A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors

Carr, Andrew; Samaras, Katherine; Burton, Samantha; Law, Matthew; Freund, Judith; Chisholm, Donald J.; Cooper, David A.

doi:10.1097/00002030-199807000-00003

Cited by 2,226 publications

(1,513 citation statements)

References 17 publications

Supporting

Mentioning

1,372

Contrasting

Unclassified

Order By: Relevance

“…Metabolic side-effects may occur in up to 60% of HAART-treated patients, depending on host factors (presence of "traditional" risk factors for Type 2 diabetes) and on the specific agents used in the cocktail [3,4]. Further clinical and pharmacological studies have identified the HIV protease inhibitors as a class of agents that may independently contribute to the development of peripheral insulin resistance [5], as well as to impaired pancreatic beta cell function [6]. Yet adipose tissue alterations appear to lie at the centre of this metabolic syndrome, since it is frequently associated with adipose tissue redistribution, i.e.…”

Section: Introductionmentioning

confidence: 99%

“…Yet adipose tissue alterations appear to lie at the centre of this metabolic syndrome, since it is frequently associated with adipose tissue redistribution, i.e. lipodystrophy of subcutaneous "peripheral" adipose tissue, but an increase in abdominal adipose mass (central adiposity) [5,7,8]. Furthermore, impaired glucose tolerance and dyslipidaemia frequently occur, with elevated circulating levels of non-esterified fatty acids signifying abnormal regulation of adipocyte lipid metabolism [6].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

View full text Add to dashboard Cite

Aims/hypothesis. Chronic exposure of 3T3-L1 adipocytes to the HIV protease inhibitor nelfinavir induces insulin resistance, recapitulating key metabolic alterations of adipose tissue in the lipodystrophy syndrome induced by these agents. Our goal was to identify the defect in the insulin signal transduction cascade leading to nelfinavir-induced insulin resistance. Methods. Fully differentiated 3T3-L1 adipocytes were exposed to 30 µmol/l nelfinavir for 18 h, after which the amount, the phosphorylation and the localisation of key proteins in the insulin signalling cascade were evaluated.Results. Insulin-induced interaction of phosphatidylinositol 3′-kinase (PI 3-kinase) with IRS proteins was normal in cells treated with nelfinavir, as was IRS-1-associated PI 3-kinase activity. Yet insulin-induced phosphorylation of Akt/protein kinase B (PKB), p70S6 kinase and extracellular signal-regulated kinase 1/2 was significantly impaired. This could not be attributed to increased protein phosphatase 2A activity or to increased expression of phosphoinositide phosphatases (SHIP2 or PTEN). However, insulin failed to induce translocation of the PI 3-kinase effectors Akt/PKB and protein kinase C-ζ (PKC-ζ) to plasma membrane fractions of nelfinavir-treated adipocytes. Conclusions/interpretation. We therefore conclude that nelfinavir induces a defect in the insulin signalling cascade downstream of the activation of PI 3-kinase. This defect manifests itself by impaired insulin-mediated recruitment of Akt/PKB and PKC-ζ to the plasma membrane.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

et al. 2004

View full text Add to dashboard Cite

show abstract

“…12 In HIV, the HS etiology is most likely multifactorial 13 relating to metabolic factors, e.g., insulin resistance/DM/dyslipidemia and lipodystrophy, all of which may be linked to antiretroviral therapy (ART). Protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI) have been related to insulin resistance 14 and lipodystrophy 15 ; NRTI may cause mitochondrial dysfunction with subsequent direct hepatotoxic effects. 16 Moreover, HIV infection itself may facilitate DM by way of tumor necrosis factor-a stimulation and mitochondria damage.…”

mentioning

confidence: 99%

Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: A meta-analysis of the risk factors

2010

View full text Add to dashboard Cite

Hepatic steatosis (HS) is frequent in patients with hepatitis C virus (HCV) infection, occurring in 40%-80%, associating with metabolic and virus-related factors, namely, genotype 3 and viral load. Human immunodeficiency virus (HIV) infection and antiretroviral treatment seem to be risk factors for HS. Several studies addressed this issue in coinfected patients, with discrepant results. A meta-analysis was performed on the HS risk factors in coinfected patients. Eligible studies were identified through structured keywords including coinfection, HCV, HIV, and steatosis in relevant databases including PubMed. Pooled odds ratios (ORs) and confidence limits (CIs) were obtained with the random-effects model and the DerSimonian-Laird method. Twelve studies, including 1,989 coinfected patients, were selected. Twenty percent were infected with HCV genotype 3. The overall prevalence of HS was 50.8% (23%-72%). Four studies also included 1,540 HCV monoinfected patients, not showing an increased risk for HS in coinfected patients (OR 1.61, 95% CI 0.84-3.10, P 5 0.151). In coinfected patients, HS was associated with higher body mass index (OR 1.13, 95% CI 1.07-1.19, P < 0.001), diabetes mellitus (OR 2.32, 95% CI 1.32-4.07, P 5 0.003), elevated alanine aminotransferase levels (OR 1.28, 95% CI 1.02-1.61, P 5 0.035), necroinflammatory activity (OR 1.72, 95% CI 1.11-2.67, P 5 0.016), and fibrosis (OR 1.67, 95% CI 1.20-2.34, P 5 0.003). No associations were found between HS and gender, other metabolic factors (dyslipidemia, glucose, metabolic syndrome), HCV-related factors (genotype, viral load), or HIV-related factors (viral load, CD4 count, antiretroviral therapy, and class of medication). Conclusion: In coinfected patients, HS does not seem to be more frequent than in HCV monoinfected patients and is mostly associated with metabolic factors, such as increased weight, diabetes mellitus, and more severe liver disease. The fact that no associations with HCV factors were found may be due to the small percentage of genotype 3-infected patients. (HEPATOLOGY 2010;52:71-78)

show abstract

“…Lowering the potential to develop drug toxicities is an extremely important issue when ARV programs select one regimen. Choice of regimens which may include thymidine analogs [27,28] and nevirapine (NVP) [29] must be balanced by accumulating toxicities of long term therapy, increased cost, and potential for development of resistance prior to onset of symptomatic AIDS. This is highlighted by the 62.7% resistance seen after 6 months of ZDV/ddI/NVP in China [9].…”

Section: Key Principles and Complexities Of Antiretroviral Therapymentioning

confidence: 99%

“…HIV management also includes dealing with the toxicities of these drugs [27,28,[30][31][32][33], drug-drug interactions, difficulties with the need for 100% adherence [34], lack of long-term efficacy of regimens in real life settings [35][36][37][38][39], cost, co-morbid illnesses such as hepatitis and tuberculosis, opportunistic infections and their prophylaxis, substance abuse, mental illness, and the social situations of patients (housing, nutrition, stigma, family/reproductive counseling, secondary prevention, etc.). Adding to the complexity is the fact that there is no one answer for any of these issues.…”

Section: Key Principles and Complexities Of Antiretroviral Therapymentioning

confidence: 99%

Approaches to antiretroviral therapy in China

Gilliam

Redfield

2005

Cell Res

View full text Add to dashboard Cite

China has recognized the threat of HIV to its population and responded with a national antiretroviral treatment (ART) program. However, high ART failure rates and the spread of resistance within populations are important realities to consider when developing and managing ART programs in China and worldwide. Concepts which will define treatment success and local and national programmatic goals are 1) access to ART, 2) durability of ART at the patient level, 3) scalability of treatment modalities, and the 4) sustainability of the program at the community or national level. In the face of limited resources, China must also consider when to start ARV therapy, which agents to use, when to switch them, and how to treat highly experienced patients with drug resistance. The optimal ARV regimen to start with is changing frequently with the introduction of new agents and the presentation of new data. Currently, a regimen including tenofovir, emtricitabine or lamivudine and a nonnucleoside reverse transcriptase inhibitor appears to have optimal characteristics to treat HIV/AIDS in China. However, critical to all of these choices is the evaluation of programs implemented to insure wide scale success. China has wisely begun this process of evaluating the performance of local programs through systematic monitoring and evaluation of treatment outcomes. This will allow regimens and programs that work to be expanded, and programs with high failure rates to be eliminated. In the end, evidence based data supporting treatment strategies will allow China to successfully confront its AIDS epidemic early and prevent its tragic consequences

show abstract

A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors

Abstract: A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Cited by 2,226 publications

References 17 publications

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-?

Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: A meta-analysis of the risk factors

Approaches to antiretroviral therapy in China

Contact Info

Product

Resources

About