- Email: [email protected]
HIV-1, antiretroviral therapy, and malaria
COMMENTARY
endogenous response could be mimicked by a single neuroprotective drug.9 Despite that criticism, one way to identify transcription factors specific for ischaemia and ischaemic tolerance is to find common DNA-regulatory element(s) in the promoter regions of the genes that are upregulated in distinct cell types by ischaemic tolerance.10 Identification of these sequences and transcription factors that bind to them could become a class of future molecular targets and novel drugs. Small molecules capable of activating transcription factors induced by ischaemia could augment an endogenous protective response. Identification of a class of transcriptional activators in human beings would open a window into guided endogenous neuroprotection and possibly also towards further developments to use these mechanisms in the treatment of acute stroke and other disorders of the central nervous system. For example, because Hsp70 is overexpressed in cells that are more resistant to various stresses, Hsp70 gene-transfer has been successfully used to abrogate ischaemic damage.11 The most effective breakthrough in the treatment of cerebral ischaemia has been the successful establishment of systemic thrombolysis.12,13 With the increasing knowledge about the dynamics of pathophysiological and molecular mechanisms leading to ischaemia-related cell damage and about the presumed molecular targets of treatments counteracting these mechanisms, combined strategies based on thrombolysis and endogenous neuroprotection could be developed. Understanding ischaemic tolerance is a good way to unravel the molecular mechanisms involved in neuroprotection, and might improve therapeutic strategies for patients with stroke or other ischaemia-related diseases. We have no conflict of interest to declare.
*Bernhard Schaller, Rudolf Graf, Andreas H Jacobs Max Planck Institute for Neurological Research, Cologne, Germany (BS, AHJ, RG); and Department of Neurology, Cologne, Germany (AHJ) (e-mail: [email protected]). 1
2 3
4
5
6
7
8
9 10
11
12
13
Schaller B, Graf R. Cerebral ischemic preconditioning: an experimental phenomenon or clinical important entity of stroke prevention? J Neurol 2002; 11: 1503–11. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003; 26: 248–54. Moncayo J, deFreitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology 2000; 54: 2089–94. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001; 98: 4687–92. Bickler PE, Donohoe PH, Buck LT. Molecular adaptations for survival during anoxia: lessons from lower vertebrates. Neuroscientist 2002; 8: 234–42. Prass K, Ruscher K, Kursch M, et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J Cereb Blood Flow Metab 2002; 22: 520–25. Kapinya KJ, Lowl D, Futterer C, et al. Tolerance against ischemic neuronal injury can be induced by volatile anaesthetics and is inducible NO synthase dependent. Stroke 2002; 33: 1889–98. Shimizu K, Lacza Z, Rajapakse N, Horiguchi T, Snipes J, Busija DW. MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am J Physiol Heart Circ Physiol 2002; 283: H1005–11. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol 2003; 53: 10–20. DeGracia DJ, Kumar R, Owen CR, Krause GS, White BC. Molecular pathways of protein synthesis inhibition during brain reperfusion. J Cereb Blood Flow Metab 2002; 22: 393–403. Yenari MA, Fink SL, Sun GH, et al. Gene therapy with Hsp72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 1998; 44: 584–91. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87. Heiss WD, Grond M, Thiel A, von Stockhausen HM, Rudolf J. Ischaemic brain tissue salvaged from infarction with alteplase. Lancet 1997; 349: 1599–600.
1008
HIV-1, antiretroviral therapy, and malaria See page 1039 The advent of the AIDS epidemic in Africa has triggered investigations into interactions between HIV-1 and other coexisting infections. Surprisingly little evidence was initially found for interaction between HIV-1 and malaria infection,1 until studies in pregnant Malawian women showed a higher prevalence and density of Plasmodium falciparum parasitaemia in HIV-1-infected women than in uninfected women.2 This association has been confirmed in other pregnant women3 and adults,4 and symptomatic malaria infection increases HIV-1 viral load.5 HIV-1-infected adults who are not immune to malaria may also be predisposed to severe malaria disease.6 The low prevalence of HIV-1 in children, the group at most risk of severe malaria makes studies in this group logistically difficult. A cardinal feature of P falciparum infection is accumulation of mature-stage parasitised erythrocytes in the microvasculature. Adhesion to endothelial cells is mediated by interactions between the variable protein P falciparum erythrocyte membrane protein 1 and various host receptors. Of these receptors, two seem especially important outside the specific circumstances of pregnancy. Most P falciparum isolated from patients adhere to the scavenger receptor CD36, and many also to intercellular adhesion molecule 1 (ICAM-1) in vitro.7 In pregnant women, the situation differs, with adhesion to the glycosaminoglycans chondroitin sulphate A and hyaluronic acid being common, and binding to CD36 and ICAM-1 rare.8 The regulation of endothelial expression of CD36 and ICAM-1, and the consequences of adhesion to these receptors, are very different. ICAM-1 is more highly expressed in the brain than CD36, and its expression is increased by inflammatory cytokines, such as tumour necrosis factor ␣ and interleukin-1, blood levels of which are increased in malaria.9 CD36, on the other hand, may be regulated through peroxisome proliferation-activatedreceptor ␥-retinoid X-receptor, agonists of which can also decrease cytokine production.10 Adhesion to CD36 has several possible roles in malaria (figure). CD36 is expressed on some but not all endothelial cells. Low expression in the brain suggests CD36-adherent parasites might be less likely to cause cerebral malaria. Parasitised erythrocytes interact with dendritic cells via CD36, which is thought to down-regulate the immune response to malaria,11 whereas CD36 on monocytes might be involved in phagocytic clearance of parasitised erythrocytes.12 In this issue of The Lancet, Salima Nathoo and colleagues show that, in vitro, 10 mol/L concentrations of the HIV-1-protease inhibitors ritonavir and saquinavir but not the non-nucleoside reverse-transcriptase inhibitor nevirapine, decrease CD36-mediated adhesion of parasitised erythrocytes and non-opsonic phagocytosis of parasitised erythrocytes by human macrophages. Although the concentrations of saquinavir, in particular, are higher than those routinely obtained in patients, clinical exposure to protease inhibitors can reduce monocyte CD36 expression in most HIV-1-infected and uninfected individuals.13 What are the implications of Nathoo and colleagues’ study? There is intense interest in mastering the difficult logistics of offering access to antiretroviral therapy to those people in desperate need in Africa. It is hoped, perhaps optimistically, that 3 million people in developing countries might be started on antiretroviral therapy by 2005. Many people will be residents of malaria-endemic areas. Although few will initially receive protease inhibitors, changes induced by these agents in CD36 expression could THE LANCET • Vol 362 • September 27, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
3
HIV-malaria interactions 4 1 HIV increases malaria infections and parasite density in adults and pregnant women 5 More ring-stage malaria parasites in peripheral blood
6
2 Malaria increases HIV viral load 7 Increased HIV production in T cells 8 3 Increased severe malaria in non-immune adults 9 Severe malaria more common in HIV-1 infected adults 10 4 Possible consequences of protease inhibitors on malaria disease processes
11
12 CD36 on endothelial cells adhesion of malariainfected erythocytes
CD36 on monocytes non-opsonic phagocytosis
CD36 on dendritic cells immune modulation
affect adhesion to endothelium, perhaps favouring parasitised erythrocytes able to bind to other receptors, such as ICAM-1. Antiretroviral therapy might decrease phagocytosis of parasitised erythrocytes, leading to higher parasite density and possibly more severe infection. And there might be less dendritic cell-induced suppression of immune response,11 and more active cellular immunity. The understanding of innate immunity to malaria remains limited, and the importance of non-opsonic compared with opsonic phagocytosis in vivo is unknown. Before ascribing disease implications to the observations of Nathoo and colleagues, more data are needed. Besides effects on CD36 expression, immune reconstitution after antiretroviral therapy may restore humoral immunity, important for protection against malaria,14 which might reduce the burden of malarial disease in infected individuals. Further work should focus on the effects of antiretroviral therapy on the unique characteristics of P falciparum adhesion in pregnant women. And the impact of the known metabolic complications of protease inhibitors deserves close scrutiny. It will be important to examine effects of antiretroviral therapy on all-cause mortality, rather than HIV-1-specific mortality. Whether these potential interactions between antiretroviral therapy and malaria (or other diseases) are important clinically requires careful investigation, as antiretroviral therapy is rolled out into the regions where there is greatest need. I have no conflict of interest to declare.
Stephen Rogerson Department of Medicine (RMH/WH), University of Melbourne, Royal Melbourne Hospital, Parkville VIC 3050, Australia (e-mail: [email protected]) 1
2
Chandramohan D, Greenwood BM. Is there an interaction between human immunodeficiency virus and Plasmodium falciparum? Int J Epidemiol 1998; 27: 96–301. Steketee RW, Wirima JJ, Bloland PB, et al. Impairment of a pregnant woman’s acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 1996; 55: 42–49.
13 14
van Eijk AM, Ayisi JG, ter Kuile FO, et al. HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya. AIDS 2003; 17: 595–603. Whitworth J, Morgan D, Quigley M, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda. Lancet 2000; 356: 1051–56. Hoffman IF, Jere CS, Taylor TE, et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 1999; 13: 487–94. Grimwade K, French N, Mbatha DD, Zunga DD, Dedicoat M, Gilks CF. HIV-infection as a co-factor for severe falciparum malaria in adults living in a region of unstable malaria transmission in South Africa. AIDS (in press). Newbold C, Warn P, Black G, et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg 1997; 57: 389–98. Beeson JG, Rogerson SJ, Cooke BM, et al. Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nat Med 2000; 6: 86–90. Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586–91. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–86. Urban B, Ferguson D, Pain A, et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 1999; 400: 73–77. McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 2000; 96: 3231–40. Serghides L, Nathoo S, Walmsley S, Kain KC. CD36 deficiency induced by antiretroviral therapy. AIDS 2002; 16: 353–58. Cohen S, McGregor IA, Carrington SC. Gamma-globulin and acquired immunity to human malaria. Nature 1961; 192: 733–37.
Registration of trials and protocols Selective reporting of clinical trials may bias meta-analyses and misdirect guidelines committees. In a retrospective review of 130 trials,1 those with positive results (ie, p<0·05) were three times more likely to be published with a significantly shorter time to publication than those with negative results. Dickersin and Rennie2 recently called on all stakeholders in medical research to ensure a comprehensive registration of all trials that have started. On Sept 19, the UK National Health Service (NHS) joined the worldwide effort to document the start of randomised clinical trials and launched a register of those studies in England which it funds totally.3 Publicly accessible inventories of trials that have started, with each project assigned a unique identifier—the International Standard Randomised Controlled Trial Number (ISRCTN)—can address the distortion of information due to publication bias. Registration of clinical trials has to go hand in hand with unbiased editorial policies.4 For example, The Lancet offers to peer-review protocols of randomised clinical trials, metaanalyses, and prospective observational studies. Once a protocol passes scrutiny, the investigators post a 500-word summary on the journal’s website. In return, the journal commits to at least peer-review the primary clinical manuscript from the study. Key to the process is that an editorial commitment is made before the results are known. Innovation and scientific rigour are two principles that give good reason for the registration of trials, but are generally less appreciated. Within the drug industry, market-dealers and scientists approach clinical research from different and often competing angles. Some clinical trials stopped prematurely, because business interests changed.5 After the discovery of a new drug class, other companies often strive to develop agents similar to the parent compound and engage in fierce competition for the largest share of the market, usually by large-scale trials designed to highlight the superiority of the analogue. Such studies may replicate earlier experiments beyond what is
THE LANCET • Vol 362 • September 27, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1009
endogenous response could be mimicked by a single neuroprotective drug.9 Despite that criticism, one way to identify transcription factors specific for ischaemia and ischaemic tolerance is to find common DNA-regulatory element(s) in the promoter regions of the genes that are upregulated in distinct cell types by ischaemic tolerance.10 Identification of these sequences and transcription factors that bind to them could become a class of future molecular targets and novel drugs. Small molecules capable of activating transcription factors induced by ischaemia could augment an endogenous protective response. Identification of a class of transcriptional activators in human beings would open a window into guided endogenous neuroprotection and possibly also towards further developments to use these mechanisms in the treatment of acute stroke and other disorders of the central nervous system. For example, because Hsp70 is overexpressed in cells that are more resistant to various stresses, Hsp70 gene-transfer has been successfully used to abrogate ischaemic damage.11 The most effective breakthrough in the treatment of cerebral ischaemia has been the successful establishment of systemic thrombolysis.12,13 With the increasing knowledge about the dynamics of pathophysiological and molecular mechanisms leading to ischaemia-related cell damage and about the presumed molecular targets of treatments counteracting these mechanisms, combined strategies based on thrombolysis and endogenous neuroprotection could be developed. Understanding ischaemic tolerance is a good way to unravel the molecular mechanisms involved in neuroprotection, and might improve therapeutic strategies for patients with stroke or other ischaemia-related diseases. We have no conflict of interest to declare.
*Bernhard Schaller, Rudolf Graf, Andreas H Jacobs Max Planck Institute for Neurological Research, Cologne, Germany (BS, AHJ, RG); and Department of Neurology, Cologne, Germany (AHJ) (e-mail: [email protected]). 1
2 3
4
5
6
7
8
9 10
11
12
13
Schaller B, Graf R. Cerebral ischemic preconditioning: an experimental phenomenon or clinical important entity of stroke prevention? J Neurol 2002; 11: 1503–11. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003; 26: 248–54. Moncayo J, deFreitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology 2000; 54: 2089–94. Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001; 98: 4687–92. Bickler PE, Donohoe PH, Buck LT. Molecular adaptations for survival during anoxia: lessons from lower vertebrates. Neuroscientist 2002; 8: 234–42. Prass K, Ruscher K, Kursch M, et al. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J Cereb Blood Flow Metab 2002; 22: 520–25. Kapinya KJ, Lowl D, Futterer C, et al. Tolerance against ischemic neuronal injury can be induced by volatile anaesthetics and is inducible NO synthase dependent. Stroke 2002; 33: 1889–98. Shimizu K, Lacza Z, Rajapakse N, Horiguchi T, Snipes J, Busija DW. MitoKATP opener, diazoxide, reduces neuronal damage after middle cerebral artery occlusion in the rat. Am J Physiol Heart Circ Physiol 2002; 283: H1005–11. Fisher M, Ratan R. New perspectives on developing acute stroke therapy. Ann Neurol 2003; 53: 10–20. DeGracia DJ, Kumar R, Owen CR, Krause GS, White BC. Molecular pathways of protein synthesis inhibition during brain reperfusion. J Cereb Blood Flow Metab 2002; 22: 393–403. Yenari MA, Fink SL, Sun GH, et al. Gene therapy with Hsp72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 1998; 44: 584–91. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87. Heiss WD, Grond M, Thiel A, von Stockhausen HM, Rudolf J. Ischaemic brain tissue salvaged from infarction with alteplase. Lancet 1997; 349: 1599–600.
1008
HIV-1, antiretroviral therapy, and malaria See page 1039 The advent of the AIDS epidemic in Africa has triggered investigations into interactions between HIV-1 and other coexisting infections. Surprisingly little evidence was initially found for interaction between HIV-1 and malaria infection,1 until studies in pregnant Malawian women showed a higher prevalence and density of Plasmodium falciparum parasitaemia in HIV-1-infected women than in uninfected women.2 This association has been confirmed in other pregnant women3 and adults,4 and symptomatic malaria infection increases HIV-1 viral load.5 HIV-1-infected adults who are not immune to malaria may also be predisposed to severe malaria disease.6 The low prevalence of HIV-1 in children, the group at most risk of severe malaria makes studies in this group logistically difficult. A cardinal feature of P falciparum infection is accumulation of mature-stage parasitised erythrocytes in the microvasculature. Adhesion to endothelial cells is mediated by interactions between the variable protein P falciparum erythrocyte membrane protein 1 and various host receptors. Of these receptors, two seem especially important outside the specific circumstances of pregnancy. Most P falciparum isolated from patients adhere to the scavenger receptor CD36, and many also to intercellular adhesion molecule 1 (ICAM-1) in vitro.7 In pregnant women, the situation differs, with adhesion to the glycosaminoglycans chondroitin sulphate A and hyaluronic acid being common, and binding to CD36 and ICAM-1 rare.8 The regulation of endothelial expression of CD36 and ICAM-1, and the consequences of adhesion to these receptors, are very different. ICAM-1 is more highly expressed in the brain than CD36, and its expression is increased by inflammatory cytokines, such as tumour necrosis factor ␣ and interleukin-1, blood levels of which are increased in malaria.9 CD36, on the other hand, may be regulated through peroxisome proliferation-activatedreceptor ␥-retinoid X-receptor, agonists of which can also decrease cytokine production.10 Adhesion to CD36 has several possible roles in malaria (figure). CD36 is expressed on some but not all endothelial cells. Low expression in the brain suggests CD36-adherent parasites might be less likely to cause cerebral malaria. Parasitised erythrocytes interact with dendritic cells via CD36, which is thought to down-regulate the immune response to malaria,11 whereas CD36 on monocytes might be involved in phagocytic clearance of parasitised erythrocytes.12 In this issue of The Lancet, Salima Nathoo and colleagues show that, in vitro, 10 mol/L concentrations of the HIV-1-protease inhibitors ritonavir and saquinavir but not the non-nucleoside reverse-transcriptase inhibitor nevirapine, decrease CD36-mediated adhesion of parasitised erythrocytes and non-opsonic phagocytosis of parasitised erythrocytes by human macrophages. Although the concentrations of saquinavir, in particular, are higher than those routinely obtained in patients, clinical exposure to protease inhibitors can reduce monocyte CD36 expression in most HIV-1-infected and uninfected individuals.13 What are the implications of Nathoo and colleagues’ study? There is intense interest in mastering the difficult logistics of offering access to antiretroviral therapy to those people in desperate need in Africa. It is hoped, perhaps optimistically, that 3 million people in developing countries might be started on antiretroviral therapy by 2005. Many people will be residents of malaria-endemic areas. Although few will initially receive protease inhibitors, changes induced by these agents in CD36 expression could THE LANCET • Vol 362 • September 27, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
3
HIV-malaria interactions 4 1 HIV increases malaria infections and parasite density in adults and pregnant women 5 More ring-stage malaria parasites in peripheral blood
6
2 Malaria increases HIV viral load 7 Increased HIV production in T cells 8 3 Increased severe malaria in non-immune adults 9 Severe malaria more common in HIV-1 infected adults 10 4 Possible consequences of protease inhibitors on malaria disease processes
11
12 CD36 on endothelial cells adhesion of malariainfected erythocytes
CD36 on monocytes non-opsonic phagocytosis
CD36 on dendritic cells immune modulation
affect adhesion to endothelium, perhaps favouring parasitised erythrocytes able to bind to other receptors, such as ICAM-1. Antiretroviral therapy might decrease phagocytosis of parasitised erythrocytes, leading to higher parasite density and possibly more severe infection. And there might be less dendritic cell-induced suppression of immune response,11 and more active cellular immunity. The understanding of innate immunity to malaria remains limited, and the importance of non-opsonic compared with opsonic phagocytosis in vivo is unknown. Before ascribing disease implications to the observations of Nathoo and colleagues, more data are needed. Besides effects on CD36 expression, immune reconstitution after antiretroviral therapy may restore humoral immunity, important for protection against malaria,14 which might reduce the burden of malarial disease in infected individuals. Further work should focus on the effects of antiretroviral therapy on the unique characteristics of P falciparum adhesion in pregnant women. And the impact of the known metabolic complications of protease inhibitors deserves close scrutiny. It will be important to examine effects of antiretroviral therapy on all-cause mortality, rather than HIV-1-specific mortality. Whether these potential interactions between antiretroviral therapy and malaria (or other diseases) are important clinically requires careful investigation, as antiretroviral therapy is rolled out into the regions where there is greatest need. I have no conflict of interest to declare.
Stephen Rogerson Department of Medicine (RMH/WH), University of Melbourne, Royal Melbourne Hospital, Parkville VIC 3050, Australia (e-mail: [email protected]) 1
2
Chandramohan D, Greenwood BM. Is there an interaction between human immunodeficiency virus and Plasmodium falciparum? Int J Epidemiol 1998; 27: 96–301. Steketee RW, Wirima JJ, Bloland PB, et al. Impairment of a pregnant woman’s acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1. Am J Trop Med Hyg 1996; 55: 42–49.
13 14
van Eijk AM, Ayisi JG, ter Kuile FO, et al. HIV increases the risk of malaria in women of all gravidities in Kisumu, Kenya. AIDS 2003; 17: 595–603. Whitworth J, Morgan D, Quigley M, et al. Effect of HIV-1 and increasing immunosuppression on malaria parasitaemia and clinical episodes in adults in rural Uganda. Lancet 2000; 356: 1051–56. Hoffman IF, Jere CS, Taylor TE, et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration. AIDS 1999; 13: 487–94. Grimwade K, French N, Mbatha DD, Zunga DD, Dedicoat M, Gilks CF. HIV-infection as a co-factor for severe falciparum malaria in adults living in a region of unstable malaria transmission in South Africa. AIDS (in press). Newbold C, Warn P, Black G, et al. Receptor-specific adhesion and clinical disease in Plasmodium falciparum. Am J Trop Med Hyg 1997; 57: 389–98. Beeson JG, Rogerson SJ, Cooke BM, et al. Adhesion of Plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nat Med 2000; 6: 86–90. Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586–91. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998; 391: 82–86. Urban B, Ferguson D, Pain A, et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 1999; 400: 73–77. McGilvray ID, Serghides L, Kapus A, Rotstein OD, Kain KC. Nonopsonic monocyte/macrophage phagocytosis of Plasmodium falciparum-parasitized erythrocytes: a role for CD36 in malarial clearance. Blood 2000; 96: 3231–40. Serghides L, Nathoo S, Walmsley S, Kain KC. CD36 deficiency induced by antiretroviral therapy. AIDS 2002; 16: 353–58. Cohen S, McGregor IA, Carrington SC. Gamma-globulin and acquired immunity to human malaria. Nature 1961; 192: 733–37.
Registration of trials and protocols Selective reporting of clinical trials may bias meta-analyses and misdirect guidelines committees. In a retrospective review of 130 trials,1 those with positive results (ie, p<0·05) were three times more likely to be published with a significantly shorter time to publication than those with negative results. Dickersin and Rennie2 recently called on all stakeholders in medical research to ensure a comprehensive registration of all trials that have started. On Sept 19, the UK National Health Service (NHS) joined the worldwide effort to document the start of randomised clinical trials and launched a register of those studies in England which it funds totally.3 Publicly accessible inventories of trials that have started, with each project assigned a unique identifier—the International Standard Randomised Controlled Trial Number (ISRCTN)—can address the distortion of information due to publication bias. Registration of clinical trials has to go hand in hand with unbiased editorial policies.4 For example, The Lancet offers to peer-review protocols of randomised clinical trials, metaanalyses, and prospective observational studies. Once a protocol passes scrutiny, the investigators post a 500-word summary on the journal’s website. In return, the journal commits to at least peer-review the primary clinical manuscript from the study. Key to the process is that an editorial commitment is made before the results are known. Innovation and scientific rigour are two principles that give good reason for the registration of trials, but are generally less appreciated. Within the drug industry, market-dealers and scientists approach clinical research from different and often competing angles. Some clinical trials stopped prematurely, because business interests changed.5 After the discovery of a new drug class, other companies often strive to develop agents similar to the parent compound and engage in fierce competition for the largest share of the market, usually by large-scale trials designed to highlight the superiority of the analogue. Such studies may replicate earlier experiments beyond what is
THE LANCET • Vol 362 • September 27, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1009