received abacavir/lamivudine + atazanavir/ritonavir for 36 weeks. Subjects who were virologically suppressed by week 30 were randomized 1:1 at week 36 to either maintain or discontinue ritonavir for an additional 108 weeks. Framingham 10-year CHD risk scores (FRS) and risk category o

HIV policy: the path forward--a joint position paper of the HIV Medicine Association of the Infectious Diseases Society of America and the American College of Physicians.

Executive Summary The American College of Physicians (ACP) and the Infectious Diseases Society of America (IDSA) have jointly published 3 policy statements on AIDS, the first in 1986 [1], the second in 1988 [2], and the third in 1994 [3]. In 2001, the IDSA created the HIV Medicine Association (HIVMA), and this updated policy paper is a collaboration between the ACP and the HIVMA of the IDSA. Since the last statement, many new developments call for the need to reexamine and update our policies relating to HIV infection. First, there have been major advances in treatment for HIV infection that have transformed HIV/AIDS from a terminal illness to a chronic disease for many of those who have access to potent therapies and expert medical care [4]. Second, there has been a profound expansion and intensification of the global HIV pandemic, particularly in sub-Saharan Africa, coupled with significant US leadership and resources aimed at providing prevention and care services to affected populations in developing countries. Third, the concerns that were prevalent in the mid-1990s regarding the possibility of HIV transmission in health care settings have ultimately proven to be unfounded as the result of the adoption of universal precautions in those settings. In this article, we emphasize the public health and clinical imperatives for earlier identification of persons with HIV infection; the urgent need to expand access to state-of-the-art HIV care and treatment for infected individuals; the need for access to comprehensive prevention and education for those living with and those at risk for HIV infection; and the need for stronger national leadership to respond to the HIV epidemic in the United States and in the developing world. In December 2008, the ACP and HIVMA released a guidance statement on screening for HIV infection in health care settings that recommended that clinicians adopt routine screening for HIV infection and encourage patients to be tested. Also included in the guidance statement is a recommendation that clinicians determine the need for additional screening on an individual basis

A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less

Background: The efficacy and safety of adding a protease inhibitor to two nucleoside analogues to treat human immunodeficiency virus type 1 (HIV-1) infection are not clear. We compared treatment with the protease inhibitor indinavir in addition to zidovudine and lamivudine with treatment with the two nucleosides alone in HIV-infected adults previously treated with zidovudine. Methods: A total of 1156 patients not previously treated with lamivudine or protease inhibitors were stratified according to CD4 cell count (50 or fewer vs. 51 to 200 cells per cubic millimeter) and randomly assigned to one of two daily regimens: 600 mg of zidovudine and 300 mg of lamivudine, or that regimen with 2400 mg of indinavir. Stavudine could be substituted for zidovudine. The primary end point was the time to the development of the acquired immunodeficiency syndrome (AIDS) or death. Results: The proportion of patients whose disease progressed to AIDS or death was lower with indinavir, zidovudine (or stavudine), and lamivudine (6 percent) than with zidovudine (or stavudine) and lamivudine alone (11 percent; estimated hazard ratio, 0.50; 95 percent confidence interval, 0.33 to 0.76; P�0.001). Mortality in the two groups was 1.4 percent and 3.1 percent, respectively (estimated hazard ratio, 0.43; 95 percent confidence interval, 0.19 to 0.99; P=0.04). The effects of treatment were similar in both CD4 cell strata. The responses of CD4 cells and plasma HIV-1 RNA paralleled the clinical results. Conclusions: Treatment with indinavir, zidovudine, and lamivudine as compared with zidovudine and lamivudine alone significantly slows the progression of HIV-1 disease in patients with 200 CD4 cells or fewer per cubic millimeter and prior exposure to zidovudine. (N Engl J Med 1997;337:725-33.

Podocyte specific knock out of selenoproteins does not enhance nephropathy in streptozotocin diabetic C57BL/6 mice

<p>Abstract</p> <p>Background</p> <p>Selenoproteins contain selenocysteine (Sec), commonly considered the 21^stgenetically encoded amino acid. Many selenoproteins, such as the glutathione peroxidases and thioredoxin reductases, protect cells against oxidative stress by functioning as antioxidants and/or through their roles in the maintenance of intracellular redox balance. Since oxidative stress has been implicated in the pathogenesis of diabetic nephropathy, we hypothesized that selenoproteins protect against this complication of diabetes.</p> <p>Methods</p> <p>C57BL/6 mice that have a podocyte-specific inability to incorporate Sec into proteins (denoted in this paper as PodoTrsp^-/-) and control mice were made diabetic by intraperitoneal injection of streptozotocin, or were injected with vehicle. Blood glucose, body weight, microalbuminuria, glomerular mesangial matrix expansion, and immunohistochemical markers of oxidative stress were assessed.</p> <p>Results</p> <p>After 3 and 6 months of diabetes, control and PodoTrsp^-/-mice had similar levels of blood glucose. There were no differences in urinary albumin/creatinine ratios. Periodic acid-Schiff staining to examine mesangial matrix expansion also demonstrated no difference between control and PodoTrsp^-/-mice after 6 months of diabetes, and there were no differences in immunohistochemical stainings for nitrotyrosine or NAD(P)H dehydrogenase, quinone 1.</p> <p>Conclusion</p> <p>Loss of podocyte selenoproteins in streptozotocin diabetic C57BL/6 mice does not lead to increased oxidative stress as assessed by nitrotyrosine and NAD(P)H dehydrogenase, quinone 1 immunostaining, nor does it lead to worsening nephropathy.</p

MFA12 (MFA 2012)

Catalogue of a culminating student exhibition held at the Mildred Lane Kemper Art Museum May 4-Aug. 6, 2012. Contents include Introduction / Buzz Spector -- Think, make, show and tell / Patricia Olynyk -- Ifeoma Ugonnwa Anyaeji -- J.E. Baker / Elissa Yukiko Weichbrodt -- Natalie Baldeon / Emily Hanson -- As in a turning gear : E. Thurston Belmer / Rickey Laurentiis -- Lauren Cardenas / Nicholas Tamarkin -- Megan Sue Collins / Catherine Chiodo -- Adrian Cox -- Maya Durham / Dolly Laninga -- Erin Falker / Melissa Olson -- St. Louis dreamscape : Jieun Kim / Caitlin Tyler -- Howard Krohn -- Scape : Robert Long / Robert Whitehead -- Marie Bannerot McInerney / Elissa Yukiko Weichbrodt -- Ghost : Nikki McMahan / Rickey Laurentiis -- Michael T. Meier -- Katie Millitzer -- Reid G. Norris / Ross Rader -- Kathleen Perniciaro / Melissa Olson -- Emily Squires / Nicholas Tamarkin -- Jamie Presson Wells -- Whitney Lorene Wood / Reid G. Norris -- Andrew Woodard -- Kelly K. Wright -- Contributors -- About the Sam Fox School.https://openscholarship.wustl.edu/books/1003/thumbnail.jp

Safety, Tolerability, and Efficacy of Raltegravir in a Diverse Cohort of HIV-Infected Patients: 48-Week Results from the REALMRK Study

The racial diversity and gender distribution of HIV-infected patients make it essential to confirm the safety and efficacy of raltegravir in these populations. A multicenter, open-label, single-arm observational study was conducted in a diverse cohort of HIV-infected patients (goals: ≥25% women; ≥50% blacks in the United States), enrolling treatment-experienced patients failing or intolerant to current antiretroviral therapy (ART) and treatment-naive patients (limited to ≤20%). All patients received raltegravir 400 mg b.i.d. in a combination antiretroviral regimen for up to 48 weeks. A total of 206 patients received study treatment at 34 sites in the United States, Brazil, Dominican Republic, Jamaica, and South Africa: 97 (47%) were female and 153 (74%) were black [116 (56%) in the United States]. Of these, 185 patients were treatment experienced: 97 (47%) were failing and 88 (43%) were intolerant to current therapy; 21 patients (10%) were treatment naive. Among treatment-intolerant patients, 55 (63%) had HIV-1 RNA<50 copies/ml at baseline. Overall, 15% of patients discontinued: 13% of men, 18% of women, 14% of blacks, and 17% of nonblacks. At week 48, HIV RNA was <50 copies/ml in 60/94 (64%) patients failing prior therapy, 61/80 (76%) patients intolerant to prior therapy, and 16/21 (76%) treatment-naive patients. Response rates were similar for men vs. women and black vs. nonblack patients. Drug-related clinical adverse events were reported by 8% of men, 18% of women, 14% of blacks, and 9% of nonblacks. After 48 weeks of treatment in a diverse cohort of HIV-infected patients, raltegravir was generally safe and well tolerated with potent efficacy regardless of gender or race

Presentation and Outcomes of Infants With Idiopathic Cholestasis: A Multicenter Prospective Study

Objectives: The aim of the study was to determine the frequency and natural history of infantile idiopathic cholestasis (IC) in a large, prospective, multicenter cohort of infants. Methods: We studied 94 cholestatic infants enrolled up to 6 months of age in the NIDDK ChiLDReN (Childhood Liver Disease Research Network) "PROBE" protocol with a final diagnosis of IC; they were followed up to 30 months of age. Results: Male sex (66/94; 70%), preterm birth (22/90 with data; 24% born at 1 mg/dL and/or ALT > 35 U/L; n = 7), and exited healthy (resolved disease per study site report but without documented biochemical resolution; n = 34). Biochemical resolution occurred at median of 9 months of age. GGT was <100 U/L at baseline in 34 of 83 participants (41%). Conclusions: Frequency of IC and of death or liver transplant was less common in this cohort than in previously published cohorts, likely because of recent discovery and diagnosis of genetic etiologies of severe/persistent cholestasis that previously were labeled as idiopathic. Preterm birth and other factors associated with increased vulnerability in neonates are relatively frequent and may contribute to IC. Overall outcome in IC is excellent. Low/normal GGT was common, possibly indicating a role for variants in genes associated with low-GGT cholestasis-this warrants further study

Triple-Nucleoside Regimens versus Efavirenz-Containing Regimens for the Initial Treatment of HIV-1 Infection

BACKGROUND Regimens containing three nucleoside reverse-transcriptase inhibitors offer an alternative to regimens containing nonnucleoside reverse-transcriptase inhibitors or protease inhibitors for the initial treatment of human immunodeficiency virus type 1 (HIV-1) infection, but data from direct comparisons are limited. METHODS This randomized, double-blind study involved three antiretroviral regimens for the initial treatment of subjects infected with HIV-1: zidovudine-lamivudine-abacavir, zidovudine-lamivudine plus efavirenz, and zidovudine-lamivudine-abacavir plus efavirenz. RESULTS We enrolled a total of 1147 subjects with a mean baseline HIV-1 RNA level of 4.85 log10(71,434) copies per milliliter and a mean CD4 cell count of 238 per cubic millimeter were enrolled. A scheduled review by the data and safety monitoring board with the use ofprespecified stopping boundaries led to a recommendation to stop the triple-nucleoside group and to present the results in the triple-nucleoside group in comparison with pooled data from the efavirenz groups. After a median follow-up of 32 weeks, 82 of 382 subjects in the triple-nucleoside group (21 percent) and 85 of 765 ofthose in the combined efavirenz groups (11 percent) had virologic failure; the time to virologic failure was significantly shorter in the triple-nucleoside group (P<0.001). This difference was observed regardless of the pretreatment HIV-1 RNA stratum (at least 100,000 copies per milliliter or below this level; P≤0.001 for both comparisons). Changes in the CD4 cell count and the incidence of grade 3 or grade 4 adverse events did not differ significantly between the groups. CONCLUSIONS In this trial of the initial treatment of HIV-1 infection, the triple-nucleoside combination ofabacavir, zidovudine, and lamivudine was virologically inferior to a regimen containing efavirenz and two or three nucleosides