Intervention Review

You have free access to this content

Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals

  1. Lawrence CE Mbuagbaw1,*,
  2. James H Irlam2,
  3. Alicen Spaulding3,
  4. George W Rutherford4,
  5. Nandi Siegfried5

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 8 DEC 2010

Assessed as up-to-date: 8 FEB 2009

DOI: 10.1002/14651858.CD004246.pub3


How to Cite

Mbuagbaw LCE, Irlam JH, Spaulding A, Rutherford GW, Siegfried N. Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naïve individuals. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD004246. DOI: 10.1002/14651858.CD004246.pub3.

Author Information

  1. 1

    Centre for the Development of Best Practices in Health, Yaoundé, Cameroon

  2. 2

    University of Cape Town, Primary Health Care Directorate, Cape Town, Western Cape, South Africa

  3. 3

    University of Minnesota, Division of Epidemiology and Community Health, Minneapolis, Minnesota, USA

  4. 4

    University of California, San Francisco, Global Health Sciences, San Francisco, California, USA

  5. 5

    University of Cape Town, Department of Public Health and Primary Health Care, Cape Town, South Africa

*Lawrence CE Mbuagbaw, Centre for the Development of Best Practices in Health, Henri Dunant Avenue, PO Box 87, Yaoundé, Cameroon. mbuagbawl@yahoo.com.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 8 DEC 2010

SEARCH

References

References to studies included in this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to studies awaiting assessment
  4. Additional references
Ayala Gaytan 2004 {published data only}
  • Gaytan JJA, De La Garza ERZ, Garcia MC, Chavez SBV. [Nevirapine or efavirenz in combination with two nucleoside analogues in HIV-infected antiretroviral-naive patients]. Medicina Interna de Mexico 2004;20(1):24-33. [: CN-00641209]
Manosuthi 2009 {published data only}
  • Manosuthi W, Sungkanuparph S, Tantanathip P, Lueangniyomkul A, Mankatitham W, Prasithsirskul W, et al. A randomized trial comparing plasma drug concentrations and efficacies between 2 nonnucleoside reverse-transcriptase inhibitor-based regimens in HIV-infected patients receiving rifampicin: the N2R Study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2009;48(12):1752-9. [PUBMED: 19438397]
Nunez 2002 {published data only}
  • Nunez M, Soriano V, Martin-Carbonero L, Barrios A, Barreiro P, Blanco F, et al. SENC (Spanish efavirenz vs. nevirapine comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV Clinical Trials 2002;3(3):186-94. [PUBMED: 12032877]
Sow 2006 {published data only}
  • Sow PG, Badiane M, Diallo PD, Lo I, Ndiaye B, Gaye AM. Efficacy and safety of lamivudine+zidovudine+efavirenz and lamivudine+zidovudine+nevirapine in treatment HIV1 infected patients. A cross study analysis [Abstract CDB0584]. XVI International AIDS Conference. Toronto, Canada, 13-18 August 2006.
Swaminathan 2009 {published data only}
  • Swaminathan S, Padmapriyadarsini C, Venkatesan P, Narendran G, Kumar R, Iliayas S, et al. Once-daily Nevirapine vs Efavirenz in the Treatment of HIV-infected Patients with TB: A Randomized Clinical Trial. 16 th Conference on Retroviruses and Opportunistic Infections. Montreal, February 8-11.
van den Berg-Wolf 2008 {published data only}
  • van den Berg-Wolf M, Hullsiek KH, Peng G, Kozal MJ, Novak RM, Chen L, et al. Virologic, immunologic, clinical, safety, and resistance outcomes from a long-term comparison of efavirenz-based versus nevirapine-based antiretroviral regimens as initial therapy in HIV-1-infected persons. HIV Clinical Trials 2008;9(5):324-36. [PUBMED: 18977721]
van Leth 2004a {published data only}
  • van Leth F, Phanuphak P, Ruxrungtham K, Baraldi E, Miller S, Gazzard B, et al. Comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2NN Study. Lancet 2004;363(9417):1253-63. [PUBMED: 15094269]

References to studies excluded from this review

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to studies awaiting assessment
  4. Additional references
Bannister 2008 {published data only}
  • Bannister WP, Ruiz L, Cozzi-Lepri A, Mocroft A, Kirk O, Staszewski S, et al. Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA. AIDS (London, England) 2008;22(3):367-76. [PUBMED: 18195563]
Bruck 2008 {published data only}
  • Bruck S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine. European Journal of Medical Research 2008;13:343-8.
de Beaudrap 2008 {published data only}
Han 2005 {published data only}
  • Han XX, Zhang M, Cui WG, Liu BG, Wang Y, Zhang ZN, et al. Efficacy of anti-HIV treatment and drug-resistance mutations in some parts of China [Mandarin]. Zhonghua Yi Xue Za Zhi 2005;85:760-4.
Hartmann 2005a {published data only}
  • Hartmann M, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Comparison of efavirenz and nevirapine in HIV-infected patients (NEEF Cohort). International Journal of STD & AIDS 2005;16(6):404-9. [PUBMED: 15969773]
Hartmann 2005b {published data only}
  • Hartmann M, Brust J, Schuster D, Mosthaf F, Procaccianti M, Rump JA, et al. Rashes in HIV-infected patients undergoing therapy with nevirapine or efavirenz [Arzneimittelexantheme bei Therapie der HIV-Infektion mit Efavirenz und Nevirapin]. Hautarzt 2005;56(9):847-53.
Hartmann 2005c {published data only}
  • Hartmann M, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Comparison of efavirenz and nevirapine in HIV-infected patients (NEEF Cohort). International Journal of STD & AIDS 2005;16:404-9.
Lapphra 2008 {published data only}
  • Lapphra K, Vanprapar N, Chearskul S, Phongsamart W, Chearskul P, Prasitsuebsai W, et al. Efficacy and tolerability of nevirapine- versus efavirenz-containing regimens in HIV-infected Thai children. International Journal of Infectious Diseases : IJID : official publication of the International Society for Infectious Diseases 2008;12(6):e33-8. [PUBMED: 18573672]
Manfredi 2004 {published data only}
  • Manfredi R, Calza L, Chiodo F. Efavirenz versus nevirapine in current clinical practice: a prospective, open-label observational study. Journal of Acquired Immune Deficiency Syndromes 2004;35:492-502.
Manfredi 2005 {published data only}
  • Manfredi R, Calza L, Chiodo F. Prospective, open-label comparative study of liver toxicity in an unselected population of HIV-infected patients treated for the first time with efavirenz or nevirapine. HIV Clinical Trials 2005;6:302-11.
Manfredi 2006 {published data only}
  • Manfredi R, Calza L. Nevirapine versus efavirenz in 742 patients: no link of liver toxicity with female sex, and a baseline CD4 cell count greater than 250 cells/microl. AIDS 2006;20:2233-6.
Manosuthi 2004 {published data only}
Nachega 2008 {published data only}
  • Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaissona RE, Regensberg L, et al. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008;22:2117-25.
Negredo 2004 {published data only}
  • Negredo E, Paredes R, Peroire J, Pedrol E, Côte H, Gel S, et al. Alteration of antiretroviral drug regimens for HIV infection: Efficacy, safety and tolerability at week 96 of the Swatch Study. Antiviral Therapy 2004;9:889-93.
Puthanakit 2009a {published data only}
  • Puthanakit T, Aurpibul L, Sirisanthana T, Sirisanthana V. Efficacy of non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy in Thai HIV-infected children aged two years or less. The Pediatric Infectious Disease Journal 2009;28(3):246-8. [PUBMED: 19165130]
Puthanakit 2009b {published data only}
  • Puthanakit T, Kerr SJ, Ananworanich J, Bunupuradah T, Boonrak P, Sirisanthana V. Pattern and predictors of immunologic recovery in Human Immunodeficiency Virus-infected children receiving non-nucleoside reverse transcriptase inhibitor-based highly active antiretroviral therapy. Pediatric Infectious Disease Journal 2009;28:488-92.

References to studies awaiting assessment

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to studies awaiting assessment
  4. Additional references
Anonymous 2007 {published data only}
  • Anonymous. NNRTI data in naive patients. AIDS Patient Care and STDS 2007;21(4):287-8.
Antela 2004 {published data only}
  • Antela A, Iribarren JA, Mahillo B, Santos I, Ribera E, Gutierrez C, et al. Final analysis of a prospective, randomized, open-label, multicentre trial in naive, HIV-1-infected patients, comparing ZDV/3TC vs d4T/ddI, plus Efavirenz, Nevirapine or Indinavir/Ritonavir (AMADEUS 01 study). International Conference on AIDS. Bangkok,Thailand., 2004 Jul 11-16; Vol. 15:abstract no. B11920.

Additional references

  1. References to studies included in this review
  2. References to studies excluded from this review
  3. References to studies awaiting assessment
  4. Additional references
Ananworanich 2005
  • Ananworanich J, Moor Z, Siangphoe U, Chan J, Cardiello P, Duncombe C, et al. Incidence and risk factors for rash in Thai patients randomized to regimens with nevirapine,efavirenz or both drugs. AIDS 2005;19:185-92.
Annan 2009
  • Annan NT, Nelson M, Mandalia S, Bower M, Gazzard BG, Stebbing J. The nucleoside backbone affects durability of efavirenz- or nevirapine-based highly active antiretroviral therapy in antiretroviral-naive individuals. Journal of Acquired Immune Deficiency Syndromes 2009;51:140-6.
Aranzabal 2005
  • Aranzabal L, Casado JL, Moya J, Quereda C, Diz S, Moreno A, et al. Influence of liver fibrosis on highly active antiretroviral therapy-associated hepatotoxicity in patients with HIV and hepatitis C virus coinfection. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 2005;40:588-93.
Aurpibul 2007
  • Aurpibul L, Puthanakit T, Lee B, Mangklabruks A, Sirisanthana T, Sirisanthana V. Lipodystrophy and metabolic changes in HIV-infected children on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy. Antiviral Therapy 2007;12:1247-54.
Beck 2008
  • Beck EJ, Mandalia S, Brettle R, Fisher M, Gompels M, Kinghorn G, et al. Treatment outcome and cost-effectiveness of different highly active antiretroviral therapy regimens in the UK (1996-2002). International Journal of STDs and AIDS 2008;19:297-304.
Bendavid 2009
Berenguer 2008
  • Berenguer J, Bellon JM, Miralles P, Alvarez E, Castillo I, Cosin J, et al. Association between exposure to nevirapine and reduced liver fibrosis progression in patients with HIV and hepatitis C virus coinfection. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America 2008;46:137-43.
BHIVA 2001
Boulle 2007
  • Boulle A, Orrel C, Kaplan, Van Cutsem G, McNally M, Hilderbrand K, et al. Substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large South African cohort. Antiviral Therapy 2007;12:753-60.
Boulle 2008
  • Boulle A, Van Cutsem G, Cohen K, Hilderbrand K, Mathee S, Abrahams M, et al. Outcomes of nevirapine- and efavirenz-based antiretroviral therapy when co-administered with rifampicin-based antitubercular therapy. Journal of the American Medical Association 2008;300:530-9.
Braithwaite 2007
  • Braithwaite RS, Kozal MJ, Chang CC, Roberts MS, Fultz SL, Goetz MB, et al. Adherence, virological and immunological outcomes for HIV-infected veterans starting combination antiretroviral therapies. AIDS 2007;21:1579-89.
CDC 2002
  • Centers for Disease Control and Prevention. Recommendations of the Panel on Clinical Practices for Treatment of HIV. Morbidity and Mortality Weekly Report 2002;51(RR-7):1-55.
Cooper 2007
Deeks 2001
DHHS 2001
  • Department of Health and Human Sciences. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL04072005001.pdf.pages 58-63 (accessed 10/09/08).
Division of AIDS 2004
  • Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Table for Grading the Severity of Adult and Pediatric Adverse Events. Bethesda, Maryland: National Institutes of Health, December 2004.
Ena 2003
  • Ena J, Amador C, Benito C, Fenoll V, Pasquau F. Risk and determinants of developing severe liver toxicity during therapy with nevirapine-and efavirenz-containing regimens in HIV-infected patients. International Journal of STD and AIDS 2003;14:776-81.
Furukawa 2006
  • Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N. Imputing missing standard deviations in meta-analyses can provide accurate results. Journal of Clinical Epidemiology 2006;59(1):7-10.
George 2009
Gilks 2006
  • Gilks CF, Crowley S, Ekpini R, Gove S, Perriens J, Sutherland D, et al. The WHO public-health approach to antiretroviral treatment against HIV in resource-limited settings. Lancet August 2006;368 (9534):505-10.
GradePro 2008
  • Jan Bozek, Andrew Oxman, Olger Schunemann. Gradepro. 3.2 for Windows 2008.
Guyatt 2008
  • Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. British Medical Journal 2008;336(7650):924-6.
Hammer 2008
  • Hammer SM, Eron JJ Jr, Reiss P, Schooley RT, Thompson MA, Walmsley S, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. Journal of the American Medical Association 2008;300(5):555-70.
Higgins 2008
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. In: Higgins JPT, Green S editor(s). Cochrane Handbook for Systematic Reviews of Interventions. Chichester: John Wiley and Sons, 2008.
Hogg 1997
Ioannidis 2006
  • Ioannidis JPA, Chou R, Rongwei F, Huffman LH, Korthuis PT. Initial highly-active antiretroviral therapy with a protease inhibitor versus a non-nucleoside reverse transcriptase inhibitor : discrepancies between direct and indirect meta-analyses. Lancet 2006;368(1470):1503-1515.
Kappelhoff 2005a
  • Kappelhoff BS, van Leth F, MacGregor TR, Lange J, Beijnen JH, Huitema AD, et al. Nevirapine and efavirenz pharmacokinetics and covariate analysis in the 2NN study. Antiviral Therapy 2005;10:145-55.
Kappelhoff 2005b
  • Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations. Antiviral Therapy 2005;10:489-98.
Keiser 2002
  • Keiser P, Nassar N, White C, Koen G, Moreno S. Comparison of nevirapine- and efavirenz-containing antiretroviral regimens in antiretroviral-naïve patients: a cohort study. HIV Clinical Trials 2002;3:296-303.
Lau 2007
  • Lau B, Gange S, Kirk G, Mehta S, Merriman B, Moore R. Predictive Value of Plasma HIV RNA Levels for Rate of CD4 Decline and Clinical Disease Progression. 14th Conference on Retroviruses and Opportunistic Infections (CROI). Los Angeles, California, February 25-28, 2007, issue Abstract 140 (oral).
MacArthur 2001
  • MacArthur RD, Chen L, Mayers DL, Besch CL, Novak R, Van den Berg-Wolf M, Yurik T, Peng G, Schmetter B, Brizz B, Abrams D. The rationale and design of the CPCRA (Terry Beirn Community Programs for Clinical Research on AIDS) 058 FIRST (Flexible Initial Retrovirus Suppressive Therapies) trial. Controlled Clinical Trials 2001;22:176-190.
Manosuthi 2008
Martin-Carbonero 2003
  • Martín-Carbonero L, Núñez M, González-Lahoz J, Soriano V. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clinical Trials 2003;4:115-20.
Matthews 2002
  • Matthews GV, Sabin CA, Mandalia S, Lampe F, Phillips AN, Nelson MR, et al. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. AIDS 2002;16:53-61.
Mellors 2007
  • Mellors J, Margolick J, Phair J, Rinaldo C, Detels R, Jaconson L, et al. Comparison of plasma HIV-1 RNA, CD4 Cell Count, and CD38 Expression on CD8 T cells as predictors of progression to AIDS and CD4 cell decline among untreated participants in the multicenter AIDS cohort study. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, California, February 25-28, 2007.
Mocroft 1998
  • Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 1998 Nov;28;352(9142):1725-30.
Moyle 2000
Neuwelt 2003
  • Neuwelt MD, Bacon O, Kennedy GE, Rutherford GW. Systematic review of nevirapine versus efavirenz- containing three-drug regimens for initial treatment of HIV infection. 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Paris, France, July 13-16 2003; Vol. 8 (Suppl 1):S332-S333.
Palella 1998
  • Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. New England Journal of Medicine 1998;338(13):853-60.
Palmon 2002
  • Palmon R, Koo BC, Shoultz DA, Dieterich DT. Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors. Journal of Acquired Immune Deficiency Syndromes 2002;29:340-5.
Patel 2006
  • Patel AK, Pujari S, Patel K, Patel J, Shah N, Patel B, et al. Nevirapine versus efavirenz based antiretroviral treatment in naive Indian patients: comparison of effectiveness in clinical cohort. The Journal of the Association of Physicians of India 2006;54:915-18.
Sanne 2005
  • Sanne I, Mommeja-Marin H, Hinkle J, Bartlett JA, Lederman MM, Maartens G, et al. Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. The Journal of Infectious Diseases 2005;191:825-9.
Shipton 2009
  • Shipton LK, Wester CW, Stock S, Ndwapi N, Gaolathe T, Thior I, et al. Safety and efficacy of nevirapine- and efavirenz-based antiretroviral treatment in adults treated for TB-HIV co-infection in Botswana. The International Journal of Tubercosis and Lung Disease: the official publication of the International Union against Tuberculosis and Lung Disease 2009;13:360-6.
Siegfried 2006
UNAIDS 2008
  • Report on the global HIV/AIDS epidemic 2008. UNAIDS/08.27E / JC1511E July 2008.
UNAIDS 2009
  • UNAIDS 2009. Report on global AIDS epidemic. http://data.unaids.org/pub/Report/2009/2009_epidemic_update_en.pdf. (accessed 15/12/2009).
van den Berg-Wolf 2006
  • van den Berg-Wolf M, Peng G, Xiang Y, Huppler Hullsiek K, Chen L, MacArthur RD, et al. Efficacy and safety of nevirapine versus efavirenz when combined in ART regimens in HIV-infectedantiretroviral-naïve persons (the NNRTI sub study of FIRST-CPCRA 058). XVI International AIDS Conference. Toronto, Canada, 13-18 August 2006.
van Leth 2004b
  • van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JM, et al. Virologic failure in antiretroviral therapy naive patients Is only determined by extreme low values of CD4+ cells or high values of HIV-1 RNA concentration, not by choice of treatment with nevirapine or efavirenz. 11th Conference on Retroviruses and Opportunistic infections (CROI); 2004 Feb 8-11. San Francisco, California, 2004.
van Leth 2004c
  • van Leth F, Conway B, Laplumé H, Martin D, Fisher M, Jelaska A, Wit FW, Lange JM, 2NN study group. Qualityof life in patients treated with first-line antiretroviral therapy containing nevirapine and/or efavirenz. Antiviral Therapy 2004;9:721-8.
van Leth 2004d
  • van Leth F, Phanuphak P, Stroes E, Gazzard B, Cahn P, Raffi F, et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Medicine 2004;1(1):e19.
van Leth 2005
  • van Leth F, Andrews S, Grinsztejn B, Wilkins E, Lazanas MK, Lange JM, et al. The effect of baseline CD4 cell count and HIV-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line HAART. AIDS 2005;19:463-71.
van Leth 2005b
  • van Leth F, Huisamen CB, Badaro R, Vandercam B, de Wet J, Montaner JS, et al. Plasma HIV-1 RNA decline within the first two weeks of treatment is comparable for nevirapine,efavirenz, or both drugs combined and is not predictive of long-term virologic efficacy: A 2NN sub study. Journal of Acquired Immune Deficiency Syndromes 2005;38:296-300.
van Leth 2006
van Leth 2006b
  • van Leth F, Kappelhoff BS, Johnson D, Losso MH, Boron-Kaczmarska A, Saag MS, Hall DB, Leith J, HuitemaAD, Wit FW, Beljnen JH, Lange JM, 2NN Study Group. Pharmacokinetic parameters of nevirapine and efavirenz in relation to antiretroviral efficacy. AIDS Research and Human Retroviruses 2006;22:232-39.
Varma 2009
  • Varma J, Nateniyom S, Akksilp S, Mankatittham W, Sirinak C, SattayawuthipongW, et al. HIV care and treatment factors associated with survival duringTB treatment in Thailand: an observational study. BMC Infectious Diseases 2009;9:42.
Veldkamp 2001
WHO 2002
  • WHO. Scaling up antiretroviral therapy in low in resource-limited settings. Guidelines for a public health approach. World Health Organisation, Geneva, Switzerland 2002.
WHO 2006
  • WHO. Antiretroviral therapy for HIV infection in adults and adolescents: Recommendations for a public health approach. 2006 revision. http://whqlibdoc.who.int/publications/2006/9789241594677_eng.pdf (accessed 25/09/08):page 28.
WHO 2007
  • WHO. WHO Model List of Essential Medicines. 15th List. http://www.who.int/medicines/publications/essentialmedicines/en/index.html (accessed 10/09/2008).
WHO 2009
  • WHO. Rapid advice: Antiretroviral therapy for HIV infection in adults and adolescents. World Health Organisation, Geneva, Switzerland 2009.