Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir

Haerter, Georg; Manfras, Burkhard; Mueller, Markus; Kern, Peter; Trein, Andreas

doi:10.1097/00002030-200404090-00016

Cited by 34 publications

(23 citation statements)

References 10 publications

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“…Haerter et al (80) reported three case reports of HIV-infected patients switched to atazanavir from a previous PI who subjectively noted regression of abdominal and dorsoclavicular fat accumulation; however, more objective measures were needed to evaluate body composition. Regimens of atazanavir or ritonavir-boosted atazanavir in combination with an NRTI backbone of stavudine and lamivudine in treatment-naïve HIV-infected patients caused a significant increase in VAT and trunk fat at 96 weeks, but there was no statistical difference between groups.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Srinivasa

Grinspoon

2014

European Journal of Endocrinology

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In the absence of a cure, HIV-infected patients are being successfully treated with antiretroviral therapies (ART) and living longer. Indeed, an increasing number of HIV-infected patients are living beyond the age of 50 years, and in that regard, the use of ART has transformed HIV into a chronic medical condition. As more HIV-infected patients are virologically controlled and living longer, the trajectory of disease morbidity has shifted, however, primarily from opportunistic infections and immune dysfunction to metabolic complications. Evidence suggests that HIV-infected patients acquire significant metabolic risks, including lipodystrophic changes, subclinical atherosclerosis, and insulin resistance. The etiology of these metabolic complications specifically in HIV-infected patients is not entirely clear but may be related to a complex interaction between long-term consequences of infection and HIV itself, chronic use of antiretrovirals, and underlying inflammatory processes. Previous classes of ART, such as protease inhibitors (PIs) and reverse transcriptase inhibitors, have been implicated in altering fat redistribution and lipid and glucose homeostasis. Advances in drug development have introduced newer ART with strategies to target novel mechanisms of action and improve patient adherence with multi-class drug combinations. In this review, we will focus on these newer classes of ART, including selected entry inhibitors, integrase inhibitors, and multi-class drug combinations, and two newer PIs, and the potential of these newer agents to cause metabolic complications in HIV-infected patients. Taken together, further reduction of morbidity in HIV-infected patients will require increasing awareness of the deleterious metabolic complications of ART with subsequent management to mitigate these risks.

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Section: European Journal Of Endocrinologymentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Srinivasa

Grinspoon

2014

European Journal of Endocrinology

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“…Lipodystrophic syndrome is more frequent in patients treated with PI, except for atazanavir, a new and potent PI not yet recommended for children [22,50]. Besides substituting traditional PI for atazanavir, other therapeutic options to attenuate dyslipidemia, insulin resistance and lipodistrophy include substitution of this PI with nevirapine (NNRTI), abacavir (NRTI), or efavirenz (NNRTI) [37,51].…”

Section: Antiretroviral Therapy Adjustmentmentioning

confidence: 99%

Lipodystrophic syndrome in children and adolescents infected with the human immunodeficiency virus

2008

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The introduction of highly active antiretroviral therapy (HAART) for the treatment of acquired immunodeficiency syndrome (AIDS) has resulted in greater survival of patients infected with the human immunodeficiency virus (HIV). However, the use of these drugs has been associated with lipodystrophic syndrome (LS), which is characterized by metabolic alterations (dyslipidemia, insulin resistance, diabetes, and lactic acidosis) and abnormal corporal fat distribution. Clinically, LS may manifest as three different forms: lipohipertrophy (accumulation of fat in the central part of the body), lipoatrophy (loss of fat in the extremities, face and buttocks) and mixed (lipohipertrophy + lipoatrophy). Although its physiopathology has not been elucidated, some mechanisms have been described, including leptin and adiponectin deficiency, mitochondrial dysfunction and use of antiretroviral drugs. The type, dose and duration of the antiretroviral treatment, as well as age and puberty are the main risk factors. LS is also associated with increased incidence of cardiovascular illnesses, atherosclerosis and diabetes mellitus. Treatment includes physical activity, cautious restriction of caloric intake, changes in antiretroviral therapy, and use of insulin-sensitizing and lipid-lowering agents. Follow up must be periodic, consisting of measurement of body fat distribution, evaluation of the lipid profile and insulin resistance.

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“…The dysregulation of lipogenesis and the ER stress responses in liver and adipocyte cellular models was seen at concentrations near or below respective therapeutic plasma levels in patients, suggesting that they could be related to the clinical lipid profiles of the protease inhibitors (Haas et al, 2003;Murphy et al, 2003;Sanne et al, 2003;Calza et al, 2004;Squires et al, 2004). Although controlled long term data on changes in body fat distribution are not yet available, it is interesting to note that peripheral fat loss and lipodystrophy have not been observed on atazanavir-containing HAART regimens at up to 48-week treatment (Haerter et al, 2004).…”

Section: Er Stress and Lipid Regulation By Hiv Protease Inhibitors 1917mentioning

confidence: 99%

Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors

Parker

Flint²,

Mulvey³

et al. 2005

Mol Pharmacol

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The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, timedependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.The development and clinical use of HIV protease inhibitors have contributed greatly to treatment of HIV-AIDS as a critical component of highly active antiretroviral therapy (HAART) regimens. With this efficacy has come recognition of an associated syndrome of metabolic side effects that is relevant in evaluating the long-term risk/benefit of treatment options (Calza et al., 2004). The constellation of metabolic problems with protease inhibitors includes hyperlipidemia, insulin resistance, peripheral lipoatrophy, central fat accumulation, and hepatic steatosis. Despite several hypotheses to explain clinical findings, the cellular and molecular mechanisms underlying this lipodystrophy-like syndrome are incompletely understood. Recent clinical studies in patients (Woerle et al., 2003;Calza et al., 2004) and in normal subjects (Purnell et al., 2000;Noor et al., 2002Noor et al., , 2004 have confirmed a direct connection between some protease inhibitors and metabolic effects, despite the complexity of multidrug therapy and virological and immunological responses during HAART. The recent emergence of a newer generation of protease inhibitor that exhibits antiviral efficacy without adverse affects on lipid or glucose parameters in the clinic (Haas et al

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Regression of lipodystrophy in HIV-infected patients under therapy with the new protease inhibitor atazanavir

Cited by 34 publications

References 10 publications

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

MECHANISMS IN ENDOCRINOLOGY: Metabolic and body composition effects of newer antiretrovirals in HIV-infected patients

Lipodystrophic syndrome in children and adolescents infected with the human immunodeficiency virus

Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors

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