QT-Interval Prolongation, Torsades de Pointes, and Heart Failure With EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: Systematic Review.

A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC.

Enhancing Pharmacovigilance from the US Experience: Current Practices and Future Opportunities.

This review is intended to present perspectives from the US experience in enhancing pharmacovigilance on current practices and future opportunities. Best practices concepts could be applied worldwide through the presentation of how three pillars of pharmacovigilance: (1) medical and scientific excellence, (2) operational and compliance excellence, and (3) knowledge sharing and experts development in the field could serve as a framework for the establishment of an efficient and successful global pharmacovigilance system.

Prevalence and cost of HIV-associated weight loss in a managed care population.

OBJECTIVE: To estimate the prevalence of HIV-associated weight loss among HIV patients in a US managed care population, and compare demographic and clinical characteristics of HIV patients with and without evidence of HIV-associated weight loss. RESEARCH DESIGN AND METHODS: A retrospective observational study was conducted using a large, geographically diverse US managed care population to identify commercial enrollees with HIV/AIDS from 1/1/2005-7/31/2007, based on a combination of HIV/AIDS diagnosis codes or antiretroviral treatment. HIV-associated weight loss status was defined according to an algorithm combining evidence for weight loss-associated conditions, anorexia symptoms, and various treatments for weight loss or wasting. Among HIV patients continuously enrolled in the health plan for one year, patient demographics, treatments, and comorbidities were compared between patients with and without evidence for weight loss. RESULTS: A total of 22,535 patients with HIV/AIDS were identified, including 2098 who met the criteria for weight loss (estimated prevalence 9.3%; 95% CI: 8.9% - 9.7%). Among 12,187 continuously enrolled patients with HIV, 1006 (8.3%) had evidence of HIV-associated weight loss. Patients with HIV-associated weight loss were older (44.1 vs. 42.6 years), and more men had HIV-associated weight loss than women (8.8% vs. 5.3%). A number of comorbidities were more common among patients with HIV-associated weight loss. On average, these patients also had more ambulatory (24.0 vs. 13.4), ER (1.4 vs. 0.8), and inpatient visits (0.5 vs. 0.1). Total annual health care costs for patients with HIV-associated weight loss were more than double (mean $45,686 vs. $19,960) the costs for HIV patients without weight loss. CONCLUSIONS: Despite the availability of effective antiretroviral therapy, weight loss remains a problem among patients with HIV. Based on this analysis, almost 1 in 10 managed care patients with HIV have evidence of HIV-associated weight loss. These patients tend to have more comorbidities, use more health care resources, and incur greater costs compared to patients without HIV-associated weight loss. Patients with HIV-associated weight loss were generally sicker than the non-weight loss cohort; thus, the increased costs observed in this population may not be directly or wholly attributable to HIV-associated weight loss. In addition, limitations common to analyses of administrative claims data should be considered when interpreting these results.

Treatment options for HIV-associated central fat accumulation.

Central fat accumulation is increasingly recognized as a problem for patients with HIV infection. The term "lipodystrophy" has been used to describe collectively a constellation of body habitus changes and metabolic abnormalities commonly observed in HIV-infected patients, particularly since the advent of highly active antiretroviral therapy. Visceral fat accumulation can place patients at increased risk of coronary artery disease.Furthermore, body shape changes are a source of distress to patients that may compromise treatment adherence.Reduction of abdominal obesity can therefore be considered part of therapy in HIV-positive patients with visceral adipose tissue (VAT) accumulation. Currently, there are no drugs approved by the Food and Drug Administration for the treatment of HIV-associated central fat accumulation. Lifestyle modifications such as diet and exercise and switching antiretroviral therapies appear to be of limited value in reducing VAT. Metformin has shown some benefit in reducing VAT but at the expense of accelerating peripheral fat loss, and the thiazolidinediones have no effect on VAT. Similarly, testosterone does not appear to reduce VAT in these patients,and there are no data on anabolic steroids. Two large, randomized controlled trials have demonstrated the efficacy of recombinant human growth hormone (rhGH) in reducing visceral adipose tissue. There are also promising data regarding treatment with growth hormone releasing hormone (GHRH).

Role of recombinant human growth hormone in HIV-associated wasting and cachexia: pathophysiology and rationale for treatment.

BACKGROUND: Wasting, or cachexia, is a significant, debilitating, and potentially life-threatening complication of HIV infection. It is associated with reduced strength and functional ability, reduced ability to withstand opportunistic infections, and increased risk of mortality. Although the incidence of HIV-associated wasting may have declined since the introduction of highly active antiretroviral therapy (HAART), it continues to be a concern in this patient population. OBJECTIVE: This paper reviews available data on the etiology and clinical impact of HIV-associated wasting, the role of the growth hormone/insulin-like growth factor-I axis in the pathophysiology of this condition, and the rationale for its treatment with recombinant human growth hormone (rhGH). METHODS: MEDLINE was searched for articles published in English through August 2007 using the terms HIV, wasting (and related terms), and growth hormone. Preference was given to clinical studies (including randomized clinical studies), meta-analyses, and guidelines. Review articles were evaluated and the bibliographies examined for additional relevant articles. The analysis was restricted to studies conducted in developed countries. RESULTS: Alterations in the growth hormone/insulin like growth factor-I axis have been observed in patients with HIV-associated wasting, including elevated levels of the former and reduced levels of insulin-like growth factor I. In randomized, placebo-controlled studies, rhGH significantly improved lean body mass by approximately 3 kg compared with placebo (P < 0.001) and total body weight by approximately 3 kg (P < 0.001), and was associated with significant improvements in physical endurance and quality of life (P < 0.001). Common adverse events with rhGH therapy include blood glucose elevations, arthralgia (36.4%), myalgia (30.4%), and peripheral edema (26.1%), but these usually respond to dose reduction or drug discontinuation. CONCLUSIONS: Physicians should be alert to the possibility of wasting in HIV-infected patients receiving HAART and should consider treatment to improve patients' stamina and quality of life. The evidence supports a role for rhGH in the treatment of patients with HIV-associated wasting. Regular blood glucose monitoring is advised when treating wasting with rhGH.

HIV-associated adipose redistribution syndrome (HARS): definition, epidemiology and clinical impact.

A segment of the HIV infected population develops abnormal and excessive accumulation of adipose tissue in the trunk, including accumulation of visceral (deep abdominal) adipose tissue. This condition, known as HIV-related adipose redistribution syndrome (HARS), may also be accompanied by fat accumulation in the upper back/neck (dorsocervical region) and/or depletion of subcutaneous adipose tissue from the abdomen, face, limbs, or buttocks. HARS is estimated to occur in up to 32% of patients and is associated with health risks similar to those of metabolic syndrome. Techniques to detect and measure HARS include physician and patient assessments and radiologic or anthropometric methods.

HIV-associated adipose redistribution syndrome (HARS): etiology and pathophysiological mechanisms.

Human immunodeficiency virus (HIV)-associated adipose redistribution syndrome (HARS) is a fat accumulation disorder characterized by increases in visceral adipose tissue. Patients with HARS may also present with excess truncal fat and accumulation of dorsocervical fat ("buffalo hump"). The pathophysiology of HARS appears multifactorial and is not fully understood at present. Key pathophysiological influences include adipocyte dysfunction and an excessive free fatty acid release by adipocyte lipolysis. The contributory roles of free fatty acids, cytokines, hormones including cortisol, insulin and the growth hormone-adipocyte axis are significant. Other potential humoral, paracrine, endocrine, and neural influences are also discussed.

Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review.

There are likely many scenarios and pathways that can lead to metabolic syndrome. This paper reviews mechanisms by which the accumulation of visceral adipose tissue (VAT) may contribute to the metabolic syndrome, and explores the paradigm of a critical VAT threshold (CVATT). Exceeding the CVATT may result in a number of metabolic disturbances such as insulin resistance to glucose uptake by cells. Metabolic profiles of patients with visceral obesity may substantially improve after only modest weight loss. This could reflect a significant reduction in the amount of VAT relative to peripheral or subcutaneous fat depots, thereby maintaining VAT below the CVATT. The CVATT may be unique for each individual. This may help explain the phenomena of apparently lean individuals with metabolic syndrome, the so-called metabolically normal weight (MONW), as well as the obese with normal metabolic profiles, i.e., metabolically normal obese (MNO), and those who are "fit and fat." The concept of CVATT may have implications for prevention and treatment of metabolic syndrome, which may include controlling dietary carbohydrates. The identification of the CVATT is admittedly difficult and its anatomical boundaries are not well-defined. Thus, the CVATT will continue to be a work in progress.

Inflammation and its relationship to insulin resistance, type 2 diabetes mellitus, and endothelial dysfunction.

In the past decade, clinical, laboratory, and epidemiological research have coalesced to give rise to a new paradigm for understanding type 2 diabetes mellitus (DM). In this review, we present data that DM has an inflammatory etiology and that inflammation plays a role in diabetic complications, especially cardiovascular disease. This new paradigm offers insight into the relationship between DM and obesity. It also suggests possible new avenues of treatment.

Inflammation and its association with glucose disorders and cardiovascular disease.

This review article presents data to show that insulin resistance and diabetes mellitus are conditions associated with low-grade inflammation. It shows that inflammation pre-dates the detection of diabetes and predicts its occurrence. Furthermore, it discusses the inter-relationship between inflammation associated with insulin resistance and diabetes, and the inflammation associated with atherosclerosis, the main complication of insulin resistance and diabetes. These data provide a new paradigm for understanding how insulin resistance, diabetes, and cardiovascular disease are related to one another. This paradigm also has the potential for opening up new areas of research and treatment.