1. 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
Professor Di Gibb, 13 Dec 2011

2. 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

3. 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
‘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
‘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
‘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

4. 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

5. 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

6. 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
years
ART (start or re-start) when CD4% <20% or clinical event (<25% from August 2006)
Professor Di Gibb, 13 Dec 2011

7. 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

8. 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

9. 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

10. Cost per child [2009 US$] Scenario Early therapy Deferred therapy
Gesine Meyer-Rath et al XVIII International AIDS Congress Vienna July 18 –
Cost per child [2009 US$]
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, ,464
1, ,889
2, ,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

11. 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

12. Professor Di Gibb, 13 Dec 2011

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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

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
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

21. 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

22. LANCET 2010; 375:
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
Professor Di Gibb, 13 Dec 2011

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

24. 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

25. 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

26. 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
Professor Di Gibb, 13 Dec 2011

27. 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

28. Components of Lablite Mapping baseline survey
National level data from M&E
More in-depth Survey of 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

29. 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

30. 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

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

32. Professor Di Gibb, 13 Dec 2011

33. 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

34. 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

35. 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

36. 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

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

38. 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

39. 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

40. 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

41. 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

42. 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

43. Professor Di Gibb, 13 Dec 2011

44. 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

45. Thank you
Professor Di Gibb, 13 Dec 2011