TITLE:  New Paradigms for Reducing HIV-Related Tuberculosis

DATES:  September 1, 2002 through August 31, 2003

Awarded Amount:  $1,456,997

 

 

I.            Objectives & Activities:  

The Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE), is a consortium of investigators and public health practitioners under the leadership of the Johns Hopkins Center for Tuberculosis Research, with the goal of identifying and evaluating novel strategies to reduce tuberculosis incidence in populations with high rates of HIV and tuberculosis co-infection.  The ultimate goal of CREATE is to manage a portfolio of studies that identify those strategies that are the most effective methods to improve tuberculosis control in populations and areas with high levels of HIV infection and tuberculosis.  By combining traditional and newer technologies for tuberculosis management with new paradigms of disease control, CREATE will make a major contribution to the identification of efficacious strategies to reduce suffering and death from HIV-related tuberculosis worldwide.

Objective 1.     Form a consortium of investigators, public health authorities and other experts to develop a portfolio of studies to identify and evaluate innovative strategies for controlling HIV-related tuberculosis, and organize Core Groups in biostatistics, training and advocacy to support consortium activities.

Objective 2.     Design at least six community-level trials to assess novel public health interventions to reduce TB incidence in populations with high HIV prevalence.

Objective 3.     Promote and secure stakeholder support of proposed studies.

Objective 4.     Plan and initiate site preparation activities to acquire baseline information, establish surveillance and other systems, and support research team development.

Objective 5.     Successfully implement, complete and analyze proposed trials.

Objective 6.     Change global policies for control of HIV-related TB through evidence-based advocacy.

CREATE is on schedule with initiating or accomplishing all of the deliverables proposed for the initial funding period.  A strong consortium has been formed; a scientific program committee meeting was held; protocols have been developed and reviewed; a peer review process has been established; a biostatistical core has been formed and is functioning actively; a policy and advocacy core has been established within the STOP TB program at the WHO; and plans for providing training through the consortium have been prepared.

 

II.          Accomplishments:

1.      Consortium Formation: CREATE was launched with a Scientific Program Committee Meeting in September 2002 in Annecy, France.  The meeting served to clarify CREATE’s goals and identified appropriate intervention strategies for study.  An Executive Committee was recruited to manage the development of the portfolio, and subcontracts were made to key participants to support development of protocols.  The CREATE Executive Committee Meeting in February 2003 in Boston reviewed 10 protocols and concept sheets for responsiveness to CREATE aims, moving one forward to peer review and making recommendations for revision of the others. 

2.      Development of Biostatistics, Policy and Advocacy, and Training Cores.  These Core Groups were organized to provide service and support to CREATE investigators both during the protocol development process and during and after implementation or projects.  The Biostatistics Core is led by Larry Moulton of Johns Hopkins and Richard Hayes of the London School of Hygiene and Tropical Medicine.  This Core has been enormously helpful in developing appropriate statistical methods to plan community and cluster randomized trials, and has provided extensive support to protocol writing teams.  The Advocacy and Policy Core is led by Mario Raviglione and Paul Nunn at STOP-TB/WHO, and has been instrumental in coordinating support for CREATE activities with National TB and HIV Programs, as well as contributing insight and assistance to the protocols.  The Training Core is led by Linda Watkinson of Johns Hopkins, and is supported by collaborators at the CDC, the London School, and the University of Amsterdam.

3.      CREATE Active Case-Finding Working Group Meeting in June, 2003, in London, thoroughly examined the evidence base for active case finding and created a forum for investigators to methodically explore pertinent questions related to individual studies and to the entire portfolio of proposals.  A comprehensive literature review on active case finding was completed by Jonathan Golub and presented to the consortium.  Following revision based on additional input from CREATE participants, the review will be published.   This was followed by the Biostatistics Core Meeting in July 2003, also in London, where a number of important methodological issues relating to cluster randomized trials were discussed and resources to support investigators were prepared and placed on line. An informational website for all of CREATE was also launched http://www.tbhiv-create.org/.

4.      13 concept sheets and proposals for trials of novel public health interventions to reduce HIV-related TB were submitted and underwent intensive review by the Executive Committee.  After discussions with the staff of the Bill and Melinda Gates Foundation, these were winnowed down to four proposals that address each of the principal strategies identified by the Scientific Program Committee as being most appropriate for evaluation: active case finding, preventive therapy, antiretrovirals with TB preventive therapy, and joint TB/HIV interventions at the community level.  Complete protocols and budgets for these four trials have been submitted and are currently undergoing peer review.  A CREATE investigators’ meeting is scheduled with the leadership of the Global Health Program at the Gates Foundation to finalize these protocols and prepare to enter Phase 2 of the consortium’s work plan.

5.      Independent Peer Review Panel chaired by Dr. Phil Hopewell was enlisted and is in the process of reviewing protocols.  This panel will also be asked to serve as an ongoing review committee in the form of a Data Safety and Monitoring Board.

 

III.        Lessons Learned:

We have learned that there are a large group of investigators and public health authorities who are truly committed to transforming public health practices related to TB/HIV.  Thus, rather than undertaking a Quixotic effort to force changes in how health systems respond to the TB/HIV crisis, we feel we are engaged in a productive collaboration with partners who can make changes and who are open to alternative strategies.  We have also learned that the field is moving so quickly that it is difficult to have a static baseline against which change can be measured.  This has required us to modify our study designs and develop new analytic approaches for documenting impact of interventions that are occurring against a backdrop of rapidly evolving practices.

 

IV.         Changes:  

Within the consortium, we have modified the structure of our Executive Committee and reduced the number of protocols being developed in response to advice from the Bill and Melinda Gates Foundation.  The change in committee structure reflects an evolution of function, as the consortium moves from a broad-reaching process of inclusion and solicitation of ideas and concepts to implementation of the most promising strategies.  Reduction in the number of protocols is a result of both scientific and budgetary considerations.  Both changes have been warmly received by most members of the CREATE consortium.  External to the consortium, the landscape of HIV treatment has been changing rapidly, as well.  The principal changes that relate to our mission are the announcement in August by the South African Health Minister that antiretroviral drugs (ARVs) will be made available in the public sector in the near future and the proposal by the WHO and UN to put 3 million people on ARVs by 2005.  Additionally, President Bush has proposed investing $15 billion for HIV treatment and prevention over the next several years, though the amount eventually provided is likely to be less.  These developments could affect some of the studies we have proposed, particularly in Kenya and Zambia/South Africa.  The CREATE Biostatistics Core has been working with study teams to assure that study designs take into account the impact that secular changes such as these could have on measuring outcomes.  We have also attempted to respond to these very positive advances by developing a protocol to determine the relative impact of increased availability of ARVs on TB incidence versus other, TB-specific interventions, such as preventive therapy.  All of our protocols will address this to some extent, but we have not been able yet to design an appropriate protocol in an African setting that will specifically focus on this issue, though we remain committed to doing so.

 

V.           Challenges:  

We have faced two principal challenges in undertaking our mission during the first year of CREATE.  The first has been the actual design of intervention strategies that can be feasibly implemented in the field and evaluated for their impact on HIV-related TB.  Our theoretical concepts encounter daunting design, implementation and logistical barriers when translated into protocols.  We have dealt with these in a variety of ways, including the use of modeling, reviewing the case finding literature for consensus methodologies and operational study results, and modifying preliminary proposals to be more focused and less all-embracing of potential modes of effect.  The other greatest challenge has been to expand the spectrum of CREATE decision-makers (Scientific Committee, Executive Committee) to more fully represent stakeholders.  Those in-country program personnel who are most capable of contributing their insights and perspectives are also the busiest and most difficult to engage in the process.  Action was taken to maximize CREATE’s exposure to stakeholders by participation in the STOP TB TB/HIV Core Working Group Meeting in April, 2003 in The Hague and the TB/HIV Working Group Meeting in June, 2003 in Montreux.  At the country level, all of the investigative teams have made extensive efforts to include a wide range of stakeholders, including National Program directors, affected communities, professional and industrial groups, and other interested parties.  The Foundation has been extremely helpful in facilitating engagement of stakeholders at the global level, and this will continue to be important in the future.

 

VI.         Other Sources of Project Support: 

No additional project support was received during this pilot phase of the project.  We anticipate that considerable in-kind support will be provided by collaborating institutions during the implementation of protocols, especially at the clinical and laboratory levels.

 

VII.          Budget Variances:

Overall spending for Year 1 was at 95% of the total approved budget, but variances occurred in several budget areas.  Only 71% of salary funds were utilized during the year, reflecting delays in bringing on staff and availability of support from other sources for several key personnel.  Consultants’ fees were only expended at 10%, because the peer review process has only just been started.  We anticipate that these expenses will be fully charged over the next several months.  Travel costs were substantially greater than anticipated, at 231% of the initial budget; these additional expenditures are the result of travel for investigators and key staff to the active case finding meeting in London in June and to the STOP-TB Core Group meeting in the Hague in April.  Use of these funds for travel was offset by underspending in salaries.  Other direct costs were also overexpended, at 205%.  This spending was necessitated because of an acute need to obtain additional furnished office space for CREATE staff, and for expenses related to establishing subcontracts with our partners.  Again, these expenses were offset by reduced spending for personnel.