Description of trials: Description of trials

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:

• Impact on Guidelines
• Uptake into National Policies
• Implementation

• 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:

• Consider treatment for all infants at diagnosis
• Use of clinical / CD4 / viral load criteria
• Data for these approaches based on cohort analysis

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

• 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?)

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)

• 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

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………..