TITLE:  New Paradigms for Reducing HIV-Related Tuberculosis

DATES:  September 1, 2002 through March 31, 2005

Awarded Amount:  $3,000,000

I.          Introduction

The Consortium to Respond Effectively to the AIDS/TB Epidemic (CREATE), is a global health consortium of investigators, public health practitioners and institutions 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.

Overall goal:  To develop, evaluate, and if appropriate, promote new applications of existing tools to as to reduce the incidence of tuberculosis in settings of high HIV prevalence.

Primary Objectives (Phase I and II):

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 (Phase I Objective).

Objective 2.     Design community-level trials to assess novel public health interventions to reduce TB incidence in populations with high HIV prevalence (Phase I Objective).

Objective 3.     Promote and secure stakeholder support of proposed studies (Phase I and II Objective).

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

Objective 5.     Successfully implement, and complete and analyze proposed trials (Phase II Objective).

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

II.                Accomplishments:

Phase I Objectives:

• We have successfully assembled a global consortium of investigators with strong public health linkages with broad expertise in tuberculosis, HIV, clinical trials, disease control, advocacy and biostatistics.  The CREATE consortium has developed an organizational structure and capacity that have enabled us to produce a compelling portfolio of trials that will answer critical questions concerning novel approaches to controlling HIV-related TB.  Over the two years of the first phase of CREATE, more than 60 investigators and public health workers from more than a dozen countries contributed to developing our overall scientific agenda and individual proposals for protocols.  Six scientific meetings were held to generate concepts, review literature and preliminary data, develop statistical methods, and prepare and refine trial proposals. 
• Concept sheets were written for 12 individual studies, followed by internal critical review and revision.  Final proposals and budgets for four community-based trials were completed with extensive input from inside and outside CREATE, and underwent rigorous, independent peer review.  In addition, detailed proposals for biostatistical, policy and advocacy, education and training, and administrative cores were completed.
• Stakeholder input and support was obtained in each of the study sites, and numerous meetings and forums with affected and interested parties were held.  Community advisory groups have been established for each study site.
• The final grant proposal to the BMGF was awarded, with 3 of the 4 proposed studies approved for funding. 
• Baseline studies have been conducted in six sites: South African gold mines, Zambia, Western Kenya, rural Uganda, Cambodia, and Brazil.  Data from these studies will provide important guidance to studies conducted during Phase II of CREATE, as well as contribute to general knowledge of the HIV/TB co-epidemics.
• Phase II of CREATE was launched at a press briefing during the World AIDS Conference in Bangkok, with a powerful endorsement from Nelson Mandela, who eloquently exhorted the global community to battle TB as an essential part of the fight against AIDS.  Mr. Mandela’s speech was on of the most important acts of public advocacy for TB control in decades, and received wide attention in the press.

III.          Lessons Learned:

• The major lesson learned is that the task we are undertaking is very difficult.  This was underscored by our failure to obtain approval for the Western Kenya Active Case Finding study that was submitted as part of our Phase II proposal.  Despite intensive efforts on the part of the study team, we were not able to make the case for pursuing this study adequately, largely due to the infrastructure and resource constraints at the study site.  While we believe that a household-to-household case finding study is worth pursuing, we agree that it must be done under better circumstances than were available at the Western Kenya site.
• We have been impressed that a synergistic collaboration with our partners, rather than a traditional academic competition, maximizes our ability to transform public health practices related to TB/HIV.  The commitment and expertise of our consortium collaborators was demonstrated by the critical thinking and productive discussions during our Investigator’s Meeting at the Bill and Melinda Gates Foundation in November, 2003.

• We already knew that the Biostatistics Core was one of our consortium’s greatest strengths:  consistent, pro-active and involved every step of the way.  We now know that the Policy and Advocacy Core is not only committed but able and ready to promote the necessary ongoing dialogue between stakeholders and investigators, at international venues and on site and in-country. 

IV.                Changes:  

• The major change we have made is the removal of the Western Kenya study team from the CREATE Consortium.  The Western Kenya study was not approved for funding, and the study team felt that continued involvement in CREATE was not appropriate.  The remainder of the CREATE partnership strongly encouraged the team to stay involved in the effort, but our collaborators in Kenya have not accepted this invitation.  We remain hopeful that additional funding sources can be identified to modify, improve and carry out the Western Kenya study, because we believe it addresses a key strategy that is not otherwise included in our portfolio.

V.                   Challenges:  

• There are a number of challenges that confront CREATE, many of which were outlined in our proposal of January 28, 2004.  The principal challenge is the rapidly changing environment in which our studies are going to be carried out.  The challenges we face are a welcome change, as they represent important improvements in health services for underserved populations.  Nevertheless, they illustrate the difficulties of conducting large, population-based trials of public health interventions.

• In South Africa, an ARV rollout has begun in earnest, and the potential impact of HIV therapy on TB case finding and preventive treatment is unknown, but potentially substantial.
• In Zambia, ARVs are less readily available, but over the course of the ZAMSTAR study they will become more widespread.  Evaluating the impact of phased-in ARVs in the setting of our community-based interventions for TB will be difficult, but essential.
• In Brazil, we face a different type of changing landscape.  While ARVs are widely available, and a key component of our study, HIV counseling and testing has not been well-utilized.  A massive campaign by the Brazilian government is now underway to encourage millions of people to be tested.  This will potentially increase the population enrolled in our study, and could result in some unexpected changes in TB incidence, as a result of patients with less advanced HIV disease being recruited to clinics.

VI.          Other Sources of Project Support: 

• The only other source currently providing support for this project at present is the South African Safety in Mines Research Advisory Committee (SIMRAC), which has funded pilot work in the South African gold mines study for $400,000. 
• We anticipate partnering with a number of funding agencies to pursue activities that will support or contribute to our goals.  In addition to the local and national governments in our study countries, we hope to receive additional funding for specific substudies or spin-off studies from USAID, the CDC, the NIH, and other donors and funders.

V.                Budget Variances:

• Overall spending in Phase I of CREATE was 87% of budgeted funds, which leaves an unspent balance of $400,000 to roll over into Phase II. 
• Personnel costs were 88% of budgeted funds, owing partly to other support available to several key staff during the study period.  Dr. Chaisson was supported by a Career Development Award from the NIH, which expired in June 2004. 
• Consultant costs were much lower than anticipated because a planned meeting of reviewers was not held, and proposals were reviewed by email.
• Travel costs were considerably over the original budget, as a result of several meetings that were not anticipated when the budget was initially submitted.  Investigator meetings in London (Active Case Finding Meeting) and Seattle (meeting with BMGF staff) accounted for most of the budget variance. 
• Other direct costs were overrspent by 12$.  This reflects increased expenses in Year 1 when new offices and equipment were required in an off-campus location.  Year 2 expenditures were below budget, but the entire Phase I expenditure was higher than originally anticipated.
•  Subcontracted costs were 85% of the amount originally budgeted.  This is entirely due to concerted efforts by collaborators to reduce spending after the award was announced to us in May 2004, in order to maintain a budget surplus to carry over into Phase II.