Di Gibb MRC Clinical Trials Unit d.gibb@ctu.mrc.a.cuk Pathways from evidence to guidelines/policy to implementation; examples from recent trials in Africa Some Thoughts….. Di Gibb MRC Clinical Trials Unit d.gibb@ctu.mrc.a.cuk Professor Di Gibb, 13 Dec 2011

Outline Description of 3 trials: Compare and contrast: CHER (Children with HIV Early antiRetroviral therapy) DART (Development of AntiRetroviral Therapy in Africa) FEAST (Fluid Expansion As Supportive Therapy) Compare and contrast: Impact on Guidelines Uptake into National Policies Implementation Reflections, messages to consider and lessons learned Professor Di Gibb, 13 Dec 2011

Large pragmatic, multicentre individual patient trials in East & South Africa; addressing strategy questions Trial Population Countries dates Questions CHER IDMC advised modification 2007; main trial finished 09/2011 415 Asymptomatic HIV-infected young infants South Africa 2005-2011 ‘Can early limited antiretroviral therapy reduce HIV disease progression and death?’ ‘When to start ART in infants?’ DART Completed 2009 3315 Sick HIV-infected adults Uganda and Zimbabwe 2003-2009 ‘Can antiretroviral therapy be safely given without monitoring for safety and efficacy?’ FEAST IDMC advised stop Jan 2011 3145 Acutely sick febrile children with shock Uganda, Kenya, Tansania 2009-2011 ‘Does early rapid fluid resuscitation reduce 48 hour mortality in sick children (mainly malaria and sepsis) admitted to hospital with shock’ Professor Di Gibb, 13 Dec 2011

Rationale for CHER Trial(2004) Children with HIV Early antiRetroviral therapy Diagnosis and treatment of HIV infected infants is complex: High mortality and fast disease progression in infancy Laboratory markers poorly predict disease progression Antiretroviral therapy is life-long No trials; variation in approaches from different guidelines (US, Europe, WHO) and over time: Consider treatment for all infants at diagnosis Use of clinical / CD4 / viral load criteria Data for these approaches based on cohort analysis Professor Di Gibb, 13 Dec 2011

CHER Trial Question 2 Sites in South Africa; funding from NIH Will early therapy (commenced within 3 months after birth) given for a limited time (to first or second birthday) improve HIV disease prognosis in resource-poor settings? 2 Sites in South Africa; funding from NIH MRC CTU role: design, analysis, execution Professor Di Gibb, 13 Dec 2011

CHER Trial Part A n= 375 FOLLOW UP HIV infection diagnosed before 12 weeks and CD4% >25% Arm 1 Deferred treatment N=125 Arm 2 Short course (to first birthday) Arm 3 Long course ( to second birthday) FOLLOW UP 3.5 - 6 years ART (start or re-start) when CD4% <20% or clinical event (<25% from August 2006) Professor Di Gibb, 13 Dec 2011

Recommended modifying the trial Independent Data Monitoring Committee Review (20 June 2007; median follow-up 32 weeks) Recommended modifying the trial Immediate release of results of Arm 1 (deferred ART) versus Arms 2&3 (early ART) combined infants in Arm 1 urgently assessed for ART trial follow-up to continue Professor Di Gibb, 13 Dec 2011

CHER Trial Death Disease progression At median follow-up 32wk, Children with Early ART) At median follow-up 32wk, 76% reduction in mortality P=0.0002; 75% reduction in disease progression; Between early arms and deferred arm Disease progression Bottom line…after only 32 weeks follow-up 4 fold differnece in progression to death or aids in deferred group vs early ART groups. Mortlaity in early art group similar to in uninfected infants. In deferred arm, babiues died rapdily…one third at home….nmot aids diagnoses What is happening now, trial continues ….5 year trial. Of note no continuous arm….. Power to detect differences betweeen 2 and 3 limited. DMC met in september and meeting again in april Violari et al, IAS June 2007; NEJM 359;21 Nov 20, 2008 Professor Di Gibb, 13 Dec 2011

Timelines for CHER early results and influence on Guidelines IDMC June 2007, while enrolment still ongoing Presented as late breaker at International meeting July 2007 Paper submitted December 2007 to NEJM US guidelines change February 2008 WHO guidelines meeting April 2008, launch June 2008 at World AIDS PENTA guidelines change Nov 2008 Paper published in NEJM Nov 2008 South African guidelines Essential Drug List Committee approved Nov 2008 Final National Guideline – Dec 2010, following economic work Professor Di Gibb, 13 Dec 2011

Cost per child [2009 US$] Scenario Early therapy Deferred therapy Gesine Meyer-Rath et al XVIII International AIDS Congress Vienna July 18 – 23 2010 Cost per child [2009 US$] Scenario Early therapy Deferred therapy Routine care Mean time in care 10 months 9 months 3 months Cost item Cost % ARVs $245 18% $127 5% $35 1% Diagnostics $243 $341 14% $58 2% Staff / overheads $515 38% $726 30% $266 9% Total outpatient cost $1,004 74% $1,195 49% $359 12% Total inpatient cost $346 26% $1,237 51% $2,523 84% Total cost $1,349 $2,432 $2,908 95% CI 1,244 - 1,464 1,982 - 2,889 2,273 - 3,743 Cost difference mostly due to hospitalization: Early: 2 days/ child (max: 68 days) Deferred: 7 days/ child (max: 84 days) Routine: 13 days/ child (max: 121 days) Professor Di Gibb, 13 Dec 2011 10

Influence of CHER Results Further evidence of rapid disease progression BUT most babies were infected despite pMTCT ? Generalisability of results to all infected infants Rapid guideline change; influence of NIH and US paediatricians? Implementation required focus on: Early HIV diagnosis (also influenced by CHER itself in SA) ART formulations for infants ? Effect on prevention of mother-to-child transmission ? Effect on family orientated care (mother and baby?) Professor Di Gibb, 13 Dec 2011

Professor Di Gibb, 13 Dec 2011

ART coverage for HIV-infected children in Africa ONLY 21% WHO report Dec 2011 Professor Di Gibb, 13 Dec 2011

Policy-related questions and implementation How should decision makers make best use of infant diagnosis? Entry points into treatment and care for majority infected infants (i.e. other than pMTCT) How best to close the gap between diagnosis and getting on ART? Balancing costs and gain between pMTCT and treatment for infants Professor Di Gibb, 13 Dec 2011

The Development of AntiRetroviral Therapy in Africa (DART) trial Routine vs clinically driven laboratory monitoring of HIV antiretroviral therapy in Africa: a randomised non-inferiority trial Professor Di Gibb, 13 Dec 2011 15 15

Anti-HIV treatment in low-income countries Strategies to treat millions Even today, 6.6M on antiretroviral treatment (ART) end 2010; 7.6M cannot get it Coverage in adults 47% Goal of treatment to reduce morbidity & mortality Population-based approach: Adopted by World Health Organisation (2003-) Standardised first and second-line regimens Strategies to treat millions, focused on key aspects of reducing morbidity and mortality Adopted by WHO with limited formulary, Cannot use individual and lab heavy approach to ART used in north and imposed vertically in Afriica through a number of programs from the west. Professor Di Gibb, 13 Dec 2011

Rationale for DART Development of Antiretroviral Therapy in Africa In resource-rich countries, standard of care for HIV-infected patients taking ART includes routine laboratory monitoring for toxicity (haematology, biochemistry) efficacy (CD4 cell count, viral load) The level of monitoring required has never been established In Africa, laboratory monitoring is not widely available (infrastructure, personnel etc) is costly to maintain (reagents, quality control etc) Question: can ART be given safely with clinically driven, rather than routine, laboratory monitoring? Professor Di Gibb, 13 Dec 2011 17

DART Trial Design 3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease, CD4<200 cells/mm3 initiating ART randomise Laboratory and Clinical Monitoring (LCM) 12 weekly biochemistry, FBC & CD4 Other investigations & concomitant medications if clinically indicated Switch to second-line for new/recurrent WHO 4 (or multiple WHO 3) CD4<100 cells/mm3 Clinically Driven Monitoring (CDM) 12 weekly biochemistry, FBC & CD4; FBC & biochemistry only returned if clinically indicated (or grade 4 toxicity); CD4 never returned Other investigations & concomitant medications if clinically indicated Switch to second-line for new/recurrent WHO 4 (or multiple WHO 3) Professor Di Gibb, 13 Dec 2011 18 As per WHO guidelines, switching before 48 weeks discouraged in both arms 18

Safety of antiretroviral drugs No effect of Monitoring Strategy on laboratory or clinical side effects (clinical (CDM) vs laboratory LCM) arms) 1.0 Serious Adverse Event p=0.2 0.8 ART-modifying AE p=0.85 0.6 Proportion event-free Grade 4 AE p=0.18 0.4 Grade 3/4 AE p=0.52 0.2 First key result…..dont need lab tests to give ART safely LCM CDM 0.0 1 2 3 4 5 Years from randomisation (ART initiation) Professor Di Gibb, 13 Dec 2011 19

Survival: 3% additional mortality benefit of CD4 monitoring after 2 years on therapy; only cost-effective if CD4 costs <$3.8 LCM: 2.2/100 PY 1.0 0.90 0.87 CDM:2.9/100 PY 0.8 0.6 Proportion alive 0.4 0.2 0.0 Adding lab monitroing does nothing for first 2 years on ART…by end of 5 years, 90% survival…ie gain 3 percentage points… Further analyses show switching at lower CD4 in CDM; Economic analyses are key…but tests need to be point of care and cost <$4 to be cost effective 1 2 3 4 5 Years from enrolment Professor Di Gibb, 13 Dec 2011 20

Survival: 3% additional mortality benefit of CD4 monitoring after 2 years on therapy; only cost-effective if CD4 costs <$3.8 LCM: 2.2/100 PY 1.0 0.90 0.87 0.08 CDM:2.9/100 PY 0.8 0.6 Proportion alive 0.4 0.2 EC: 57.7/100 PY 0.0 Adding lab monitroing does nothing for first 2 years on ART…by end of 5 years, 90% survival…ie gain 3 percentage points… Further analyses show switching at lower CD4 in CDM; Economic analyses are key…but tests need to be point of care and cost <$4 to be cost effective 1 2 3 4 5 Years from enrolment Professor Di Gibb, 13 Dec 2011 21

LANCET 2010; 375: 123-31 DART Population level benefits would be maximised by increasing access to drugs, rather than spending money on routine laboratory monitoring for fewer treated people (particularly toxicity tests as no benefit and costly) Main Paper published in Lancet www.ctu.mrc.ac.uk/dart Professor Di Gibb, 13 Dec 2011

Policy Brief, Film, Policy Video on u-tube, dissemination activities Professor Di Gibb, 13 Dec 2011

Challenges Although economics data presented with main results, following more modelling work (+25 year extrapolation), still not published Generalisability to non-research settings questioned How exactly to do clinical monitoring? Timing with respect to 2010 WHO Guidelines (available only as an abstract at the time) Minimal impact on several US-led programs: leaders have stated in public that DART trial results have “no relevance” Viewed as ‘going backwards’, ‘double standards’; ‘taking something away’ from programmes already doing CD4 +/- Viral load (externally funded) Professor Di Gibb, 13 Dec 2011

BUT……….. DART has provided reassurance that ART roll-out to lower level facilities nearer to where people live can be done with minimal/no monitoring Of interest/relevance because of level or decreasing funding: reduction in “slots” for new patients needing to start ART (even if CD4 <250) DART put tenofovir on the map…… ? Benchmarking the cost for Point of care CD4? Professor Di Gibb, 13 Dec 2011

Lab-Lite Project “Optimising Clinical Care Strategies and Laboratory Monitoring for Cost-effective Roll-Out of Antiretroviral Therapy in Africa” Funded by Department for International Development, UK Malawi, Zimbabwe, Uganda In collaboration with Ministries of Health 2011-2014 Professor Di Gibb, 13 Dec 2011

Lab-Lite Project Objectives Describe & compare national & inter-country delivery of training, clinical care & use of laboratories & monitoring in health centres Demonstrate how a decentralised “lab-lite” monitoring package would work in lower level health centres Assess the costs, coverage, and equity implications of decentralised "lab-lite" patient monitoring for scale up of service delivery in Africa Professor Di Gibb, 13 Dec 2011

Components of Lablite Mapping baseline survey National level data from M&E More in-depth Survey of 15-20 Health centres ‘Lablite’ Demonstration Project 4 representative non-research sites - Uganda(2), Zimbabwe(1), Malawi(1) health centres clustered around a referral centre (hub and spoke) Overarching: Programme of health economic analyses Dissemination and communication including with policymakers and stakeholders, politicians, NGOs and communities Professor Di Gibb, 13 Dec 2011

Economics Components of Work Economic Modelling and Budget Impact B1. Cost-effectiveness modelling of the costs and health outcomes of the treatment alternatives B2. Budget impact analysis of the alternative strategies (from the perspective of MOH) Equity and Patient Level Effects B3. Equity – financial protection and equity of access B4. Productivity – basic estimates of income and welfare effects Health Systems Implications B5. Impacts on laboratory infrastructures B6. Human resources for health implications Mention issue of comparator groups for facilities here. Also, whether it is at all possible to get comparision groups at the patient level for equity work (issue of budget and time of key personnel) Professor Di Gibb, 13 Dec 2011

Lab Lite Teams Multidisciplinary (nearly all in Africa) Healthcare professionals, epidemiologists, social scientists, economists, modellers, training and communication expertise, community Expertise and interactions Both in research and implementation Drawn from within and outside DART teams Key involvement of Ministries of Health Capacity building is key Professor Di Gibb, 13 Dec 2011

Christine in N. Uganda is still travelling 60 miles to get ARVs 2008 2011 Professor Di Gibb, 13 Dec 2011

Professor Di Gibb, 13 Dec 2011

FEAST: Background Highest rates of child mortality are in Africa 1 in 8 children dies before age 5 (20-fold the mortality in industrialized countries) 15-30% mortality among children admitted to hospitals in sub-Saharan Africa despite being on antibiotics and quinine >50% deaths occur within 24 hours of admission supportive therapies often not considered/unavailable ETAT (Emergency Triage Assessment and Treatment) recently introduced Includes rapid fluid resuscitation for shock (routinely used in well-resourced countries (relatively weak level of evidence; no trials) Professor Di Gibb, 13 Dec 2011

FEAST Controversies and Challenges Adult physicians: “unethical to give fluids in malaria” Paediatricians: “unethical not to give fluids in sepsis” Challenges Issues around: Informed consent for very sick children Blinding Giving fluids without intensive care and without ‘the right’ infrastructure There was a need for a controlled trial to give evidence and resolve continuing uncertainty but there were controversies and challenges to designing and getting funding for the trial that was needed. From doctors who said it was unethical to give Albumin to children with malaria to those who said it was unethical NOT to give fluids as they had such a belief that they worked. Much thought was needed on how to take informed consent from parents/guardians in an emergency care situation, whether there could be any blinding, and whether you can give fluids in places without intensive care. Professor Di Gibb, 13 Dec 2011 34

FEAST : large pragmatic trial Questions: Is early rapid fluid resuscitation safe and result in a lower mortality compared to current care (control: no bolus)? Are colloid fluids (albumin) better than crystalloids (saline)? 3-arm trial: maintenance fluids only vs albumin bolus vs normal saline bolus (20ml/kg) 3600 children with febrile illness and shock (two-thirds with malaria); exclude gastroenteritis, burns, malnutrition Primary Endpoint: 48-hour mortality So FEAST was conceived to try and answer these two specific questions…. Simple clinical criteria for trial eligibility as there was no time for lab tests to diagnose certain diseases/conditions for eligibility (although these were used after admission for management of the child and definitions for subgroups). This would also then make the trial generalisable and address the questions under real life conditions. It aimed to have an eligible population relevant to clinical practise and comparable to the several paediatric shock definitions that are available (apart from the WHO definition which is much stricter). And it was powered to be large enough to identify important subgroups such as malaria. Professor Di Gibb, 13 Dec 2011

FEAST partners UGANDA (4 centres) KENYA TANZANIA Teule Support: Mulago Hospial, Kampala Mbale Soroti Lacor Hospital, Gulu Funded by MRC, UK Albumin and Saline donated by Baxter, KENYA Kilifi UNITED KINGDOM MRC Clinical Trials Unit, London & Imperial College, London (Sponsor) TANZANIA Teule Professor Di Gibb, 13 Dec 2011 36 36 36

§ Soroti Hospital, Uganda 8000 admissions per year Professor Di Gibb, 13 Dec 2011

IDMC meeting January 2011 IDMC met in January 2011 to review 5th interim analysis report (with 2987 patients). Their recommendation to TSC was that further randomisation to the trial should stop. Also to note that the trial was nearly at its full sample size at the time of the meeting (3170 children). So after the IDMC gave their recommendation, the very next day the sites were called and ask to stop recruitment. Fortuitously the TMT had already organised a face-to-face meeting a week after the IDMC meeting so the TSC replaced their planned call with a meeting and the decision was endorsed at the meeting. Professor Di Gibb, 13 Dec 2011

Kaplan-Meier plot-time to death in first 48 hours 3.3% increase in mortality in bolus arms vs control There was an absolute difference of 3.3% mortality between the no bolus arm and the bolus arms. Professor Di Gibb, 13 Dec 2011

Follow-up ongoing until August 2011 Fast track; May 2011 4 months after IDMC stop Follow-up ongoing until August 2011 Professor Di Gibb, 13 Dec 2011

Response to the trial The trial made it onto the BBC News website, the Guardian news website and in the paper itself, and we’ve had commentaries about the trial in other journals including Critical Care and The Lancet. Professor Di Gibb, 13 Dec 2011

Post FEAST ‘Disbelief’ from intensive care community in well-resourced countries Feeling run high about fluid management! Questioning generalisability Pondering mechanisms; subgroups… Further analysis Dissemination WHO guidance – complex message planning to review evidence in 2012 Changes in ETAT? What do results mean for settings outside Africa? Professor Di Gibb, 13 Dec 2011

Professor Di Gibb, 13 Dec 2011

Some Thoughts from all 3 trials…… Place of Guidelines (strong in HIV; (too strong?) Timing and relation to the guideline process Who is funding the programmes on the ground? Role of actors on the ground Researchers, community Decision makers on trial committees Interest and Relevance of results to other settings? How does that help? Eg FEAST trial results in well-resourced countries DART toxicity results in well-resourced countries Impact of the research process (and associated capacity building) on national guidelines, clinical practice, health systems Measuring uptake/coverage of an intervention and thus the impact of research? (eg cotrimoxazole prophylaxis) Role of health economics The ethical issues associated with ‘taking something away’ are different from ‘not adding something new’…so timing……….. Professor Di Gibb, 13 Dec 2011

Thank you Professor Di Gibb, 13 Dec 2011