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Fat accumulation and HIV-1 protease inhibitors
CORRESPONDENCE
Aortic stenosis and ACE inhibitors Sir—Helen Rimington and co-workers and Michael Poullis (Sept 5, pp 820, 821)1,2 argue that inhibitors of angiotensin-converting enzyme (ACE) may be dangerous in patients with aortic stenosis. Their arguments, although interesting, remain theoretical. Our paper,3 which they comment on, outlined the data on the actual use of ACE inhibitors in such patients. We believe that the published studies and the absence of case reports of dangerous rections suggest that patients with aortic stenosis may not be at particular risk of ACE inhibitor side-effects. We agree that the best treatment for aortic stenosis is surgical, although for older patients particularly, surgery is usually not done.4 In any case, there may be a potential role for ACE inhibitors in patients whose condition is declining or who are not fit for surgery. Furthermore, the available data suggest that there is no reason to deny ACE inhibitors to patients with heart failure of other cause associated with mild degrees of aortic stenosis. We reiterate our conclusions that systematic research is needed on the use of ACE inhibitors in patients with aortic stenosis to find out whether there are any unacceptable immediate or longterm side-effects and to evaluate any long-term benefits. *N L T Cox, A R Abdul-Hamid, G P Mulley Beckett Wing, St James’s Hospital, Leeds LS9 7TF, UK 1
2 3
4
Rimington H, Takeda S, Chambers J. Aortic stenosis and ACE inhibitors. Lancet 1997; 352: 821. Poullis M. Aortic stenosis and ACE inhibitors. Lancet 1997; 352: 821. Cox NLT, Abdul-Hamid AR, Mulley GP. Why deny ACE inhibitors to patients with aortic stenosis? Lancet 1998; 352: 111–12. Abdul-Hamid AR, Mulley GP. Why do so few older people with aortic stenosis have valve replacement surgery? Age Ageing (in press)
particular, the two insulin-degrading enzymes cited by the researchers are probably not affected by HIV-1 protease inhibitors, which block aspartic proteases.2 Therefore we wish to offer a more comprehensive explanation. HIV-1 protease inhibitors interact with cellular enzymes, specifically aspartic proteases 3 Among these cellular aspartic proteases, a group called cathepsins is responsible for the degradation of glucagon, insulin, insulin-like growth factors and binding proteins.4,5 We postulate that HIV-1 protease inhibitors interfere with cellular cathepsins, which leads to increased concentrations of these metabolic hormones and their binding sites with consequent fat accumulation. 3 Secondary hyperglycaemia might also arise after longterm cathepsin inhibition. Our hypothesis would account for both the beneficial metabolic effects and the eventual side-effects of therapy with HIV-1 protease inhibitors. An intriguing possibility based on this hypothesis is that parsimonious treatment with aspartic protease inhibitors might be useful for non-HIV diseases that are associated with wasting, particularly malignant diseases. *Raphael B Stricker, Billi Goldberg *California Pacific Medical Center, San Francisco, CA 94120, USA; and International DNCB Study Group, San Francisco 1
2
3
4
5
Martinez E, Gatell J. Metabolic abnormalities and use of HIV-1 protease inhibitors. Lancet 1998; 352: 821–22. Goldberg B, Stricker RB. HIV protease and the pathogenesis of AIDS. Res Virol 1996; 147: 375–79. Stricker RB, Goldberg B. Weight gain associated with protease inhibitor therapy in HIV-infected patients. Res Virol 1998; 149: 123–26. Authier F, Mort JS, Bell AW, Posner BI, Bergeron JJ. Proteolysis of glucagon within hepatic endosomes by cathespins B and D. J Biol Chem 1995; 270: 15798–807. Cclaussen M, Kubler B, Wendland M, et al. Proteolysis of insulin-like growth factors (IGF) and IGF binding proteins by cathespin D. Endocrinology 1997; 138: 3797–803.
Fat accumulation and HIV-1 protease inhibitors
Author’s reply
Sir—In their insightful letter, Esteban Martínez and José Gatell (Sept 5, postulate that fat p 821) 1 accumulation associated with HIV-1 protease inhibitors might be caused by an iatrogenic effect on cellular (nonviral) enzymes. We previously proposed the same hypothesis. 2,3 We believe, however, that the investigators’ focus on insulin metabolism alone is too narrow. In
Sir—Raphael Stricker and Billi Goldberg state that insulin-degrading enzymes are probably not affected by HIV-1 protease inhibitors because those enzymes are not aspartyl proteases. Insulin may be a substrate of the HIV-1 protease.1 Therefore, we justified our hypothesis by considering that if a substrate (insulin) is shared by several enzymes (insulin-degrading enzymes and the HIV-1 protease), it is
1392
possible that inhibitors of one of the enzymes (the HIV-1 protease) could also inhibit any of the other enzymes (insulin-degrading enzymes). Moreover, the other published hypothesis on the pathogenesis of metabolic abnomalies and lypodystrophy associated with HIV-1 protease inhibitors 2 also implies interactions of HIV-1 protease inhibitors with human proteins that are not aspartyl proteases. Stricker and Goldberg speculate that HIV-1 protease inhibitors interact with certain aspartyl proteases called cathepsins that are involved in the degradation of glucagon, insulin, insulin-like growth factors, and insulin-like growth factor binding proteins. However, they do not offer a potential pathogenesis as to how increased concentrations of all those substrates may finally result in fat redistribution and metabolic disturbances seen in HIV-1 infected patients treated with protease inhibitors. Finally Stricker and Goldberg suggest that the treatment with aspartyl protease inhibitors such as HIV-1 protease inhibitors might be useful for non-HIV-1 diseases associated with wasting. Metabolic and body changes reported with the use of HIV-1 protease inhibitors, including weight gain because of fat accumulation, have been associated with hyperlipidaemia and insulin resistance, which are well known risk factors for cardiovascular disease. In addition, serious psychological concern exists for many HIV-1 infected patients who develop unwanted body changes such as central obesity, breast hypertrophy, cervical fat pads, or peripheral fat wasting. Although weight gain would be highly desirable for chronic diseases associated with wasting, I do not think that a kind of weight gain or fat accumulation as that associated with HIV-1 protease inhibitors would be a reasonable option for the treatment of wasting. E Martínez Infectious Diseases Unit, Hospital Clínic, 08036 Barcelona, Spain 1
2
Poorman RA, Tomasselli, AG, Heinrikson RL, Kézdy FJ. A cumulative specifity model for proteases from human immunodeficiency virus types 1 and 2, inferred from statistical analysis of an extended substrate data base. J Biol Chem 1991; 266: 14554–61. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–83.
THE LANCET • Vol 352 • October 24, 1998
Aortic stenosis and ACE inhibitors Sir—Helen Rimington and co-workers and Michael Poullis (Sept 5, pp 820, 821)1,2 argue that inhibitors of angiotensin-converting enzyme (ACE) may be dangerous in patients with aortic stenosis. Their arguments, although interesting, remain theoretical. Our paper,3 which they comment on, outlined the data on the actual use of ACE inhibitors in such patients. We believe that the published studies and the absence of case reports of dangerous rections suggest that patients with aortic stenosis may not be at particular risk of ACE inhibitor side-effects. We agree that the best treatment for aortic stenosis is surgical, although for older patients particularly, surgery is usually not done.4 In any case, there may be a potential role for ACE inhibitors in patients whose condition is declining or who are not fit for surgery. Furthermore, the available data suggest that there is no reason to deny ACE inhibitors to patients with heart failure of other cause associated with mild degrees of aortic stenosis. We reiterate our conclusions that systematic research is needed on the use of ACE inhibitors in patients with aortic stenosis to find out whether there are any unacceptable immediate or longterm side-effects and to evaluate any long-term benefits. *N L T Cox, A R Abdul-Hamid, G P Mulley Beckett Wing, St James’s Hospital, Leeds LS9 7TF, UK 1
2 3
4
Rimington H, Takeda S, Chambers J. Aortic stenosis and ACE inhibitors. Lancet 1997; 352: 821. Poullis M. Aortic stenosis and ACE inhibitors. Lancet 1997; 352: 821. Cox NLT, Abdul-Hamid AR, Mulley GP. Why deny ACE inhibitors to patients with aortic stenosis? Lancet 1998; 352: 111–12. Abdul-Hamid AR, Mulley GP. Why do so few older people with aortic stenosis have valve replacement surgery? Age Ageing (in press)
particular, the two insulin-degrading enzymes cited by the researchers are probably not affected by HIV-1 protease inhibitors, which block aspartic proteases.2 Therefore we wish to offer a more comprehensive explanation. HIV-1 protease inhibitors interact with cellular enzymes, specifically aspartic proteases 3 Among these cellular aspartic proteases, a group called cathepsins is responsible for the degradation of glucagon, insulin, insulin-like growth factors and binding proteins.4,5 We postulate that HIV-1 protease inhibitors interfere with cellular cathepsins, which leads to increased concentrations of these metabolic hormones and their binding sites with consequent fat accumulation. 3 Secondary hyperglycaemia might also arise after longterm cathepsin inhibition. Our hypothesis would account for both the beneficial metabolic effects and the eventual side-effects of therapy with HIV-1 protease inhibitors. An intriguing possibility based on this hypothesis is that parsimonious treatment with aspartic protease inhibitors might be useful for non-HIV diseases that are associated with wasting, particularly malignant diseases. *Raphael B Stricker, Billi Goldberg *California Pacific Medical Center, San Francisco, CA 94120, USA; and International DNCB Study Group, San Francisco 1
2
3
4
5
Martinez E, Gatell J. Metabolic abnormalities and use of HIV-1 protease inhibitors. Lancet 1998; 352: 821–22. Goldberg B, Stricker RB. HIV protease and the pathogenesis of AIDS. Res Virol 1996; 147: 375–79. Stricker RB, Goldberg B. Weight gain associated with protease inhibitor therapy in HIV-infected patients. Res Virol 1998; 149: 123–26. Authier F, Mort JS, Bell AW, Posner BI, Bergeron JJ. Proteolysis of glucagon within hepatic endosomes by cathespins B and D. J Biol Chem 1995; 270: 15798–807. Cclaussen M, Kubler B, Wendland M, et al. Proteolysis of insulin-like growth factors (IGF) and IGF binding proteins by cathespin D. Endocrinology 1997; 138: 3797–803.
Fat accumulation and HIV-1 protease inhibitors
Author’s reply
Sir—In their insightful letter, Esteban Martínez and José Gatell (Sept 5, postulate that fat p 821) 1 accumulation associated with HIV-1 protease inhibitors might be caused by an iatrogenic effect on cellular (nonviral) enzymes. We previously proposed the same hypothesis. 2,3 We believe, however, that the investigators’ focus on insulin metabolism alone is too narrow. In
Sir—Raphael Stricker and Billi Goldberg state that insulin-degrading enzymes are probably not affected by HIV-1 protease inhibitors because those enzymes are not aspartyl proteases. Insulin may be a substrate of the HIV-1 protease.1 Therefore, we justified our hypothesis by considering that if a substrate (insulin) is shared by several enzymes (insulin-degrading enzymes and the HIV-1 protease), it is
1392
possible that inhibitors of one of the enzymes (the HIV-1 protease) could also inhibit any of the other enzymes (insulin-degrading enzymes). Moreover, the other published hypothesis on the pathogenesis of metabolic abnomalies and lypodystrophy associated with HIV-1 protease inhibitors 2 also implies interactions of HIV-1 protease inhibitors with human proteins that are not aspartyl proteases. Stricker and Goldberg speculate that HIV-1 protease inhibitors interact with certain aspartyl proteases called cathepsins that are involved in the degradation of glucagon, insulin, insulin-like growth factors, and insulin-like growth factor binding proteins. However, they do not offer a potential pathogenesis as to how increased concentrations of all those substrates may finally result in fat redistribution and metabolic disturbances seen in HIV-1 infected patients treated with protease inhibitors. Finally Stricker and Goldberg suggest that the treatment with aspartyl protease inhibitors such as HIV-1 protease inhibitors might be useful for non-HIV-1 diseases associated with wasting. Metabolic and body changes reported with the use of HIV-1 protease inhibitors, including weight gain because of fat accumulation, have been associated with hyperlipidaemia and insulin resistance, which are well known risk factors for cardiovascular disease. In addition, serious psychological concern exists for many HIV-1 infected patients who develop unwanted body changes such as central obesity, breast hypertrophy, cervical fat pads, or peripheral fat wasting. Although weight gain would be highly desirable for chronic diseases associated with wasting, I do not think that a kind of weight gain or fat accumulation as that associated with HIV-1 protease inhibitors would be a reasonable option for the treatment of wasting. E Martínez Infectious Diseases Unit, Hospital Clínic, 08036 Barcelona, Spain 1
2
Poorman RA, Tomasselli, AG, Heinrikson RL, Kézdy FJ. A cumulative specifity model for proteases from human immunodeficiency virus types 1 and 2, inferred from statistical analysis of an extended substrate data base. J Biol Chem 1991; 266: 14554–61. Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 1998; 351: 1881–83.
THE LANCET • Vol 352 • October 24, 1998