Description of trials: Description of trials

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Description of 3 trials:

  • 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:

  • Reflections, messages to consider and lessons learned





Diagnosis and treatment of HIV infected infants is complex:

  • 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:



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?

  • 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





  • 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




IDMC June 2007, while enrolment still ongoing

  • 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




Further evidence of rapid disease progression

  • Further evidence of rapid disease progression

  • 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?)







How should decision makers make best use of infant diagnosis?

  • 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





Strategies to treat millions

  • 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


In resource-rich countries, standard of care for HIV-infected patients taking ART includes routine laboratory monitoring for

  • 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?















Although economics data presented with main results, following more modelling work (+25 year extrapolation), still not published

  • 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)


DART has provided reassurance that ART roll-out to lower level facilities nearer to where people live can be done with minimal/no monitoring

  • 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?





Describe & compare national & inter-country delivery of training, clinical care & use of laboratories & monitoring in health centres

  • 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



Mapping baseline survey

  • 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




Multidisciplinary (nearly all in Africa)

  • Multidisciplinary (nearly all in Africa)

  • 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







Highest rates of child mortality are in Africa

  • 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)


Controversies:

  • Controversies:

  • Adult physicians: “unethical to give fluids in malaria”

  • Paediatricians: “unethical not to give fluids in sepsis”



  • 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







  • 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.









‘Disbelief’ from intensive care community in well-resourced countries

  • ‘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?





Place of Guidelines (strong in HIV; (too strong?)

  • 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………..






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