Rapid advice - WHO

1 Rapid adviceAntiretroviral therapy for HIV infection in adults and adolescents NoVember 2009 WHO Library Cataloguing-in-Publication DataRapid advice : antiretroviral therapy for HIV infection in adults and adolescents -November 2009 [electronic version].Electronic version for the agents - pharmacology. infections - therapy . infections - prevention and control. countries. Health Organization. ISBN 978 92 4 159895 8 (NLM classification: WC ) World Health organization 2009 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; email: Requests for permission to reproduce or translate WHO publications whether for sale or for noncom-mercial distribution should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: 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.))

2 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. In no event shall the World Health Organization be liable for damages arising from its use. Printed in Switzerland Rapid adviceAntiretroviral therapy for HIV infection in adults and adolescents NoVember 2009 Abbreviations3TC lamivudineABC abacavirART antiretroviral therapyARV antiretroviral (drug)ATV atazanavir AZT zidovudine (also known as ZDV)bPI boosted protease inhibitorCD4 T-lymphocyte bearing CD4+ receptorCDC Centers for Disease Control and PreventionCIPRA HT001 Comprehensive International Program of Research on AIDS in Haiti (clinical trial)DART Development of antiretroviral therapy in Africa (clinical trial)d4T stavudineddI didanosineEFV efavirenzFBC full blood countFDC fixed-dose combinationFTC emtricitabineGRADE Grading of Recommendations, Assessment, Development and EvaluationHBAC Home Based AIDS Care (clinical trial)

3 HIV human immunodeficiency virusHBV hepatitis B virusIAS International AIDS SocietyIRIS immune reconstitution inflammatory syndromeLPV lopinavirNNRTI non-nucleoside reverse transcriptase inhibitorNRTI nucleoside reverse transcriptase inhibitorNVP nevirapinePEPFAR US President s Plan for Emergency AIDS ReliefPI protease inhibitorPMTCT prevention of mother-to-child transmissionPLHIV people living with HIV/r low-dose ritonavirRCT randomized clinical trialRTI reverse transcriptase inhibitorRTV ritonavirSAPIT Starting antiretroviral therapy at Three Points In Tuberculosis therapy (clinical trial)TB tuberculosisTDF tenofovir disoproxil fumarateVL viral loadUNAIDS Joint United Nations Programme on HIV/AIDSWHO World Health OrganizationContentsAbbreviations 21. overview background Why a revision? Guiding principles 42. The revision process retrieving, summarizing and presenting the evidence Consensus, external review and updating 53.

4 Guideline timing and publication 64. Dissemination, adaptation, implementation and evaluation 75. Declarations of interest 86. Collaboration with external partners 97. Key recommendations 108. references 159. Annex 1 174 Rapid advice : antiretroviral therapy fOR HIV INfECTION IN ADuLTS AND ADOLESCENTS5 Rapid advice : antiretroviral therapy fOR HIV INfECTION IN ADuLTS AND ADOLESCENTS1. backgroundThe guideline antiretroviral therapy for hiv infection in adults and adolescents, developed by World Health Organization (WHO), was first published in 2002, simplified in 2003 and was updated in 2006. The guideline continues to follow the principles of a public health approach, aiming to optimize outcomes, including the quality of life and survival, of people living with HIV (PLHIV), and to act as a reference tool for countries to adopt and adapt according to their national 2009, WHO has worked to update the guideline through a series of coordinated efforts to review and synthesize emerging evidence on when to initiate antiretroviral therapy (ART), what drug regimens to use, and the management of co-infections and treatment failure.

5 This evidence has been assembled following systematic reviews, GRADE* profile preparation and analysis, consultations with PLHIV, cost and economic impact studies, country-level feasibility assessment, and comparisons of current country guidelines. The groups who developed this revised guideline were: an internal WHO ART Guideline Working Group (convened in April 2009), the ART Guideline Drafting Group (convened in September 2009), the external ART Peer Review Panel (con-vened in September 2009), and the full ART Guideline Review Committee (convened in October 2009). The members are listed in Annex Why a revision?Since the last guideline revision in 2006, new and compelling evidence has become available, particularly concerning the earlier start of ART. There is increasing evidence of improved survival and reduced HIV-related illnesses with the earlier initiation of antiretroviral therapy . Studies support that improved access to ART has a significant impact on the prevention of HIV transmis-sion.

6 Stavudine (d4T) continues to play a critical role in the scaling-up of ART in low- and middle-income countries; however, its cumulative toxicity is unacceptable to PLHIV and to many health care providers. Newer, more patient friendly but currently more expensive ART regimens are available. The aim of the guideline is to outline standards for high quality care of PLHIV, by providing evidence-based recommendations, while considering the risks and benefits, acceptability, feasibility, cost and financial implications.* The target audience is primarily national treatment advisory key recommendations contained herein are released as Rapid advice because several countries with the highest burden of HIV infection currently are in the process of changing their national guideline for HIV treatment and care, and updating estimates for 2010 Universal Access reporting. This Rapid advice focuses on two key areas of the full guideline; when to start ART and what ARVs to use in adults, adolescents, pregnant women, tuberculo-sis (TB) and hepatitis B (HBV) co-infection.

7 Guiding principlesThe ART Guideline Review Committee discussed and agreed upon a set of principles that should be used in developing national treatment recommendations. The principal consideration was that public health interventions should secure the greatest likelihood of survival and quality of life for the greatest numbers of Do no harmWhen introducing changes preserve access for the sickest and most in ensure access and equityAll clinically eligible people should be able to enter treatment services (including ART) with fair and equitable distribution of treatment Promote quality and efficiencyEnsure delivery of the highest standards of care within a public health approach so as to achieve the greatest health impact with the optimal use of available human and financial ensure sustainabilityUnderstand the long-term consequences of change with the vision of providing continued, life-long access to ART for those in this context, the individual rights of PLHIV should not be forfeited in the course of a public health approach.

8 4 Rapid advice : antiretroviral therapy fOR HIV INfECTION IN ADuLTS AND ADOLESCENTS5 Rapid advice : antiretroviral therapy fOR HIV INfECTION IN ADuLTS AND ADOLESCENTS 52. The revision retrieving, summarizing and presenting the evidenceThe PICO** questions to be considered were agreed upon by the internal WHO ART Guideline Working Group in May 2009. A series of activities then were undertaken to prepare for the October 2009 guideline review meeting: 1. GRADE profiles were prepared for the key PICO questions: i. when to start ART; ii. what to use in first-line and second-line antiretroviral regimens; iii. when to switch to a second-line Systematic reviews of the literature were conducted on ARV drug interactions with drugs for TB, hepatitis, malaria, and opioids; ART management for HIV/HBV co-infection; ART toxicity summaries for tenofovir, zidovudine, nevirapine and stavudine; the safety of efavirenz; the teratogenicity of efavirenz; a low-dose stavudine safety profile; and reviews of CD4 and viral load laboratory An impact assessment was conducted to estimate the number of PLHIV in need of treatment according to various proposed CD4 initiation Consultations were conducted with three organizations representing PLHIV and the findings Costing information was prepared based on studies of procurement and production of A feasibility assessment was conducted for the introduction of the proposed guideline in Malawi (a similar assessment is ongoing in Tanzania).

9 7. A report was produced on issues related to adherence to ART for PLHIV, including adolescents. 8. A review was undertaken to study and compare current ART guidelines from 26 ART failure criteria were reviewed using data from ART-LINC and other GRADE evidence profiles, and the full set of supporting docu-mentation will be included and or referenced in the guideline.** PICO is an acronym that describes the elements of a well-formed clinical ques-tion. The structure includes: P for the patient or population; I for the intervention of interest; C for comparison; and O for outcome** The full set of background materials can be requested by emailing Consensus, external review and updatingExisting recommendations were reviewed and revised at the September 2009 meeting of the ART Guideline Drafting Group. Based on presentations and individual review of the available evidence described above, the group compiled risk-benefit analysis for each area of interest.

10 A table that includes the follow-ing domains: existing recommendations; new recommendations; quality and grade of evidence for the critical outcomes (mortality, disease progression and serious adverse events); benefits; risks; values; acceptability; costs; feasibility; gaps and research needs was prepared for each set of recommendations. Disagreements were debated during plenary and group sessions and consensus ART Peer Review Panel reviewed and revised the risk-benefit tables and draft recommendations prepared by the ART Guideline Drafting Group and responded with their comments and other input via the ART Guidelines 2009 page of WHO s EZCollab website. Reviewers debated and exchanged ideas within EZCollab and during teleconferences. Their suggestions and com-ments were collated and posted on the EZCollab website. The revised recommendations were presented to the ART Guideline Review Committee in October the October 2009 ART Guideline Review Meeting, each subject area was reviewed, discussed and consensus sought on each recommendation and the ranking of each recommendation.