di gibb mrc clinical trials unit [email protected]
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Pathways from evidence to guidelines/policy to implementation; examples from recent trials in Africa Some Thoughts…. Di Gibb MRC Clinical Trials Unit [email protected]. Outline. Description of 3 trials: CHER ( C hildren with H IV E arly anti R etroviral therapy) - PowerPoint PPT PresentationTRANSCRIPT
Pathways from evidence to guidelines/policy to implementation; examples from recent trials in Africa
Some Thoughts…..Di Gibb
MRC Clinical Trials [email protected]
Professor Di Gibb, 13 Dec 2011
Outline Description of 3 trials:
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 learnedProfessor Di Gibb, 13 Dec 2011
Large pragmatic, multicentre individual patient trials in East & South Africa; addressing strategy questionsTrial Population Countries
datesQuestions
CHER IDMC advised modification 2007; main trial finished 09/2011
415Asymptomatic HIV-infected young infants
South Africa2005-2011
‘Can early limited antiretroviral therapy reduce HIV disease progression and death?’‘When to start ART in infants?’
DART Completed 2009
3315Sick HIV-infected adults
Uganda and Zimbabwe2003-2009
‘Can antiretroviral therapy be safely given without monitoring
for safety and efficacy?’FEAST IDMC advised stop Jan 2011
3145Acutely sick febrile children with shock
Uganda, Kenya, Tansania2009-2011
‘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
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
HIV infection diagnosed before 12 weeks and CD4% >25%
Arm 1
Deferred treatment
N=125
Arm 2 Short course
(to first birthday)
N=125
Arm 3 Long course
( to second birthday)
N=125
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
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 TrialChildren 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
Death
Disease progression
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$]Cost per child [2009 US$]
ScenarioEarly therapy
Deferred therapy
Routine care
Mean time in care 10 months 9 months 3 months
Cost item Cost % Cost % Cost %
ARVs $245 18% $127 5% $35 1%
Diagnostics $243 18% $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
10
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)
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)
Gesine Meyer-Rath et al XVIII International AIDS Congress Vienna July 18 – 23 2010Gesine Meyer-Rath et al XVIII International AIDS Congress Vienna July 18 – 23 2010
Professor Di Gibb, 13 Dec 2011
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
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
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
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
18
DART Trial Design3316 ART-naive adults with stage WHO 2, 3 or 4 HIV disease,
CD4<200 cells/mm3 initiating ART
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)
randomise
As per WHO guidelines, switching before 48 weeks discouraged in both arms
Professor Di Gibb, 13 Dec 2011
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion
even
t-fr
ee
0 1 2 3 4 5
Years from randomisation (ART initiation)
LCM CDM
Grade 4 AEp=0.18
Serious Adverse Event p=0.2
ART-modifying AEp=0.85
Safety of antiretroviral drugsNo effect of Monitoring Strategy on laboratory or clinical
side effects (clinical (CDM) vs laboratory LCM) arms)
Grade 3/4 AEp=0.52
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 0.90
0.87
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion
aliv
e
Years from enrolment
LCM: 2.2/100 PYCDM:2.9/100 PY
Professor Di Gibb, 13 Dec 2011
21
0.90
0.87
0.08
0 1 2 3 4 5
0.0
0.2
0.4
0.6
0.8
1.0
Pro
port
ion
aliv
e
Years from enrolment
EC: 57.7/100 PY
LCM: 2.2/100 PYCDM:2.9/100 PY
Survival:3% additional mortality benefit of CD4 monitoring after 2 years on
therapy; only cost-effective if CD4 costs <$3.8
Professor Di Gibb, 13 Dec 2011
LANCET 2010; 375: 123-31
www.ctu.mrc.ac.uk/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)
Professor Di Gibb, 13 Dec 2011
Policy Brief, Film, Policy Video on u-tube, dissemination activitiesProfessor 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 ProjectObjectives
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 implicationsProfessor 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
Fluid Expansion As a Supportive TherapyFluid Expansion As a Supportive Therapy
malaria
consortium
Disease Control, Better Health www.malariaconsortium.org
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
FEASTControversies and Challenges
Controversies: Adult physicians:
“unethical to give fluids in malaria”
Paediatricians: “unethical not to give fluids in sepsis”
ChallengesIssues around: Informed consent for very
sick children Blinding Giving fluids without
intensive care and without ‘the right’ infrastructure
Professor Di Gibb, 13 Dec 2011
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
Professor Di Gibb, 13 Dec 2011
36
KENYAKilifi
TANZANIATeule
UGANDA (4 centres)Mulago Hospial, KampalaMbale SorotiLacor Hospital, Gulu
UNITED KINGDOM
MRC Clinical Trials Unit, London&Imperial College, London (Sponsor)
Albumin and Saline donated by Baxter,
Funded by MRC, UK
FEAST partnersSupport:
Professor Di Gibb, 13 Dec 2011
§Soroti Hospital, Uganda8000 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.
Professor Di Gibb, 13 Dec 2011
0.9%1.4%1.7%2.0%3.5%3.8%1.4%2.0%1.7%0.4%0.9%0.6%0.6%0.7%0.8%0.9%1.5%1.3%1.3%1.1%1.2%%
9131620343814201749667891513141213Died
975945954996980992101110011010101510101016102110181024103010331037104410471050At risk
NSANSANSANSANSANSA NS A
Twenty-fourthto forty-eighth
Ninth to twenty-fourthFifth to eighthFourthThird hourSecond hourFirst hour
A-Albumin Bolus, S-Saline Bolus, N-No Bolus control
0.00
0.02
0.04
0.06
0.08
0.10
0.12C
umul
ativ
e pr
obab
ility
of d
eath
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48Hours from randomisation
Albumin-bolus
Saline-bolusNo bolus
Kaplan-Meier plot-time to death in first 48 hours
3.3% increase in mortality in bolus arms vs control
Professor Di Gibb, 13 Dec 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
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