Description of trials: Description of trials
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Description of 3 trials: Description of 3 trials: CHER (C H E R DART (D A R T FEAST (F E A S T 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 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 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: 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 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 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 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……….. Dostları ilə paylaş:
