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1 ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS: Recommendations for a public health approach 2006 revisionStrengthening health services to fight HIV/AIDSHIV/AIDS ProgrammeIMPORTANT: ADDENDUM TO 2006 WHO GUIDELINES ON ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS NEW DOSAGE RECOMMENDATIONS FOR STAVUDINE (d4T) Stavudine (d4T) is now recommended at the dose of 30 mg twice daily for all adult and adolescent patients regardless of body weight.[A-III] After the publication of WHO s 2006 guidelines for HIV therapy in adults and adolescents, the WHO Guidelines Development Group (GDG) reviewed evidence for the use of stavudine (d4T) at reduced doses. Previously, the preferred d4T dosing was weight-based.

2 Dosing for patients >60 kg was recommended at 40 mg twice daily; dosing for patients <60 kg was recommended at 30 mg twice daily. A systematic review of nine randomized trials and six observational cohort studies strongly suggests that stavudine-containing regimens maintain clinical and virologic efficacy when stavudine is dosed at 30 mg twice daily, and that this reduced dose is associated with lower rates of toxicity, especially peripheral neuropathy, compared to the 40 mg twice daily dose. Complementary studies have also demonstrated a significant reduction of mitochondrial DNA depletion in patients on the 30 mg twice daily dose. However, there are limited data available about reducing the incidence of lactic acidosis with this strategy.

3 Based on available evidence, the GDG has concluded that the 30 mg formulation of stavudine, dosed twice daily, should be used for all adult and adolescent patients, irrespective of body weight. This recommendation, which was previously considered an option, is now established as the preferred approach when d4T is used as part of an ARV therapeutic regimen. Programmatic implications: 1) All new patients with weight over 60 kg being prescribed a stavudine-containing regimen should be started on d4T 30 mg only. No patients already receiving d4T 30mg should be stepped up to d4T 40 mg. 2) All patients receiving d4T 30 mg or 40 mg with evidence of stavudine-related toxicity (even with no signs of treatment failure) should be moved to a non-stavudine containing regimen , according to current WHO ART guidelines.

4 3) All patients receiving d4T 40 mg without evidence of stavudine toxicity, should be moved to d4T 30 mg , as soon as possible, considering the programmatic feasibility. 4) Any new procurement orders of stavudine in either single or fixed dose combinations should only include d4T 30 mg. 5) Any procurement orders of d4T 40 mg in either single or fixed dose combinations should, to the extent possible, be cancelled and be replaced with d4T 30 mg containing products. Other technical and operational recommendations related to the clinical management of stavudine in the 2006 WHO guidelines are unchanged. References: Hill A, Ruxrungtham K, Hanvanich M et al. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment.

5 Expert Opin Pharmacother. 2007;8(5):679-88. S nchez-Conde M, Mendoza C, J menez-Nacher I et al. Reductions in stavudine dose ameliorate mitochondrial-associated complications without compromising antiviral activity. HIV Clin Trials 2005; 6(4):1075-90. Wolf E, Koegl C, Hoffmann C et al. Low dose stavudine: as effective as standard dose but with less side effects. XV International AIDS Conference, Bangkok, 11-16 July 2004 [Abstract WePe B5861]. WHO Library Cataloguing-in-Publication DataAntiretroviral therapy for HIV infection in adults and adolescents : recommendations for a public health approach. 2006 rev. The work was coordinated by Charles Gilks and Marco Vit ria of WHO/HTM/HIV, Geneva, Switzerland agents - therapeutic use.

6 Agents - pharmacology. infections drug therapy. countries. , Charles. ria, Marco. Health 92 4 159467 5 (NLM classification: WC )ISBN 978 92 4 159467 7 World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.))

7 Dotted lines on maps represent approximate border lines for which there may not yet be full mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader.

8 In no event shall the World Health Organization be liable for damages arising from its use. Printed in ANTIRETROVIRAL THERAPY FOR HIV INFECTION IN ADULTS AND ADOLESCENTS Recommendations for a public health approach 2006 revision A N T I R E T ROV I R A L T H ER A P Y F O R H I V I N F EC T I O N I N A D U LT S A N D A D O L ES CEN T S The preparation of this document would not have been possible without the participation of experts in the consultations that led to the formulation of the treatment World Health Organization wishes to express its special gratitude to the Guidelines Development Group, which developed the document. The Group was chaired by Professor Scott Hammer of Columbia University (New York City, USA).

9 The other members of the Group were: Ay e Riley (MASA National ARV Programme , Botswana), Alexandra Calmy (M decins Sans Fronti res and St Vincent s Hospital, Australia), Anthony Harries (National TB Programme , Malawi), Chris Duncombe (HIV-NAT, Thailand), Diane Havlir (University of California at San Francisco, USA), Ellie Katabira (Makerere University, Uganda), Fabio Scano (WHO/HTM/STB, Switzerland), Jean-Ellie Malkin (ESTHER, France), Joep Lange (International Antiviral Therapy Evaluation Centre, Netherlands), Joia Mukerjee (Partners in Health, USA), Judith Currier (University of California at Los Angeles, USA), Lynne Mofenson (National Institutes of Health, NICHD, USA), Mark Harrington (Treatment Action Group, USA)

10 , Mauro Schechter (Universidade Federal do Rio de Janeiro, Brazil), N. Kumarasamy ( YRG Centre for AIDS Research and Education, India), Papa Salif Sow (University of Dakar, Senegal), Paula Munderi (Uganda Virus Research Institute, Uganda), Sylvia Ojoo (National AIDS and STI Control Programme , Kenya), Pedro Cahn (Fundaci n Huesped, Argentina), Praphan Pranuphak (Thai Red Cross AIDS Centre, Thailand), Sergie Eholie (Treichville Hopital, C te d Ivoire), Wafaa El Sadr (Columbia University, USA),William Rodriguez (Harvard Medical School and the Clinton Foundation HIV/AIDS Initiative, USA).WHO also wishes to acknowledge comments and contributions by Annette Verster (WHO/HTM/HIV, Switzerland), Diane Bennett (WHO/HTM/HIV, Switzerland), Donald Sutherland (WHO/HTM/HIV, Switzerland), Gerald Friedland ( Yale School of Medicine, USA), Igor Olyinik (University of Berlin, Germany), Jeroen van Gorkom (KNCV TBC, Netherlands), Monica Alonso (WHO/AMRO,USA), Silvia Bertagnolio (WHO/HTM/HIV, Switzerland), Siobhan Crowley (WHO/HTM/HIV, Switzerland), Paula Fujiwara (IUATLD, France), Ramzi Asfour (WHO/HTM/HIV, Switzerland) and Ying Ru-Lo (WHO/SEARO, India).