Lipid metabolism, protease inhibitors

Metabolic disturbances are frequent in patients with HIV infection and represent a multifactorial condition related both to the underlying disease and to the antiviral treatment. HIV infection itself appears to cause hyperlipidemia and insulin resistance in some patients. Protease inhibitor therapy is a major contributor to fat accumulation, hyperlipidemia, and insulin resistance. NNRTIs contribute mainly through augmentation of lipid concentrations and NRTIs to the development of lipid-associated toxicity. NRTIs can cause mitochondrial dysfunction. 

Lee GA, Rao MN, Granfeld C. The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Rep. 2004 6 471H-82. 

Combination antiretroviral therapy is associated with redistribution of body fat in some patients ( lipodystrophy syndrome ), and protease inhibitors may disturb lipid and glucose metabolism. Appropriate laboratory tests to monitor these effects should be performed. 

Answer B. AIDS patients being treated with protease inhibitors (e.g., indinavir) have developed a syndrome involving derangement of lipid and CHO metabolism. Changes in lipid metabolism and distribution occur quite commonly, and type 2 diabetes has also been reported. Indinavir is also notable for its tendency to precipitate in the urinary tract, causing nephrolithiasis unless the patient is maintained in a high state of hydration. 

Adverse effects of protease inhibitors are similar to those seen with reverse transcriptase inhibitors. In addition, this group of drugs causes metabolic disturbances, particularly insulin resistance and hyperglycaemia, and fat redistribution leading to raised plasma lipid levels, which increases the risk of heart disease. These effects are collectively known as lipodystrophy syndrome, which appears to be similar to what happens with long-term corticosteroid use. 

D. Effects on Carbohydrate and Lipid Metaboiism The use of protease inhibitors in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with protease inhibitors used in HAART regimens, with an incidence of 30-50% and a median onset time of approximately 1 year s duration of treatment. 

Zhou H, Gurley EC, Jarujaron S, Ding H, Eang Y, Xu Z, Pandak WM, Hylemon PB (2006) HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatoeytes. Am J Physiol Gastrointest Liver Physiol 291 1071—1080... 

The protease inhibitors, especially ritonavir, are known to be strong inhibitors of the cytochrome P450 isoenzyme CYP3A4. The levels of statins metabolised by this isoenzyme (notably simvastatin, and to some extent atorvastatin) are therefore increased. See Lipid regulating drugs , (p.l086) for information on the metabolism of the individual statins. 

Metabolism In a systematic review of nine randomized controlled studies of atazanavir or atazanavir-I-ritonavir in 3346 patients, there were changes in plasma lipid concentrations, which were lower after 48 weeks of therapy with atazanavir-I-ritonavir than with other ritonavir-boosted protease inhibitor regimens [104 ]. Total and non-HDL cholesterol were higher with atazanavir-I-ritonavir than with atazanavir alone. 

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