1. IPT and ICF Guidelines Update Reuben Granich HIV/AIDS Department World Health Organization Haileyesus Getahun STOP TB Department World Health Organization

2. TB related questions Background Guidelines Review Committee (GRC) Timeline GRC process Committee PICOT Questions Criteria Other considerations

3. Havlir, Getahun et al. 2008 JAMA 300(4):423- 430 CD4 level is associated with TB incidence Courtesy Abhishek Sharma_adapted from Havlir et al "TB death zone"

4. A. Establish NTP-NACP collaborative mechanisms  Set up coordinating bodies for effective TB/HIV activities at all levels  Conduct surveillance of HIV prevalence among TB cases  Carry out joint TB/HIV planning  Monitor and evaluate collaborative TB/HIV activities B. Decrease burden of TB among PLHIV (the "Three I's")  Establish intensified TB case finding  Introduce INH preventive therapy  Ensure TB infection control in health care and congregate settings C. Decrease burden of HIV among TB patients  Provide HIV testing and counselling  Introduce HIV prevention methods  Introduce co-trimoxazole preventive therapy  Ensure HIV/AIDS care and support  Introduce ARVs WHO 2004 policy on collaborative TB/HIV activities

5. WHO/UNAIDS 1998 IPT Policy

6. WHO TB/HIV Clinical Manual

7. WHO Guidelines for National TB Programmes on the management of children

8. WHO HIV/AIDS Department Priority Interventions (IAS Mexico 2008) IPT is recommended for PLHIV

9. Implementation progress

10. & Call for rigor and transparency

11. Guidelines Review Committee rationale For principle and/or controversial recommendations: Synthesis of ALL available evidence Evidence summaries for group meetings using standard template Formal assessment of quality of evidence Consideration of resource use and costs Link evidence to recommendations, explaining reasons for judgements

12. 1. Scoping the document: reasons for choosing the topic, problems with existing guidelines, variations and gaps, 2. Group composition 3. Conflict of interest 4. Formulations of the questions and choice of the relevant outcomes 5. Evidence retrieval, evaluation and synthesis (balance sheet, evidence table) 6. Benefit/risk profile: integrating evidence with values and preferences, equity and costs 7. Formulation of the recommendations 8. Committee review/finalization (January 25th 2010) 9. Submission to GRC for approval 10. Dissemination IPT/ICF guideline revision process HIV/AIDS and STOP TB Departments (Getahun and Granich) Standards for evidence: GRADE system Reporting standard and process Benefit/risk profile: affected community

13. Ideal recommendations Screening algorithm for IPT and further TB evaluation Recommendations regarding diagnostic methods for ruling out TB Preferred regimen for adults and children Answer questions regarding duration, toxicity, cost, and resistance Populations being considered HIV+ adults, adolescents and children HIV+ pregnant women Relevant outcomes Mortality Disease progression (morbidity) Severe or regimen limiting adverse events Adherence and retention on IPT Durability of IPT regimen effect Cost effectiveness IPT/ICF guideline revision process

14. Expected functions of the guideline group Review scope and questions for guideline Identify outcomes critical for decision making Provide end user input Assist in evidence retrieval, evaluation and synthesis (balance sheet, evidence table) Formulate recommendations Review drafts of guideline document Review and approve final recommendations

15. PICOT framework 1.What is the best combination of signs, symptoms and diagnostic procedures (e.g., smear microscopy, radiography, serum-based tests such as IGRA, etc.) as a screening tool to determine eligibility for LTBI treatment and to diagnose TB among PLHIV? 2.What is the optimal duration and drug regimen (e.g., INH, RIF, etc.) for treatment of LTBI to reduce the risk of developing Tuberculosis among PLHIV? 3.What is the optimal time to start considering IPT? (i.e., should immune status be considered and should IPT be started with ART)? 4.Does treatment for LTBI among PLHIV lead to significant development of mono-resistance against the drugs used for LTBI treatment? 5.Should PLHIV who had received TB treatment in the past be provided secondary treatment of LTBI to prevent re-infection or recurrence of Tuberculosis? 6.Will low adherence rates to LTBI treatment be a barrier to implementation of LTBI treatment among PLHIV? 7.Is provision of treatment for LTBI cost-effective? P opulation of interest I ntervention to be assessed C omparison with current standard of care Outcomes for patients and community T imeline in which each outcome needs to be assessed

16. Judgments about the strength of a recommendation – criteria to consider for WHO FactorsComments Quality of the evidence Higher the quality of the evidence the more likely a strong recommendation can be made Balance between desirable and undesirable effects Larger the gap or gradient between these then more likely a strong recommendation will be made Values and preferences If there is a great deal of variability or strong reasons that the recommended course of action is unlikely to be accepted then it is more likely a weak recommendation will be made. Costs/financial implications (resource use) Higher the cost both financial and in terms of infrastructure, equipment or requirements, and more resource intensive requirements, then less likely to make a strong recommendation Feasibility Is the intervention possible and practical in the settings where greatest impact is likely to be attained or is being sought

17. Population group: PLWHA children Intervention: IPT (Any regimen) Comparison: IPT vs Placebo Outcome: Incidence of active TB Timeframe: Lifetime No of studiesDesignLimitationsConsistency Directness or generalisability Imprecise or sparse data Other factorsQUALITY RANK 2 RCT +4 Serious limitations Serious inconsitency No serious Undirectness No serious imprecision Low Quality of evidence Outcome: MORTALITY 2 RCT +4 Serious limitations Serious inconsitency No serious Undirectness No serious imprecision Low Quality of evidence Outcome: INTERVAL to TB 1RCT Serious limitations No serious inconsistency No serious Undirectness No serious imprecision Moderate Quality of evidence Outcome: INTERVAL to DEATH 1RCT Serious limitations No serious inconsistency No serious Undirectness No serious imprecision Moderate Quality of evidence Outcome: ADVERSE EVENTS 2RCT Serious limitations ? No serious Undirectness No serious imprecision Moderate Quality of evidence No of studiesDesignLimitationsConsistency Directness or generalisability Imprecise or sparse data Other factorsQUALITY RANK 2 RCT +4 Serious limitations Serious inconsitency No serious Undirectness No serious imprecision Low Quality of evidence Outcome: MORTALITY 2 RCT +4 Serious limitations Serious inconsitency No serious Undirectness No serious imprecision Low Quality of evidence GRADE profile

18. Considering cost Resource implications, including health system changes, for each recommendation in a WHO guideline should be explored. At the minimum, a qualitative description that can serve as a gross indicator of the amount of resources needed, relative to current practice, should be provided. A scenario approach can be used, and will also need to include health system implications of the recommendations, from training, changes in supervision, monitoring and evaluation, advocacy, etc. Ideally models should be made available and designed to allow for analysts to make changes in key parameters and reapply results in their own country. Users of the guidelines need to work out the cost implications for their own service

19. End of the day…Recommendation(s)

20. Other WHO guidelines WHO normative guidelines 2009 IPT/ICF Guidelines 2009 ART Guidelines 2009 PMTCT 2010 MDR TB Guidelines 2010 WHO HIV/TB research 2010 Opportunististic Infections Ongoing WHO IMAI

21. Laws, like sausages, cease to inspire respect in proportion as we know how they are made. Otto von Bismarck 1930

22. Thank you WHO Committee Haileyesus Getahun (STOP TB Co-lead) Andrew Doupe (HIV/AIDS) Christian Gunneberg (STOP TB) Lulu Mussa Muhe (HIV/AIDS and CAH) Malgorzata Grzemska (STOP TB) Reuben Granich (HIV/AIDS) Siobhan Crowley (HIV/AIDS) Review Team: Georgina Russell (NHS) Date, Anand (CDC/CCID/NCHHSTP) Abhishek Sharma Martina Penazatto Chair (TBD) Writer (TBD)