Drug Treatment Regimens: How and why WHO makes its global recommendations Prof Charles Gilks Director, Co-ordinator Antiretroviral Treatment and Care Department of HIV/AIDS WHO Geneva.

WHO Drug Treatment Regimens Why WHO needed to make recommendations and to set global norms and standards How WHO set about doing this Consider how successful or not WHO's work has been in ART scale-up so far Revised (2008) WHO processes for making recommendations and issuing guidance

“Three by Five” 2002 / 2003: GFATM and PEPFAR established and resourced The target: three million people on treatment by the end of 2005 The goal : universal access to anti- retroviral therapy (ART) as a human right to health to all in need The treatment gap was declared a global health emergency Sept 22 nd, 2003 at UN General Assembly

Filling the treatment gap WHO entered "emergency mode" Defined the extent of the problem – end 2002, estimated 300,000 on ART – 91% of treatment gap in 34 countries Recognised the extent of the challenge –New intervention with limited experience –Countries most in need had weakest health systems –Prevailing view: ART was complex and specialised

Delivering on 3 x 5 WHO’s strategy: to catalyse rapid uptake of ART in communities where it is needed now but not widely accessible by adopting a two-pronged approach: Supporting countries to recognise and respond to their HIV/AIDS treatment gap and leveraging the necessary resources to enable ART to be scaled up rapidly in line with 3x5 target Simplifying and standardizing ART as far as possible without compromising effectiveness so it can be universally scaled up and delivered in resource constrained settings

Public Health ART Strategy Vision: Universal access to ART Elements: One global standard of care for ART –One first-line then one second-line regimen (then stop) –Sequential use of 3 drug classes –Simple recommendations for when to start switch & toxicity substitutions –Tiered laboratory support for clinical decision-making –Standard population-based HIVDR monitoring and surveillance –Pharmacovigilance/toxicity monitoring Chronic disease management Integrated and decentralised care Process: Evidence-based Simplification Standardisation

Harmonised ART Policy Guidance

Audience for guidelines Primarily national planners and policy makers engaged in public sector ART and in target-setting –What ARVs to make available in public sector first and second-line regimens –How to use: the four Ss of clinical management: when to start, substitute, switch and stop Care implementers - basic knowledge to use ARVs effectively according to national policy recommendations Trainers, M&E experts – to design appropriate tools and materials to support national policy recommendations

1 st and 2 nd line ARVs for adults StartSubstituteSwitch Stop 1 st Line2 nd line AZT, d4T, 3TC, NVP; EFV ABC, TDF ddI PI/r Recommended 1 st Line ARV Drugs Recommended as 2 nd Line Drugs Frequently Recommended as 2 nd line drugs, but also as alternative drugs in 1 st line regimens

Table 4 - Recommendations for initiating ART in adults and adolescents based on clinical stage and availability of immunological markers WHO Clinical Staging CD4 testing not available CD4 testing available 1 Do not treat [A-III] Treat if CD4 cell count < 200/mm 3 [A-III] a 2 Do not treat b [B-III] 3 Treat [A-III] Consider treatment if CD4 cell count < 350/mm 3 a c and initiate ART before CD4 cell count drops below 200/mm 3 d [B-III] 4 Treat [A-III] Treat irrespective of CD4 cell count [A-III] a CD4 cell count advisable to assist with determining need for immediate therapy for situations as pulmonary TB and severe bacterial infections, which may occur at any CD4 level. b A total lymphocyte count of ≤ 1,200/mm 3 can be substituted for the CD4 count when the latter is unavailable and mild HIV disease exist. It is not useful in the asymptomatic patients. Thus, in the absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2 should not be treated. c Initiation of ART is recommended in all HIV-infected pregnant women with WHO Clinical Stage 3 disease and CD4< 350 cells/mm 3. d The precise CD4 cell level above 200/mm 3 at which ARV treatment should be started has not been established. When to Start - adults

VirologicClinicalImmunologic Viral load CD4 count Clinical criteria "Early Switch""Late Switch" Failure / When to Switch

WHO Clinical Staging Clinical Failure (CD4 and VL not available) Immunologic Failure (VL not available) Immunologic and Virologic Failure (CD4 and VL available) 1 N/A Do Not SwitchConsider Switch 2 N/A Do Not SwitchConsider Switch 3 Switch 4 When to Switch from 1 st Line to 2 nd Line ARV Regimens for Treatment Failure Clinical failure is defined as a occurrence of new or recurrent WHO clinical stage 3 or 4 event (excluding IRIS). CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm 3. Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.

Steering Committee Time-Limited Subject Matter Working Groups WG WHO HIVResNet Laboratory Network Surveillance and Monitoring Network WHO Secretariat Modeling of The emergence and transmission of resistance HIVDR database development and support Public Health Assessment Tool For evaluation of country HIVDR data Global Laboratory Network: Criteria, Protocols, Training, QA The WHO HIVResNet is a global group of experts, laboratories, and organizations constituted to support HIVDR prevention, surveillance, and monitoring as antiretroviral treatment (ART) is rolled out worldwide. Country HIVDR Committees HIVDR monitoring & surveys WG Operational Research WG Mutation lists for Surveillance and monitoring

Universal Access 2005 G8 Summit at Gleneagles, Final Communiqué: “…working with WHO, UNAIDS and other international bodies to develop and implement a package of HIV prevention, treatment and care, with the aim of as close as possible to universal access to treatment for all those who need it by 2010.”

More children are receiving ART Increased from 75,000 in 2005 to almost 200,000 in 2007 Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008 Progress has been made with children

Revised simplified dosing

1 ADULT FDC AM & PM 1 BABY FDC AM & 1 PM 1 ADULT FDC AM & 0.5 PM 2 BABY FDC AM & PM 2 BABY FDC AM & 1 PM 0.5 ADULT FDC AM + PM WHO FDC ARV tablet regimen superimposed Same dosing irrespective of FDC, or same dosing for all three single ARV agents Most dose adjustments done in 1 st year Adapted from T. NUNN

Revised (2008) WHO process New WHO Guideline review committee Revised WHO guidelines for guidelines Minimum standards for: Reporting Processes Use of evidence Different types of guidance documents recognised to fit different purposes: E.g. Emergency, Standard, Full, 'Books ' joint guidelines?

Quality of evidence – GRADE approach Quality of evidence (summary score) Study designLower if *Higher if * High (4)Randomized trial Study quality: -1 Serious limitations -2 Very serious limitations -1 Important inconsistency Directness: -1 Some uncertainty -2 Major uncertainty -1 Sparse or imprecise data -1 High probability of reporting bias Strong association: +1 Strong, no plausible confounders, consistent and direct evidence +2 Very strong, no major threats to validity and direct evidence +1 Evidence of a Dose response gradient Moderate (3) Low (2)Observational study Very low (1)

Strength of a recommendation FactorsComments Quality of the evidenceHigher 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 preferencesIf 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 FeasibilityWhere intervention is possible and practical in the settings where greatest impact is likely to be attained or is being sought, strong recommendation is more likely

Conclusions Developing WHO drug treatment regimens is challenging – but can have great impact Balance between –being permissive; driving ART agenda forward –maintaining relevance to all countries Processes updated in WHO (GRADE) –Even more rigorous and transparant –Costs and feasibility