“Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes...We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner...Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients [insulin resistance].”                   
Murata H, Hruz PW, Mueckler M. The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy. JBC. 2000 May 9
.
“Conclusions: Osteopenia and osteoporosis are unique metabolic complications associated with protease inhibitor-containing potent antiretroviral regimens, that appear to be independent of adipose tissue maldistribution.”                                                   
Tebas P, et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antiretroviral therapy. AIDS. 2000 Mar 10;14(4):F63-7.                                             
Maugh TH. AIDS drugs linked to bone disease. Los Angeles Times. 2000 Jun 19;S3.

“Our study reports an independent association between PI use and hyperlipidemia, hyperglycemia, and lipodystrophy, on the basis of a 5-year cohort study that encompassed the pre-PI and post-PI therapeutic eras. Although these metabolic changes were occasionally observed in patients not exposed to PIs, they were much more frequent after initiation of PI therapy. Although it appears that the metabolic effects are not serious enough to warrant discontinuation of PI therapy, this decision should be left with the patients and their primary health care providers. Future studies of PI-treated patients are warranted to further address the clinical implications of these metabolic effects and examine their pathogenesis.”   
Tsiodras S. Arch Int Med. 2000 Jul 10;160(13):2050-6
archinte.ama-assn.org/issues/v160n13/full/ioi90558.html.

“Use of HIV-1 protease inhibitors is associated with endothelial dysfunction. The metabolic and phenotypic changes observed with these medications may predispose to atherosclerosis and increased vascular risk.”                                                                
Sosman JM, et al. Endothelial Dysfunction Is Associated with the Use of Human Immunodeficiency Virus-1 Protease Inhibitors. 7th Conference on Retroviruses and Opportunistic Infections. 2000 Jan 30.

“Further study is needed to characterize the association between indinavir and thrombosis [2.4 times the risk of blood clots inside blood vessels]”                                                  
 Sullivan PS, et al. Epidemiology of thrombosis in HIV-infected individuals. AIDS. 2000 Feb 18;14(3):321-4.

“We describe four men with HIV infection who sustained myocardial infarction (two of which were fatal) after 24 to 29 months of protease inhibitor therapy...Thus, AIDS, a fatal illness that is routinely and effectively managed with protease inhibitors, now seems to be presenting with potentially serious new risks associated with that therapy.”              
Flynn TE, Bricker LA. Myocardial Infarction in HIV-Infected Men Receiving Protease Inhibitors. Ann Int Med. 1999 Oct 5.

“British investigators have added two new cases to the growing list of reports of disfiguring striae [stretch-marks] in HIV-infected patients using protease inhibitors. "In both cases, the appearance of striae occurred within 3 months after the patient began treatment with the protease inhibitor indinavir," Dr. Amrit Darvay, now at St. Thomas’ Hospital in London, UK, and colleagues at Ealing Hospital report in the September issue of the Journal of the American Academy of Dermatology.”                                       
Reuters Health. 1999 Oct 4.

“Higher plasma levels of ritonavir are significantly associated with an increased risk of neurological or gastrointestinal side effects, Italian investigators report in [AIDS 1999; 13:2083-9]”                                                                                                                     
Reuters Health. 1999 Oct 18.

“Dr. Klein and her colleagues at the University of Wisconsin Medical School in Madison are conducting an ongoing pilot study with 21 HIV-infected patients who have received protease inhibitor therapy for more than 6 months and 7 HIV-infected controls...Flow-mediated vasodilation was impaired in all of the patients receiving protease inhibitors, but in none of the controls...These preliminary observations suggest that protease inhibitor use is associated with endothelial dysfunction, which may ...predispose to atherosclerosis and increased vascular risk.”                                                             
Reuters Health. 1999 Nov 9

“Hyperlipidaemia at degrees associated with cardiovascular morbidity occurred in 74% of protease-inhibitor recipients. Our cut-offs may be conservative because cholesterol concentrations above 5.0 mmol/L and triglyceride concentrations above 1.6 mmol/L have been identified as clinically significant.”                                                                         
Carr A et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun 19;353(9170):2093-9.

“71% of the protease inhibitor-treated patients had hyperlipidemia compared with only 24% of the protease inhibitor-naive patients. Among the protease inhibitor-treated patients, 44% had isolated hypertriglyceridemia, 7% had type V hyperlipidemia, 37% had type IV hyperlipidemia, 36% had type IIb hyperlipidemia, and 18% had isolated hypercholesterolemia.”                                                                                                      
Behrens G, et al. AIDS. 1999;13:F63-70.

“Despite biological plausibility, studies of protease inhibitors which evaluate survival benefit have not yet been carried out. The post-1996 AIDS conference hype that 'combination therapy including a protease inhibitor will make HIV a chronic, manageable disease just like diabetes' came back to haunt us.”                                              Carr A, Cooper DA. Gap between biology and reality in AIDS. Lancet. 1998 Dec 19;352(S5):16.

“Protease inhibitors can be associated with a non-ketosis-prone hyperglycaemia that occurs 1-7 months after starting treatment”                                                                    
Dube MP, et al. Protease inhibitor-associated hyperglycaemia. Lancet. 1997 Sep;350:713-4.