Protease inhibitors effect

Different protease inhibitors interfere with different steps in lipid metabolism and glucose metabolism, each of which may contribute a different form of metabolic disturbance to the syndrome.

  • In healthy HIV-negative adults indinavir causes a 20% reduction in insulin sensitivity within four weeks of starting treatment but was not associated with lipid elevations during the first four weeks of treatment. 1
  • Nelfinavir, saquinavir and ritonavir are more potent inhibitors of adipogenesis than indinavir and amprenavir.
  • Lopinavir, nelfinavir, ritonavir and saquinavir increase triglyceride production in mice, especially if the drugs are taken at the same time as food. 2
  • Nelfinavir and indinavir have been shown to affect gene expression related to lipid metabolism and adipocyte differentiation in pre-adipocyte studies in mice. 3 4
  • The protease inhibitors ritonavir and saquinavir have also been shown to have a direct effect on the regulation of apoprotein B in liver cells, possibly leading to increased lipoprotein (cholesterol) secretion, but not triglyceride production. Ritonavir also increased the uptake of triglyceride-rich particles by liver cells. 5 6
  • Amprenavir did not affect glucose metabolism but was associated with significant increases in cholesterol after eight weeks. 7
  • Indinavir has been shown to interfere with the insertion of SREBP-1 into the nucleus of adipocytes, preventing release of PPAR-gamma, and so leading to impaired adipocyte differentiation and reduced insulin sensitivity. 8 SREBP-1 regulates fatty acid synthesis. It has been suggested that this mechanism may account for the lack of replacement of adipocytes after apoptosis. Apoptosis is upregulated by thymidine analogues (d4T, AZT). Apoptosis is greatest when ddI, d4T and protease inhibitors are both present in cell cultures. 9
  • Protease inhibitors directly affect an enzyme called mitochondrial processing protease (MPP), which can lead to mitochondrial dysfunction. Protease inhibitors are highly hydrophobic (water insoluble), and hence may be concentrated in fatty tissues and have a greater impact on mitochondria in those tissues with chronic exposure.10

References

  1. Noor MA et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 16(5): F1-F8, 2002
  2. Lenhard J et al. HIV protease inhibitors stimulate hepatic triglyceride synthesis. Arterioscler Thromb Vasc Biol 20: 2625-2629, 2000
  3. Stevens GJ et al. Preclinical investigations into the mechanism by which HIV protease inhibitors may induce metabolic disorders. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, abstract 1288, 1999
  4. Stevens GJ et al. Inhibition of adipocyte differentiation by HIV-1 protease inhibitors: potential mechanisms based on changes in gene expression. Antiviral Therapy 5 (Supp 5): 26, 2000
  5. Liang JS et al. HIV protease inhibitors increase secretion of apolipoprotein B-lipoproteins from hepatoma cells by preventing proteasomal degradation. Antiviral Therapy 5 (Supp 5): 12, 2000
  6. Liang JS et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nature Medicine 7(12): 1327-1331, 2001
  7. Dube MP et al. Prospective, intensive study of metabolic changes associated with 48 weeks of amprenavir-based antiretroviral therapy. Clin Infect Dis 35: 475-481, 2002a
  8. Caron M et al. The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 50: 1378-1388, 2001
  9. Caron M et al. Stavudine and didanosine partly reversed the adverse effects of indinavir on cell differentiation and response to insulin but enhanced apoptosis of cultured adipocytes. Antivir Ther 7: L6, 2002
  10. Mukhopadhyay A et al. In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible contribution to lipodystrophy syndrome. Mitochondrion 2 (Sept): 54-62, 2002
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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