Pathways from evidence to guidelines/policy to implementation; examples from recent trials in Africa Some Thoughts….. Di Gibb MRC Clinical Trials Unit

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


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


http://www.ctu.mrc.ac.uk/

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)


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


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


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


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


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?)



ART coverage for HIV-infected children in Africa

ONLY 21% WHO report 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


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


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


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?


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


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


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


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


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)


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)


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?


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


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


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


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


Christine in N. Uganda is still travelling 60 miles to get ARVs

2008

2011


Fluid Expansion As a Supportive TherapyFluid Expansion As a Supportive Therapy

malaria

consortium

Disease Control, Better Health www.malariaconsortium.org


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


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


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:


§Soroti Hospital, Uganda8000 admissions per year


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.


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

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umul

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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


Fast track; May 2011

4 months after IDMC stop

Follow-up ongoing until August 2011


Response to the trial


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?



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


Documents

Pathways from evidence to guidelines/policy to implementation; examples from recent trials in Africa Some Thoughts….. Di Gibb MRC Clinical Trials Unit